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Llopiz D, Silva L, Ruiz M, Castro-Alejos C, Aparicio B, Vegas L, Infante S, Santamaria E, Sarobe P. MERTK inhibition improves therapeutic efficacy of immune checkpoint inhibitors in hepatocellular carcinoma. Oncoimmunology 2025; 14:2473165. [PMID: 40029206 PMCID: PMC11881874 DOI: 10.1080/2162402x.2025.2473165] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2024] [Revised: 01/29/2025] [Accepted: 02/24/2025] [Indexed: 03/05/2025] Open
Abstract
Immunotherapy with immune checkpoint inhibitors (ICI) in hepatocellular carcinoma (HCC) patients only achieves response rates of 25%-30%, indicating the necessity of new therapies for non-responder patients. Since myeloid-related suppressive factors are associated with poor responses to ICI in a subgroup of HCC patients, modulation of these targets may improve response rates. Our aim was to characterize the expression of the efferocytosis receptor MERTK in HCC and to analyze its potential as a new therapeutic target. In HCC patients, MERTK was expressed by myeloid cells and was associated with poorer survival. In a murine HCC model with progressive myeloid cell infiltration, MERTK was detected in dendritic cells and macrophages with an activated phenotype, which overexpressed the checkpoint ligand PD-L1. Concomitant expression of PD-1 in tumor T-cells suggested the pertinence of combined PD-1/PD-L1 and MERTK blockade. In vivo experiments in mice showed that inhibition of MERTK improved the therapeutic effect promoted by anti-PD-1 or by ICI combinations currently approved for HCC. This effect was associated with enhanced tumor infiltration and superior activity of antigen presenting cells and effector lymphocytes. Our results indicate that MERTK may behave as a relevant target for immunotherapeutic combinations in those HCC patients with tumors enriched in a myeloid component.
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Affiliation(s)
- Diana Llopiz
- Program of Immunology and Immunotherapy, Cima Universidad de Navarra, Cancer Center Clínica Universidad de Navarra (CCUN), Pamplona, Spain
- Navarra Institute for Health Research (IDISNA), Pamplona, Spain
- CIBERehd, Pamplona, Spain
| | - Leyre Silva
- Program of Immunology and Immunotherapy, Cima Universidad de Navarra, Cancer Center Clínica Universidad de Navarra (CCUN), Pamplona, Spain
- Navarra Institute for Health Research (IDISNA), Pamplona, Spain
- CIBERehd, Pamplona, Spain
| | - Marta Ruiz
- Program of Immunology and Immunotherapy, Cima Universidad de Navarra, Cancer Center Clínica Universidad de Navarra (CCUN), Pamplona, Spain
- Navarra Institute for Health Research (IDISNA), Pamplona, Spain
- CIBERehd, Pamplona, Spain
| | - Carla Castro-Alejos
- Program of Immunology and Immunotherapy, Cima Universidad de Navarra, Cancer Center Clínica Universidad de Navarra (CCUN), Pamplona, Spain
- Navarra Institute for Health Research (IDISNA), Pamplona, Spain
- CIBERehd, Pamplona, Spain
| | - Belen Aparicio
- Program of Immunology and Immunotherapy, Cima Universidad de Navarra, Cancer Center Clínica Universidad de Navarra (CCUN), Pamplona, Spain
- Navarra Institute for Health Research (IDISNA), Pamplona, Spain
- CIBERehd, Pamplona, Spain
| | - Lucia Vegas
- Program of Immunology and Immunotherapy, Cima Universidad de Navarra, Cancer Center Clínica Universidad de Navarra (CCUN), Pamplona, Spain
| | - Stefany Infante
- Program of Immunology and Immunotherapy, Cima Universidad de Navarra, Cancer Center Clínica Universidad de Navarra (CCUN), Pamplona, Spain
- DNA and RNA Medicine Division, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain
- Facultad de Medicina Humana, Universidad de Piura, Lima, Peru
| | - Eva Santamaria
- DNA and RNA Medicine Division, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain
| | - Pablo Sarobe
- Program of Immunology and Immunotherapy, Cima Universidad de Navarra, Cancer Center Clínica Universidad de Navarra (CCUN), Pamplona, Spain
- Navarra Institute for Health Research (IDISNA), Pamplona, Spain
- CIBERehd, Pamplona, Spain
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Pettas T, Lachanoudi S, Karageorgos FF, Ziogas IA, Fylaktou A, Papalois V, Katsanos G, Antoniadis N, Tsoulfas G. Immunotherapy and liver transplantation for hepatocellular carcinoma: Current and future challenges. World J Transplant 2025; 15:98509. [DOI: 10.5500/wjt.v15.i2.98509] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/27/2024] [Revised: 10/03/2024] [Accepted: 11/07/2024] [Indexed: 02/21/2025] Open
Abstract
Despite existing curative options like surgical removal, tissue destruction techniques, and liver transplantation for early-stage hepatocellular carcinoma (HCC), the rising incidence and mortality rates of this global health burden necessitate continuous exploration of novel therapeutic strategies. This review critically assesses the dynamic treatment panorama for HCC, focusing specifically on the burgeoning role of immunotherapy in two key contexts: early-stage HCC and downstaging advanced HCC to facilitate liver transplant candidacy. It delves into the unique immunobiology of the liver and HCC, highlighting tumor-mediated immune evasion mechanisms. Analyzing the diverse immunotherapeutic approaches including checkpoint inhibitors, cytokine modulators, vaccines, oncolytic viruses, antigen-targeting antibodies, and adoptive cell therapy, this review acknowledges the limitations of current diagnostic markers alpha-fetoprotein and glypican-3 and emphasizes the need for novel biomarkers for patient selection and treatment monitoring. Exploring the rationale for neoadjuvant and adjuvant immunotherapy in early-stage HCC, current research is actively exploring the safety and effectiveness of diverse immunotherapeutic approaches through ongoing clinical trials. The review further explores the potential benefits and challenges of combining immunotherapy and liver transplant, highlighting the need for careful patient selection, meticulous monitoring, and novel strategies to mitigate post-transplant complications. Finally, this review delves into the latest findings from the clinical research landscape and future directions in HCC management, paving the way for optimizing treatment strategies and improving long-term survival rates for patients with this challenging malignancy.
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Affiliation(s)
- Theodoros Pettas
- Department of Transplantation Surgery, Center for Research and Innovation in Solid Organ Transplantation, Aristotle University School of Medicine, Thessaloniki 54642, Greece
| | - Sofia Lachanoudi
- Department of Transplantation Surgery, Center for Research and Innovation in Solid Organ Transplantation, Aristotle University School of Medicine, Thessaloniki 54642, Greece
| | - Filippos F Karageorgos
- Department of Transplantation Surgery, Center for Research and Innovation in Solid Organ Transplantation, Aristotle University School of Medicine, Thessaloniki 54642, Greece
| | - Ioannis A Ziogas
- Department of Surgery, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, United States
| | - Asimina Fylaktou
- Department of Immunology, National Peripheral Histocompatibility Center, Hippokration General Hospital, Thessaloniki 54642, Greece
| | - Vassilios Papalois
- Department of Transplant Surgery, Imperial College Renal and Transplant Centre, London W12 0HS, United Kingdom
| | - Georgios Katsanos
- Department of Transplantation Surgery, Center for Research and Innovation in Solid Organ Transplantation, Aristotle University of Thessaloniki, School of Medicine, Thessaloniki 54642, Greece
| | - Nikolaos Antoniadis
- Department of Transplantation Surgery, Center for Research and Innovation in Solid Organ Transplantation, Aristotle University School of Medicine, Thessaloniki 54642, Greece
| | - Georgios Tsoulfas
- Department of Transplantation Surgery, Center for Research and Innovation in Solid Organ Transplantation, Aristotle University of Thessaloniki, School of Medicine, Thessaloniki 54642, Greece
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Liang LW, Luo RH, Huang ZL, Tang LN. Clinical observation of nivolumab combined with cabozantinib in the treatment of advanced hepatocellular carcinoma. World J Gastrointest Oncol 2025; 17:103631. [DOI: 10.4251/wjgo.v17.i4.103631] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/25/2024] [Revised: 12/25/2024] [Accepted: 02/07/2025] [Indexed: 03/25/2025] Open
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) is a particularly serious kind of liver cancer. Liver cancer ranks third in terms of mortality rate worldwide, putting it among the leading causes of deaths from cancer. HCC is the primary kind of liver cancer and makes up the vast majority of cases, accounting for approximately 90% of occurrences. Numerous research have verified this information. the progress of fatty liver, alcohol induced cirrhosis, smoking habits, obesity caused by overweight, and metabolic diseases such as diabetes. The treatment strategies for HCC can be divided into two categories: One is curative treatment, including liver transplantation, surgical resection, and ablation therapy or selective arterial radiation embolization, aimed at completely eliminating the lesion; Another type is non curative treatment options, including transarterial chemoembolization and systemic therapy, which focus on controlling disease progression and prolonging patient survival. The majority of HCC patients are found to be in an advanced stage and need systemic therapy. Sorafenib and lenvatinib are frequently used as first-line medications in traditional HCC treatment to slow the disease's progression. For second-line treatment, regorafenib, cabozantinib, or remdesizumab are used to inhibit tumors through different mechanisms and prolong survival. In recent years, with the in-depth exploration of the pathogenesis and progression mechanism of HCC, as well as the rapid progress within the domain of tumor immunotherapy, the treatment prospects for advanced HCC patients have shown a positive transformation. This transformation is reflected in the fact that more and more patients are gradually gaining significant and considerable therapeutic advantages from advanced immunotherapy regimens, bringing unprecedented improvements to their treatment outcomes. In order to enable activated T cells to attack tumor cells, immune checkpoint inhibitors interfere with the inhibitory.
AIM To evaluate the effects of nivolumab in combination with cabozantinib on patient tumor markers and immune function, as well as the therapeutic efficacy of this combination in treating advanced HCC, a study was conducted.
METHODS In all, 100 patients with advanced HCC who were brought to our hospital between July 2022 and July 2023 and who did not match the requirements for surgical resection had their clinical data thoroughly analyzed retrospectively in this study. Among them, half of the patients (50 cases) only received oral cabozantinib as a single treatment regimen (set as the control group), while the other half of the patients (50 cases) received intravenous infusion of nivolumab in addition to oral cabozantinib (set as the observation group). The objective of the probe is to examine the variations in disease control rate (DCR) and objective response rate (ORR) between two groups; At the same time, changes in the levels of T lymphocyte subsets (CD3+, CD4+, CD8+) and tumor markers, including AFP, GP-73, and AFP-L3, were evaluated; In addition, changes in liver and kidney function indicators and adverse reactions during treatment were also monitored. For patients with advanced HCC, this research also calculated and analyzed the progression free survival of two patient groups throughout the course of a 12-month follow-up to assess the effectiveness and safety of this therapeutic approach.
RESULTS Upon comparing baseline information for both groups of subjects before treatment, it was found that no statistically significant alterations had occurred (P > 0.05). After the therapeutic intervention, the observation group and control group's ORR and DCR differed statistically significantly (P < 0.05). The observation group's scores significantly improved. Subsequent examination revealed that the observation group's T lymphocyte subset levels had significantly changed, mostly exhibiting an increase in CD3+, CD4+, and CD4+/CD8+ levels while CD8+ levels had comparatively dropped. There was a significant difference (P < 0.05) between these changes and those in the control group. The observation group also showed positive improvements in tumor markers; AFP, GP-73, and AFP-L3 levels were considerably lower in the group under observation than in the control group, with statistically significant differences (P < 0.05). When liver function was assessed, total bilirubin and alanine aminotransferase were found to be considerably lower in the observation group than in the control group (P < 0.05). The incidence of adverse responses was not statistically significant (P > 0.05), indicating that the incidence of adverse responses did not differ significantly between the two groups.
CONCLUSION When treating advanced HCC, nivolumab and cabozantinib together have the ability to increase T lymphocyte numbers, reduce tumor marker levels, effectively prolong survival time, and have better efficacy than simple control treatment, with good safety.
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Affiliation(s)
- Lu-Wen Liang
- Infection and Liver Disease Center, The Second Affiliated Hospital of Chongqing Medical University, Chongqing 400000, China
| | - Rong-Hong Luo
- Department of Infectious Diseases, The Third Affiliated Hospital of Chongqing Medical University, Chongqing 401120, China
| | - Zhi-Li Huang
- Department of Infectious Diseases, The Third Affiliated Hospital of Chongqing Medical University, Chongqing 401120, China
| | - Li-Na Tang
- Department of Infectious Diseases, The Third Affiliated Hospital of Chongqing Medical University, Chongqing 401120, China
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Li Y, Bai L, Liang H, Yan P, Chen H, Cao Z, Shen Y, Wang Z, Huang M, He B, Hao Q, Mei Y, Wei H, Ding C, Jin J, Wang Y. A BPTF-specific PROTAC degrader enhances NK cell-based cancer immunotherapy. Mol Ther 2025; 33:1566-1583. [PMID: 39935175 DOI: 10.1016/j.ymthe.2025.02.013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2024] [Revised: 12/19/2024] [Accepted: 02/06/2025] [Indexed: 02/13/2025] Open
Abstract
Natural killer (NK) cell-based immunotherapy shows promise in cancer treatment, but its efficacy remains limited, necessitating the development of novel strategies. In this study, we demonstrate that the epigenetic factor bromodomain PHD-finger containing transcription factor (BPTF) hinders hepatocellular carcinoma (HCC) recognition by NK cells through its PHD finger's interpretation of H3K4me3. We have generated a small-molecule proteolysis-targeting chimera (PROTAC) that selectively degrades human and murine BPTF. The degradation of BPTF using PROTACs directly enhances the abundance of natural cytotoxicity receptor ligands on HCC cells, facilitating their recognition by NK cells and thereby augmenting NK cell cytotoxicity against HCC both in vitro and in vivo. Through multidisciplinary techniques, our findings establish targeting BPTF with PROTACs as a promising approach to overcome immune evasion of HCC from NK cells and provide a new strategy to enhance NK cell-based cancer immunotherapy.
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Affiliation(s)
- Yunjia Li
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of USTC, Key Laboratory of Immune Response and Immunotherapy, Center for Advanced Interdisciplinary Science and Biomedicine of IHM, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230027, China
| | - Lin Bai
- State Key Laboratory of Genetic Engineering, Institutes of Biomedical Sciences, Human Phenome Institute, School of Life Sciences, Zhongshan Hospital, Fudan University, Shanghai 200433, China
| | - Hao Liang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of USTC, Key Laboratory of Immune Response and Immunotherapy, Center for Advanced Interdisciplinary Science and Biomedicine of IHM, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230027, China
| | - Peidong Yan
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of USTC, Key Laboratory of Immune Response and Immunotherapy, Center for Advanced Interdisciplinary Science and Biomedicine of IHM, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230027, China
| | - Hao Chen
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of USTC, Key Laboratory of Immune Response and Immunotherapy, Center for Advanced Interdisciplinary Science and Biomedicine of IHM, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230027, China
| | - Zhuoxian Cao
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of USTC, Key Laboratory of Immune Response and Immunotherapy, Center for Advanced Interdisciplinary Science and Biomedicine of IHM, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230027, China
| | - Yiqing Shen
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of USTC, Key Laboratory of Immune Response and Immunotherapy, Center for Advanced Interdisciplinary Science and Biomedicine of IHM, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230027, China
| | - Zhongyv Wang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of USTC, Key Laboratory of Immune Response and Immunotherapy, Center for Advanced Interdisciplinary Science and Biomedicine of IHM, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230027, China
| | - Mei Huang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of USTC, Key Laboratory of Immune Response and Immunotherapy, Center for Advanced Interdisciplinary Science and Biomedicine of IHM, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230027, China
| | - Bin He
- State Key Laboratory of Functions and Applications of Medicinal Plants, Engineering Research Center for the Development and Application of Ethnic Medicine and TCM (Ministry of Education), Guizhou Provincial Key Laboratory of Pharmaceutics, School of Pharmacy, Guizhou Medical University, Guiyang 550004, China
| | - Quan Hao
- School of Biomedical Sciences, University of Hong Kong, Hong Kong, China
| | - Yide Mei
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of USTC, Key Laboratory of Immune Response and Immunotherapy, Center for Advanced Interdisciplinary Science and Biomedicine of IHM, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230027, China
| | - Haiming Wei
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of USTC, Key Laboratory of Immune Response and Immunotherapy, Center for Advanced Interdisciplinary Science and Biomedicine of IHM, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230027, China
| | - Chen Ding
- State Key Laboratory of Genetic Engineering, Institutes of Biomedical Sciences, Human Phenome Institute, School of Life Sciences, Zhongshan Hospital, Fudan University, Shanghai 200433, China.
| | - Jing Jin
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of USTC, Key Laboratory of Immune Response and Immunotherapy, Center for Advanced Interdisciplinary Science and Biomedicine of IHM, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230027, China.
| | - Yi Wang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of USTC, Key Laboratory of Immune Response and Immunotherapy, Center for Advanced Interdisciplinary Science and Biomedicine of IHM, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230027, China.
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Zheng B, Wang H, Zhai S, Li J, Lu K. Mitochondria-targeted photothermal-chemodynamic therapy enhances checkpoint blockade immunotherapy on colon cancer. Mater Today Bio 2025; 31:101542. [PMID: 40018055 PMCID: PMC11867542 DOI: 10.1016/j.mtbio.2025.101542] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2024] [Revised: 01/28/2025] [Accepted: 02/01/2025] [Indexed: 03/01/2025] Open
Abstract
Immunotherapy has emerged as a hotspot for cancer treatment. However, the response rate of monotherapy remains relatively low in clinical settings. Photothermal therapy (PTT), which employs light energy to ablate tumors, can also activate tumor-specific immune responses. This effect has been attributed in several studies to the release of damage-associated molecular patterns (DAMPs) triggered by mitochondrial injury. We propose that mitochondria-targeted PTT may better synergize with immunotherapy. Herein, we constructed a multifunctional nanoplatform that enables mitochondria-targeted photothermal-chemodynamic combination therapy by conjugating indocyanine green-thiol (ICG-SH) and mercaptoethyl-triphenylphosphonium (TPP-SH) onto polyvinyl pyrrolidone (PVP)-coated gold-copper nanoparticles (AIT). Upon near-infrared light (NIR) irradiation, AIT ablates cancer cells and amplifies the effect of chemodynamic therapy (CDT), thereby inducing apoptosis in the tumor. The combination of CDT and PTT promotes immunogenic cell death, which could synergize with checkpoint blockade immunotherapy. In a bilateral mouse colon cancer model, we observed complete eradication of light-irradiated primary tumors and significant inhibition of distant untreated tumors in the group treated with AIT plus anti-PD-1 (αPD-1). We found a significant increase in serum levels of pro-inflammatory factors, including interleukin-6 (IL-6), interferon-γ (IFN-γ), and tumor necrosis factor-α (TNF-α), following PTT/CDT/immunotherapy treatment, suggesting effective activation of the immune response. The enhanced immunogenicity caused by AIT with αPD-1 treatment resulted in efficient antigen presentation, as indicated by the increased infiltration of dendritic cells (DCs) into the tumor-draining lymph nodes (LNs). We also observed enhanced infiltration of CD8+ T cells in distant tumors in the AIT with αPD-1 group compared to αPD-1 alone. Hence, mitochondria-targeting represents an effective strategy to potentiate the combination of photothermal, chemodynamic, and immune checkpoint blockade therapies for the treatment of metastatic cancer.
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Affiliation(s)
- Benchao Zheng
- Institute of Medical Technology, Peking University Health Science Center, Beijing, 100191, PR China
- Institute of Advanced Clinical Medicine, Peking University, Beijing, 100191, PR China
| | - Hongbo Wang
- Institute of Medical Technology, Peking University Health Science Center, Beijing, 100191, PR China
- Institute of Advanced Clinical Medicine, Peking University, Beijing, 100191, PR China
| | - Shiyi Zhai
- Institute of Medical Technology, Peking University Health Science Center, Beijing, 100191, PR China
- Institute of Advanced Clinical Medicine, Peking University, Beijing, 100191, PR China
| | - Jiangsheng Li
- Key Laboratory of Carcinogenesis and Translational Research of Ministry of Education, Key Laboratory for Research and Evaluation of Radiopharmaceuticals of National Medical Products Administration, Department of Nuclear Medicine, Peking University Cancer Hospital, Beijing, 100142, PR China
| | - Kuangda Lu
- Institute of Medical Technology, Peking University Health Science Center, Beijing, 100191, PR China
- Institute of Advanced Clinical Medicine, Peking University, Beijing, 100191, PR China
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Vaghjiani R, Wu R, Tung KH, Ishikawa T, Takabe K. Angiogenesis Is Associated With Aggressive Biology That Counterbalances With Tumor Immunogenicity in Hepatocellular Carcinoma. World J Oncol 2025; 16:173-181. [PMID: 40162113 PMCID: PMC11954604 DOI: 10.14740/wjon2009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2024] [Accepted: 01/17/2025] [Indexed: 04/02/2025] Open
Abstract
Background Hepatocellular carcinoma (HCC) is an arterialized tumor; thus, anti-angiogenesis targeted therapy is in clinical practice. Herein, we hypothesized that HCC with high angiogenesis is biologically aggressive with worse survival. Methods Angiogenesis score (AS) was derived from the Molecular Signatures Database (MSigDB) Hallmark Angiogenesis Gene Set, and median was used to divide high versus low groups. Transcriptome of HCC patients of The Cancer Genome Atlas (TCGA, n = 386) and GSE76427 (n = 115) cohorts were analyzed. Results High AS correlated with angiogenesis-related gene expressions. Both microvascular and lymphatic endothelial cell infiltrations were higher in high angiogenesis HCC. Surprisingly, no survival difference was seen with varying levels of angiogenesis. High angiogenesis significantly enriched tumor aggravating signaling pathways: glycolysis, Notch, Hedgehog, KRAS, epithelial mesenchymal transition, and transforming growth factor-beta (TGF-β) in Gene Set Enrichment Analysis (GSEA), but also infiltrated less CD8+ T cells and T-helper 1 cells, and higher M1 macrophages and conventional dendritic cells (cDCs) with elevated cytolytic activity score in both cohorts. In agreement, immune response-related gene sets: inflammatory response, tumor necrosis factor-alpha (TNF-α) signaling, allograft rejection, interferon-alpha, and interferon-gamma were all enriched to high angiogenesis HCC. Programmed cell death protein 1 (PD1), programmed death ligand 1 (PD-L1), programmed death ligand 2 (PD-L2), and cytotoxic T lymphocyte-associated protein 4 (CTLA-4) were higher in high angiogenesis HCC in TCGA, but not in GSE76427 cohort. Conclusions Angiogenesis quantified using transcriptome of HCC patients demonstrated that it is associated with aggressive biology but also with tumor immunogenicity and immune response that counterbalance and did not reflect in survival. Given high expression of immune checkpoint molecules, we cannot help but speculate that immunotherapy may be useful for high angiogenesis HCC patients.
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Affiliation(s)
- Raj Vaghjiani
- Department of Surgical Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA
- These authors contributed equally to this work
| | - Rongrong Wu
- Department of Surgical Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA
- Department of Breast Surgery and Oncology, Tokyo Medical University, Tokyo, Japan
- These authors contributed equally to this work
| | - Kaity H. Tung
- Department of Surgical Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA
- Department of Surgery, University at Buffalo Jacobs School of Medicine and Biomedical Sciences, The State University of New York, Buffalo, NY, USA
| | - Takashi Ishikawa
- Department of Breast Surgery and Oncology, Tokyo Medical University, Tokyo, Japan
| | - Kazuaki Takabe
- Department of Surgical Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA
- Department of Breast Surgery and Oncology, Tokyo Medical University, Tokyo, Japan
- Department of Surgery, University at Buffalo Jacobs School of Medicine and Biomedical Sciences, The State University of New York, Buffalo, NY, USA
- Department of Surgery, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
- Department of Gastroenterological Surgery, Yokohama City University School of Medicine, Yokohama, Japan
- Department of Breast Surgery, Fukushima Medical University, Fukushima, Japan
- Department of Immunology, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA
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Chen L, Tang W, Liu J, Zhu M, Mu W, Tang X, Liu T, Zhu Z, Weng L, Cheng Y, Zhang Y, Chen X. On-demand reprogramming of immunosuppressive microenvironment in tumor tissue via multi-regulation of carcinogenic microRNAs and RNAs dependent photothermal-immunotherapy using engineered gold nanoparticles for malignant tumor treatment. Biomaterials 2025; 315:122956. [PMID: 39549441 DOI: 10.1016/j.biomaterials.2024.122956] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2024] [Revised: 11/05/2024] [Accepted: 11/07/2024] [Indexed: 11/18/2024]
Abstract
The frequent immune escape of tumor cells and fluctuating therapeutic efficiency vary with each individual are two critical issues for immunotherapy against malignant tumor. Herein, we fabricated an intelligent core-shell nanoparticle (SNAs@CCMR) to significantly inhibit the PD-1/PD-L1 mediated immune escape by on-demand regulation of various oncogenic microRNAs and perform RNAs dependent photothermal-immunotherapy to achieve precise and efficient treatment meeting the individual requirements of specific patients by in situ generation of customized tumor-associated antigens. The SNAs@CCMR consisted of antisense oligonucleotides grafted gold nanoparticles (SNAs) as core and TLR7 agonist imiquimod (R837) functionalized cancer cell membrane (CCM) as shell, in which the acid-labile Schiff base bond was used to connect the R837 and CCM. During therapy, the acid environment of tumor tissue cleaved the Schiff base to generate free R837 and SNAs@CCM. The SNAs@CCM further entered tumor cells via CCM mediated internalization, and then specifically hybridized with over-expressed miR-130a and miR-21, resulting in effective inhibition of the migration and PD-L1 expression of tumor cells to avoid their immune escape. Meanwhile, the RNAs capture also caused significant aggregation of SNAs, which immediately generated photothermal agents within tumor cells to perform highly selective photothermal therapy under NIR irradiation. These chain processes not only damaged the primary tumor, but also produced plenty of tumor-associated antigens, which matured the surrounding dendritic cells (DCs) and activated anti-tumor T cells along with the released R837, resulting in the enhanced immunotherapy with suppressive immune escape. Both in vivo and in vitro experiments demonstrated that our nanoparticles were able to inhibit primary tumor and its metastasis via multi-regulation of carcinogenic microRNAs and RNAs dependent photothermal-immune activations, which provided a promising strategy to reprogram the immunosuppressive microenvironment in tumor tissue for better malignant tumor therapy.
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Affiliation(s)
- Li Chen
- Department of Chemical Engineering, Shaanxi Key Laboratory of Energy Chemical Process Intensification, Institute of Polymer Science in Chemical Engineering, School of Chemical Engineering and Technology, Xi'an Jiaotong University, Xi'an, 710049, China
| | - Wenjun Tang
- School of Pharmacy, Health Science Center, Xi'an Jiaotong University, Xi'an, 710061, China
| | - Jie Liu
- Department of Chemical Engineering, Shaanxi Key Laboratory of Energy Chemical Process Intensification, Institute of Polymer Science in Chemical Engineering, School of Chemical Engineering and Technology, Xi'an Jiaotong University, Xi'an, 710049, China
| | - Man Zhu
- School of Pharmacy, Health Science Center, Xi'an Jiaotong University, Xi'an, 710061, China
| | - Wenyun Mu
- Department of Chemical Engineering, Shaanxi Key Laboratory of Energy Chemical Process Intensification, Institute of Polymer Science in Chemical Engineering, School of Chemical Engineering and Technology, Xi'an Jiaotong University, Xi'an, 710049, China
| | - Xiaoyu Tang
- School of Pharmacy, Health Science Center, Xi'an Jiaotong University, Xi'an, 710061, China
| | - Tao Liu
- Department of Chemical Engineering, Shaanxi Key Laboratory of Energy Chemical Process Intensification, Institute of Polymer Science in Chemical Engineering, School of Chemical Engineering and Technology, Xi'an Jiaotong University, Xi'an, 710049, China
| | - Zeren Zhu
- School of Pharmacy, Health Science Center, Xi'an Jiaotong University, Xi'an, 710061, China
| | - Lin Weng
- Department of Chemical Engineering, Shaanxi Key Laboratory of Energy Chemical Process Intensification, Institute of Polymer Science in Chemical Engineering, School of Chemical Engineering and Technology, Xi'an Jiaotong University, Xi'an, 710049, China
| | - Yumeng Cheng
- School of Pharmacy, Health Science Center, Xi'an Jiaotong University, Xi'an, 710061, China
| | - Yanmin Zhang
- School of Pharmacy, Health Science Center, Xi'an Jiaotong University, Xi'an, 710061, China.
| | - Xin Chen
- Department of Chemical Engineering, Shaanxi Key Laboratory of Energy Chemical Process Intensification, Institute of Polymer Science in Chemical Engineering, School of Chemical Engineering and Technology, Xi'an Jiaotong University, Xi'an, 710049, China.
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8
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Zhou L, Liu CH, Lv D, Sample KM, Rojas Á, Zhang Y, Qiu H, He L, Zheng L, Chen L, Cai B, Hu Y, Romero-Gómez M. Halting hepatocellular carcinoma: Identifying intercellular crosstalk in HBV-driven disease. Cell Rep 2025; 44:115457. [PMID: 40163359 DOI: 10.1016/j.celrep.2025.115457] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2024] [Revised: 01/14/2025] [Accepted: 03/04/2025] [Indexed: 04/02/2025] Open
Abstract
Hepatitis B infection can lead to liver fibrosis and hepatocellular carcinoma (HCC). Despite antiviral therapies, some patients still develop HCC. This study investigates hepatitis B virus (HBV)-induced hepatocyte-hepatic stellate cell (HSC) crosstalk and its role in liver fibrosis and HCC. Using MYC-driven liver cancer stem cell organoids, HCC-patient-derived xenograft (PDX) models, and HBV replication models, this study reveals that HBV transcription affected hepatocyte development, activated the DNA repair pathway, and promoted glycolysis. HBV activated nicotinamide phosphoribosyltransferase (NAMPT) through DNA damage receptor ATR. NAMPT-insulin receptor (INSR)-mediated hepatocyte-HSC crosstalk caused HSCs to develop a myofibroblast phenotype and activated telomere maintenance mechanisms via PARP1 multisite lactylation. Inhibition of the ATR-NAMPT-INSR-PARP1 pathway effectively blocks HBV-induced liver fibrosis and HCC progression. Targeting this pathway could be a promising strategy for chronic HBV infection management.
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Affiliation(s)
- Lingyun Zhou
- Center of Infectious Diseases, West China Hospital of Sichuan University, Chengdu, China.
| | - Chang-Hai Liu
- Center of Infectious Diseases, West China Hospital of Sichuan University, Chengdu, China
| | - Duoduo Lv
- Center of Infectious Diseases, West China Hospital of Sichuan University, Chengdu, China
| | - Klarke Michael Sample
- Center of Infectious Diseases, West China Hospital of Sichuan University, Chengdu, China
| | - Ángela Rojas
- SeLiver Group, Institute of Biomedicine of Seville (HUVR/CSIC/US), Department of Medicine, University of Seville, Seville, Spain; CIBERehd, Instituto de Salud Carlos III, Madrid, Spain; UCM Digestive Diseases, Virgen del Rocío University Hospital, Seville, Spain
| | - Yugu Zhang
- Thoracic Oncology Ward, Cancer Center, and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China
| | - Huandi Qiu
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital of Sichuan University, Chengdu, China
| | - Linye He
- Thyroid and Parathyroid Surgery Center, West China Hospital of Sichuan University, Chengdu, China
| | - Li Zheng
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital of Sichuan University, Chengdu, China
| | - Liyu Chen
- Center of Infectious Diseases, West China Hospital of Sichuan University, Chengdu, China
| | - Binru Cai
- Center of Infectious Diseases, West China Hospital of Sichuan University, Chengdu, China
| | - Yiguo Hu
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital of Sichuan University, Chengdu, China; Thyroid and Parathyroid Surgery Center, West China Hospital of Sichuan University, Chengdu, China.
| | - Manuel Romero-Gómez
- SeLiver Group, Institute of Biomedicine of Seville (HUVR/CSIC/US), Department of Medicine, University of Seville, Seville, Spain; CIBERehd, Instituto de Salud Carlos III, Madrid, Spain; UCM Digestive Diseases, Virgen del Rocío University Hospital, Seville, Spain.
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9
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Zhu W, Fan C, Zhao Y, Liu Y, Cheng Y, Zhou W. Breaking bottlenecks: the future of hepatocellular carcinoma clinical trials and therapeutic targets. Hepatol Int 2025:10.1007/s12072-025-10799-2. [PMID: 40156659 DOI: 10.1007/s12072-025-10799-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/25/2024] [Accepted: 02/15/2025] [Indexed: 04/01/2025]
Abstract
BACKGROUND To provide a reference for hepatocellular carcinoma (HCC) clinical trials, we analyzed HCC clinical trials and therapeutic targets. METHODS Using the Informa database, we analyzed the global and China HCC clinical trials. We then explored TACE, Apatinib, and emerging strategies (CAR T/NK). Additionally, we analyzed the oncogenic biomarkers and therapeutic targets. We conducted a joint analysis of therapeutic target safety using HPA-RNA, HPA-Proteins, and GTEx-RNA datasets. Finally, we analyzed the specificity and prospects of therapeutic targets using HPA pathology data and CPTAC data. RESULTS HCC clinical trials have developed rapidly over the past decade but have now reached a bottleneck, with most breakthroughs focusing on combination therapies. China and the USA dominate in the number of trials. TACE combined with systemic therapy has become an effective treatment strategy for intermediate to advanced HCC. Apatinib and TACE combined with systemic therapy are characteristic of China, while the latter is also mainly conducted in Japan and the USA. Currently, targeted immune therapies dominate the field, and CAR T/NK still in the early stages. Most therapeutic targets are related to the VEGF pathway, which indirectly confirms the predominant role of TKI-ICI combination therapy in HCC treatment. Most targets have low safety and poor specificity. However, RRM2, KDR, and AURKA have strong safety and specificity, showing excellent prospects for targeted HCC therapy. CONCLUSIONS This study analyzed and summarized the overview of HCC clinical trials and the safety and specificity of therapeutic targets, providing a reference for HCC clinical research.
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Affiliation(s)
- Weixiong Zhu
- The Second Clinical Medical College, Lanzhou University, Lanzhou, China
| | - Chuanlei Fan
- Department of Gastrointestinal Surgery, Jiangxi Province Hospital of Integrated Chinese and Western Medicine, Nanchang, Jiangxi, People's Republic of China
| | - Yongqing Zhao
- The Second Clinical Medical College, Lanzhou University, Lanzhou, China
| | - Youtao Liu
- School of Stomatology, Lanzhou University, Lanzhou, China
| | - Yusheng Cheng
- Department of General Surgery, The Second Hospital of Lanzhou University, Lanzhou, China.
| | - Wence Zhou
- The Second Clinical Medical College, Lanzhou University, Lanzhou, China.
- Department of General Surgery, The Second Hospital of Lanzhou University, Lanzhou, China.
- Key Laboratory of Environmental Oncology of Gansu Province, Chengguan District, Lanzhou City, Gansu Province, China.
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10
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Miri H, Rahimzadeh P, Hashemi M, Nabavi N, Aref AR, Daneshi S, Razzaghi A, Abedi M, Tahmasebi S, Farahani N, Taheriazam A. Harnessing immunotherapy for hepatocellular carcinoma: Principles and emerging promises. Pathol Res Pract 2025; 269:155928. [PMID: 40184729 DOI: 10.1016/j.prp.2025.155928] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/30/2024] [Revised: 03/12/2025] [Accepted: 03/26/2025] [Indexed: 04/07/2025]
Abstract
HCC is considered as one of the leadin causes of death worldwide, with the ability of resistance towards therapeutics. Immunotherapy, particularly ICIs, have provided siginficant insights towards harnessing the immune system. The present review introduces the concepts and possibilities of immunotherapy for HCC treatment, emphasizing its underlying mechanisms and capacity to enhance patient results, focusing on both pre-clinical and clinical insights. The functions of TME and immune evasion mechanisms typical of HCC would be evaluated along with how contemporary immunotherapeutic approaches are designed to address these challenges. Furthermore, the clinical application of immunotherapy in HCC is discussed, emphasizing recent trial findings demonstrating the effectiveness and safety of drugs. In addition, the problems caused by immune evasion and resistance would be discussed to increase potential of immunotherapy along with combination therapy.
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Affiliation(s)
- Hossein Miri
- Faculty of Medicine, Tehran Medical Sciences Branch, Islamic Azad University, Tehran, Iran
| | - Payman Rahimzadeh
- Surgical Research Society (SRS), Students' Scientific Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Mehrdad Hashemi
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran; Department of Genetics, Faculty of Advanced Science and Technology, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Noushin Nabavi
- Independent Researcher, Victoria, British Columbia V8V 1P7, Canada
| | - Amir Reza Aref
- Department of Vitro Vision, DeepkinetiX, Inc, Boston, MA, USA
| | - Salman Daneshi
- Department of Public Health, School of Health, Jiroft University Of Medical Sciences, Jiroft, Iran
| | - Alireza Razzaghi
- Social Determinants of Health Research Center, Research Institute for Prevention of Non-Communicable Diseases, Qazvin University of Medical Sciences, Qazvin, Iran
| | - Maryam Abedi
- Department of Pathology, Cancer Institute, Tehran University of Medical Sciences, Tehran, Iran.
| | - Safa Tahmasebi
- Department of Immunology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
| | - Najma Farahani
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran.
| | - Afshin Taheriazam
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran; Department of Orthopedics, Faculty of Medicine, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran.
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11
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Gu MY, Ma WL, Ma ZM, Ma LN, Ding XC. Expression of PSMD2 gene in hepatocellular carcinoma and its correlation with immune checkpoints and prognosis. Sci Rep 2025; 15:10111. [PMID: 40128277 PMCID: PMC11933310 DOI: 10.1038/s41598-025-94504-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2024] [Accepted: 03/14/2025] [Indexed: 03/26/2025] Open
Abstract
Hepatocellular carcinoma (HCC) is a prevalent and fatal tumor globally, characterized by a complex pathogenesis and poor prognosis. Despite significant advancements in the application of immune checkpoint inhibitors (ICIs) for cancer treatment, the efficacy of immunotherapy in HCC remains suboptimal. PSMD2, a crucial regulator of the ubiquitin-proteasome system, has attracted increasing attention for its involvement in various cancers; however, its functions and mechanisms in HCC are still poorly understood. This study aims to investigate the expression of PSMD2 in HCC, its association with prognosis, and its interaction with immune checkpoints, thus establishing a foundation for further exploration of its role in immune evasion in HCC. We analyzed the expression levels of PSMD2 in HCC and adjacent normal tissues utilizing the GEPIA and TIMER databases. Cox regression analysis was performed using R software to evaluate the relationship between PSMD2 expression and prognosis. Furthermore, we assessed the correlation between PSMD2 and immune cell infiltration, as well as immune checkpoints, including PD1, PD-L1, and CTLA-4, using R tools. Additionally, we examined the association between PSMD2 expression and immune therapy response through Tumor Immune Dysfunction and Exclusion (TIDE) analysis. Finally, we constructed a protein-protein interaction (PPI) network using the STRING database and Cytoscape software, followed by Gene Set Enrichment Analysis (GSEA). PSMD2 was significantly overexpressed in HCC and was closely correlated with poor prognosis (HR = 1.61, P = 2.0e-4). Immune infiltration analysis demonstrated that PSMD2 was positively correlated with several immune checkpoint genes, including PD1, PD-L1, and CTLA-4, as well as various immune cell types. TIDE analysis indicated that elevated PSMD2 expression was significantly associated with increased immune evasion potential and a poor response to immunotherapy. Furthermore, GSEA enrichment analysis revealed that PSMD2 is primarily enriched in the p53 signaling pathway, the ubiquitin-mediated proteolysis pathway, and other cancer-related pathways. The elevated expression of PSMD2 in HCC is not only correlated with poor prognosis but may also play a role in immune evasion by modulating tumor immunity, thereby affecting patient responses to immunotherapy. Consequently, PSMD2 presents a promising novel therapeutic target and potential biomarker for immunotherapy in HCC.
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Affiliation(s)
| | - Wan-Long Ma
- Department of Infectious Diseases, General Hospital of Ningxia Medical University, 804 Shengli Street, Xingqing District, Yinchuan, 750004, Ningxia, China
| | - Zi-Min Ma
- Weiluo Microbial Pathogens Monitoring Technology Co., Ltd. of Beijing, Beijing, 102200, China
| | - Li-Na Ma
- Department of Infectious Diseases, General Hospital of Ningxia Medical University, 804 Shengli Street, Xingqing District, Yinchuan, 750004, Ningxia, China.
- Infectious Disease Clinical Research Center of Ningxia, 804 Shengli Street, Xingqing District, Yinchuan, 750004, Ningxia, China.
- Department of Infectious Disease, General Hospital of Xiang Medical University, 804 Shengli Street, Xingqing District, Yinchuan, 750004, Ningxia, China.
| | - Xiang-Chun Ding
- Department of Infectious Diseases, General Hospital of Ningxia Medical University, 804 Shengli Street, Xingqing District, Yinchuan, 750004, Ningxia, China.
- Infectious Disease Clinical Research Center of Ningxia, 804 Shengli Street, Xingqing District, Yinchuan, 750004, Ningxia, China.
- Department of Infectious Disease, General Hospital of Xiang Medical University, 804 Shengli Street, Xingqing District, Yinchuan, 750004, Ningxia, China.
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12
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Cannet F, Sequera C, Veloso PM, El Kaoutari A, Methia M, Richelme S, Kaya M, Cherni A, Dupont M, Borg JP, Morel C, Boursier Y, Maina F. Tracing specificity of immune landscape remodeling associated with distinct anticancer treatments. iScience 2025; 28:112071. [PMID: 40124507 PMCID: PMC11930375 DOI: 10.1016/j.isci.2025.112071] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2024] [Revised: 07/18/2024] [Accepted: 02/10/2025] [Indexed: 03/25/2025] Open
Abstract
Immune cells within the tumor microenvironment impact cancer progression, resistance, response to treatments. Despite remarkable outcomes for some cancer patients, immunotherapies remain unsatisfactory for others. Here, we designed an experimental setting using the Alb-R26 Met "inside-out" mouse model, faithfully recapitulating molecular features of liver cancer patients, to explore the effects of distinct anticancer targeted therapies on the tumor immune landscape. Using two treatments in clinical trials for different cancer types, Decitabine and MEK+BCL-XL blockage, we show their capability to trigger tumor regression in Alb-R26 Met mice and to superimpose distinct profiles of immune cell types and immune-checkpoints, impacting immunotherapy response. A machine learning approach processing tumor imaging and immune profile data identified a putative signature predicting tumor treatment response in mice and patients. Outcomes exemplify how the tumor immune microenvironment is differentially reshaped by distinct anticancer agents and highlight the importance of measuring its modulation during treatment to optimize oncotherapy and immunotherapy combinations.
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Affiliation(s)
- Floriane Cannet
- Aix Marseille Univ, CNRS/IN2P3, CPPM, 13009 Marseille, France
- Aix Marseille Univ, CNRS, Inserm, Institut Paoli-Calmettes, Centre de Recherche en Cancérologie de Marseille (CRCM), 13009 Marseille, France
- Aix Marseille Univ, CNRS, Developmental Biology Institute of Marseille (IBDM), Turing Center for Living Systems, 13009 Marseille, France
| | - Célia Sequera
- Aix Marseille Univ, CNRS, Inserm, Institut Paoli-Calmettes, Centre de Recherche en Cancérologie de Marseille (CRCM), 13009 Marseille, France
- Aix Marseille Univ, CNRS, Developmental Biology Institute of Marseille (IBDM), Turing Center for Living Systems, 13009 Marseille, France
| | - Paula Michea Veloso
- Aix Marseille Univ, CNRS, Inserm, Institut Paoli-Calmettes, Centre de Recherche en Cancérologie de Marseille (CRCM), 13009 Marseille, France
| | - Abdessamad El Kaoutari
- Aix Marseille Univ, CNRS, Inserm, Institut Paoli-Calmettes, Centre de Recherche en Cancérologie de Marseille (CRCM), 13009 Marseille, France
| | - Melissa Methia
- Aix Marseille Univ, CNRS, Inserm, Institut Paoli-Calmettes, Centre de Recherche en Cancérologie de Marseille (CRCM), 13009 Marseille, France
| | - Sylvie Richelme
- Aix Marseille Univ, CNRS, Developmental Biology Institute of Marseille (IBDM), Turing Center for Living Systems, 13009 Marseille, France
| | - Muge Kaya
- Aix Marseille Univ, CNRS, Inserm, Institut Paoli-Calmettes, Centre de Recherche en Cancérologie de Marseille (CRCM), 13009 Marseille, France
| | - Afef Cherni
- Aix Marseille Univ, CNRS/IN2P3, CPPM, 13009 Marseille, France
| | - Mathieu Dupont
- Aix Marseille Univ, CNRS/IN2P3, CPPM, 13009 Marseille, France
| | - Jean-Paul Borg
- Aix Marseille Univ, CNRS, Inserm, Institut Paoli-Calmettes, Centre de Recherche en Cancérologie de Marseille (CRCM), 13009 Marseille, France
- Institut Universitaire de France, Paris, France
| | - Christian Morel
- Aix Marseille Univ, CNRS/IN2P3, CPPM, 13009 Marseille, France
| | | | - Flavio Maina
- Aix Marseille Univ, CNRS, Inserm, Institut Paoli-Calmettes, Centre de Recherche en Cancérologie de Marseille (CRCM), 13009 Marseille, France
- Aix Marseille Univ, CNRS, Developmental Biology Institute of Marseille (IBDM), Turing Center for Living Systems, 13009 Marseille, France
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13
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Vargas-Accarino E, Higuera M, Bermúdez-Ramos M, Soriano-Varela A, Torrens M, Pons M, Aransay AM, Martín JE, Rodríguez-Frías F, Merino X, Mínguez B. Harnessing Plasma Biomarkers to Predict Immunotherapy Outcomes in Hepatocellular Carcinoma: The Role of cfDNA, ctDNA, and Cytokines. Int J Mol Sci 2025; 26:2794. [PMID: 40141436 PMCID: PMC11942713 DOI: 10.3390/ijms26062794] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2025] [Revised: 03/07/2025] [Accepted: 03/17/2025] [Indexed: 03/28/2025] Open
Abstract
Immunotherapy has improved survival in patients with advanced hepatocellular carcinoma (HCC); yet, objective radiological responses occur in only about 20% of cases, suggesting variable benefits. This study aimed to identify serologic markers predictive of response to immune checkpoint inhibitors (ICIs). A cohort of 38 advanced HCC patients receiving immunotherapy was prospectively analyzed. Levels of cell-free DNA (cfDNA), circulating tumor DNA (ctDNA), and cytokines were measured pre-treatment and three months post-treatment initiation. Genomic profiling of ctDNA was also conducted. Baseline levels of cfDNA and ctDNA effectively discriminated HCC patients based on their radiological response to ICIs. Additionally, individuals with pathologic mutations in the CDKN2A gene exhibited significantly reduced survival. Patients with progressive disease (PD) as their best radiological response had significantly fewer copy number variations (CNVs) than those with a radiological response. Furthermore, levels of IL10, PD1, and TGFβ assessed after three months of treatment showed significant variations correlating with survival status. In conclusion, the analysis of cfDNA, ctDNA, and cytokines may improve treatment selection for HCC patients by predicting their expected response to immunotherapies.
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Affiliation(s)
- Elena Vargas-Accarino
- Liver Cancer Research Group, Liver Diseases, Vall d’Hebron Institut de Recerca (VHIR), Vall d’Hebron Barcelona Hospital Campus, 08035 Barcelona, Spain; (E.V.-A.); (M.H.); (M.B.-R.); (A.S.-V.); (M.T.)
- Department of Medicine, Campus de la UAB, Universitat Autònoma de Barcelona (UAB), Bellaterra, 08193 Cerdanyola del Vallès, Spain
| | - Mónica Higuera
- Liver Cancer Research Group, Liver Diseases, Vall d’Hebron Institut de Recerca (VHIR), Vall d’Hebron Barcelona Hospital Campus, 08035 Barcelona, Spain; (E.V.-A.); (M.H.); (M.B.-R.); (A.S.-V.); (M.T.)
| | - María Bermúdez-Ramos
- Liver Cancer Research Group, Liver Diseases, Vall d’Hebron Institut de Recerca (VHIR), Vall d’Hebron Barcelona Hospital Campus, 08035 Barcelona, Spain; (E.V.-A.); (M.H.); (M.B.-R.); (A.S.-V.); (M.T.)
- Department of Medicine, Campus de la UAB, Universitat Autònoma de Barcelona (UAB), Bellaterra, 08193 Cerdanyola del Vallès, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, 28029 Madrid, Spain; (M.P.); (F.R.-F.)
| | - Agnès Soriano-Varela
- Liver Cancer Research Group, Liver Diseases, Vall d’Hebron Institut de Recerca (VHIR), Vall d’Hebron Barcelona Hospital Campus, 08035 Barcelona, Spain; (E.V.-A.); (M.H.); (M.B.-R.); (A.S.-V.); (M.T.)
- Liver Unit, Hospital Universitario Vall d’Hebron, Vall d’Hebron Barcelona Hospital Campus, 08035 Barcelona, Spain
| | - María Torrens
- Liver Cancer Research Group, Liver Diseases, Vall d’Hebron Institut de Recerca (VHIR), Vall d’Hebron Barcelona Hospital Campus, 08035 Barcelona, Spain; (E.V.-A.); (M.H.); (M.B.-R.); (A.S.-V.); (M.T.)
- Liver Unit, Hospital Universitario Vall d’Hebron, Vall d’Hebron Barcelona Hospital Campus, 08035 Barcelona, Spain
| | - Mònica Pons
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, 28029 Madrid, Spain; (M.P.); (F.R.-F.)
- Liver Unit, Hospital Universitario Vall d’Hebron, Vall d’Hebron Barcelona Hospital Campus, 08035 Barcelona, Spain
| | - Ana María Aransay
- Genome Analysis Platform, CIC bioGUNE, 48160 Derio, Spain; (A.M.A.); (J.E.M.)
| | | | - Francisco Rodríguez-Frías
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, 28029 Madrid, Spain; (M.P.); (F.R.-F.)
- Microbiology and Biochemistry Department, Hospital Universitario Vall d’Hebron, Vall d’Hebron Barcelona Hospital Campus, 08035 Barcelona, Spain
| | - Xavier Merino
- Radiology Department, Hospital Universitario Vall d’Hebron, Vall d’Hebron Barcelona Hospital Campus, 08035 Barcelona, Spain;
| | - Beatriz Mínguez
- Liver Cancer Research Group, Liver Diseases, Vall d’Hebron Institut de Recerca (VHIR), Vall d’Hebron Barcelona Hospital Campus, 08035 Barcelona, Spain; (E.V.-A.); (M.H.); (M.B.-R.); (A.S.-V.); (M.T.)
- Department of Medicine, Campus de la UAB, Universitat Autònoma de Barcelona (UAB), Bellaterra, 08193 Cerdanyola del Vallès, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, 28029 Madrid, Spain; (M.P.); (F.R.-F.)
- Liver Unit, Hospital Universitario Vall d’Hebron, Vall d’Hebron Barcelona Hospital Campus, 08035 Barcelona, Spain
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14
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Zhang J, Tian T, Tian S, Yao J, Zhang Y, Xie R, Yang T, Han B. Study on the Mechanism of QRICH1 Mediating PRMT1 to Regulate the Arginine Methylation Modification of cGAS to Promote Arsenics-Induced Pyroptosis in Hepatocellular Carcinoma Cells. J Hepatocell Carcinoma 2025; 12:597-614. [PMID: 40124968 PMCID: PMC11930257 DOI: 10.2147/jhc.s505266] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2024] [Accepted: 03/04/2025] [Indexed: 03/25/2025] Open
Abstract
Purpose This study aims to investigate the mechanism of action of arsenic-based agents against hepatocellular carcinoma (HCC) and to identify effective drug targets for HCC treatment. Methods Huh7 and HepG2 cells treated with NaAsO2 were assessed for cell viability, pyroptosis, migration, and invasion after undergoing lentiviral transfection. An orthotopic liver tumor model was established and divided into a model group and a treatment group. Proteins associated with QRICH1, PRMT1, cGAS-STING, and the classical pyroptosis pathway were quantified using Western blotting. The intracellular expression and localization of PRMT1 and NLRP3 in HCC were analyzed through cellular immunofluorescence. Co-immunoprecipitation (Co-IP) was performed to examine the protein interactions between PRMT1 and cGAS, as well as between STING and NLRP3. Chromatin immunoprecipitation (ChIP) was used to confirm QRICH1 enrichment in the PRMT1 promoter region. Results NaAsO2 treatment significantly inhibited the proliferation of Huh7 and HepG2 cells and effectively blocked their migration and invasion capabilities, while promoting cellular pyroptosis. Quantitative polymerase chain reaction(QRCR) and ChIP assays confirmed that NaAsO2 regulates PRMT1 expression by down-regulate QRICH1 binding in the PRMT1 promoter region. Additionally, NaAsO2 decreased the expression of the QRICH1-PRMT1 complex and upregulated the cGAS-STING signaling pathway, activating the downstream NLRP3-dependent classical pyroptosis pathway. Overexpression of QRICH1 reversed these effects. Conclusion NaAsO2 inhibits the expression of the QRICH1-PRMT1 axis, activates cGAS-STING signaling pathway transduction, and induces pyroptosis in HCC cells, thereby increasing the infiltration of immune cells in liver cancer tissues.
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Affiliation(s)
- Jiayuan Zhang
- Department of Pathophysiology, College of Basic Medical Sciences, Guizhou Medical University, Guiyang, Guizhou, People’s Republic of China
- Guizhou Provincial Key Laboratory of Pathogenesis and Drug Research on Common Chronic Diseases, Guizhou Medical University, Guiyang, Guizhou, People’s Republic of China
| | - Tian Tian
- Department of Eugenic Genetics, Guiyang Maternal and Child Health Care Hospital, Guiyang, Guizhou, 550003, People’s Republic of China
| | - Shanshan Tian
- Department of Pathophysiology, College of Basic Medical Sciences, Guizhou Medical University, Guiyang, Guizhou, People’s Republic of China
- Guizhou Provincial Key Laboratory of Pathogenesis and Drug Research on Common Chronic Diseases, Guizhou Medical University, Guiyang, Guizhou, People’s Republic of China
| | - Jinhai Yao
- Department of Pathophysiology, College of Basic Medical Sciences, Guizhou Medical University, Guiyang, Guizhou, People’s Republic of China
- Guizhou Provincial Key Laboratory of Pathogenesis and Drug Research on Common Chronic Diseases, Guizhou Medical University, Guiyang, Guizhou, People’s Republic of China
| | - Yingwan Zhang
- Qianxinan People’s Hospital, Qianxinan Affiliated Hospital of Zunyi Medical University, Xingyi, Guizhou, 562400, People’s Republic of China
| | - Rujia Xie
- Department of Pathophysiology, College of Basic Medical Sciences, Guizhou Medical University, Guiyang, Guizhou, People’s Republic of China
- Guizhou Provincial Key Laboratory of Pathogenesis and Drug Research on Common Chronic Diseases, Guizhou Medical University, Guiyang, Guizhou, People’s Republic of China
| | - Ting Yang
- Department of Pathophysiology, College of Basic Medical Sciences, Guizhou Medical University, Guiyang, Guizhou, People’s Republic of China
- Guizhou Provincial Key Laboratory of Pathogenesis and Drug Research on Common Chronic Diseases, Guizhou Medical University, Guiyang, Guizhou, People’s Republic of China
| | - Bing Han
- Department of Pathophysiology, College of Basic Medical Sciences, Guizhou Medical University, Guiyang, Guizhou, People’s Republic of China
- Guizhou Provincial Key Laboratory of Pathogenesis and Drug Research on Common Chronic Diseases, Guizhou Medical University, Guiyang, Guizhou, People’s Republic of China
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15
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Qiu Y, Xu J, Liao W, Yang S, Wen Y, Farag MA, Zheng L, Zhao C. Ulvan derived from Ulva lactuca suppresses hepatocellular carcinoma cell proliferation through miR-542-3p-mediated downregulation of SLC35F6. Int J Biol Macromol 2025; 308:142252. [PMID: 40118430 DOI: 10.1016/j.ijbiomac.2025.142252] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2024] [Revised: 03/13/2025] [Accepted: 03/16/2025] [Indexed: 03/23/2025]
Abstract
Hepatocellular carcinoma (HCC) therapy still presents significant challenges, with a critical need for novel molecular targets and effective natural compound-based therapies. Despite its known oncogenic potential in other cancers, the role of SLC35F6 in HCC has not been previously reported, leaving a gap in our understanding of its function and therapeutic relevance. Here, we demonstrate that SLC35F6 is overexpressed in HCC and is associated with poor prognosis. Ulva lactuca polysaccharide (ULP), a natural extract with known antitumor properties, exerts its effects by upregulating miR-542-3p, which in turn inhibits SLC35F6 expression and significantly increases TP53 protein levels. Furthermore, TP53 is positively regulated by miR-542-3p, and our results indicate that SLC35F6 is a target gene of miR-542-3p. Knockdown of SLC35F6 in H22 and HepG2 cells markedly reduced cell growth while elevating TP53 expression, supporting SLC35F6 as a key regulatory factor in the miR-542-3p/TP53 axis. While this study did not confirm direct mutual regulation between SLC35F6 and TP53, our findings provide evidence that targeting SLC35F6 can suppress HCC progression. Collectively, these results identify SLC35F6 as a potential therapeutic target for HCC and provide mechanistic insights into its regulation through the miR-542-3p/SLC35F6/TP53 axis.
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Affiliation(s)
- Yinghui Qiu
- College of Marine Sciences, Fujian Agriculture and Forestry University, Fuzhou 350002, China; School of Materials Science and Engineering, Huaqiao University, Xiamen 361021, China
| | - Jingxiang Xu
- School of Basic Medicine, Gannan Medical University, Ganzhou 341000, China
| | - Wei Liao
- State Key Laboratory of Mariculture Breeding, Key Laboratory of Marine Biotechnology of Fujian Province, Fujian Agriculture and Forestry University, Fuzhou 350002, China; State Key Laboratory of Food Science and Resources, China-Canada Joint Lab of Food Science and Technology, Key Laboratory of Bioactive Polysaccharides of Jiangxi Province, Nanchang University, Nanchang 330047, China
| | - Shuxin Yang
- School of Basic Medicine, Gannan Medical University, Ganzhou 341000, China
| | - Yuxi Wen
- University of Vigo, Nutrition and Bromatology Group, Department of Analytical Chemistry and Food Science, Faculty of Science, E32004 Ourense, Spain
| | - Mohamed A Farag
- Pharmacognosy Department, College of Pharmacy, Cairo University, Cairo, Egypt
| | - Lingjun Zheng
- School of Agriculture and Biology, Shanghai JiaoTong University, Shanghai 200240, China
| | - Chao Zhao
- College of Marine Sciences, Fujian Agriculture and Forestry University, Fuzhou 350002, China; State Key Laboratory of Mariculture Breeding, Key Laboratory of Marine Biotechnology of Fujian Province, Fujian Agriculture and Forestry University, Fuzhou 350002, China.
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16
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Muhammed TM, Jasim SA, Zwamel AH, Rab SO, Ballal S, Singh A, Nanda A, Ray S, Hjazi A, Yasin HA. T lymphocyte-based immune response and therapy in hepatocellular carcinoma: focus on TILs and CAR-T cells. NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2025:10.1007/s00210-025-04035-9. [PMID: 40100377 DOI: 10.1007/s00210-025-04035-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/22/2025] [Accepted: 03/06/2025] [Indexed: 03/20/2025]
Abstract
Hepatocellular carcinoma (HCC) is among the leading causes of cancer-related death worldwide. The primary therapies for HCC are liver transplantation, hepatic tumor excision, radiofrequency ablation, and molecular-targeted medicines. An unfavorable prognosis marks HCC and has limited pharmacological response in therapeutic studies. The tumor immune microenvironment (TME) imposes significant selection pressure on HCC, resulting in its evolution and recurrence after various treatments. As the principal cellular constituents of tumor-infiltrating lymphocytes (TILs), T cells have shown both anti-tumor and protumor actions in HCC. T cell-mediated immune responses are pivotal in cancer monitoring and elimination. TILs are recognized for their critical involvement in the progression, prognosis, and immunotherapeutic management of HCC. Foxp3 + , CD8 + , CD3 + , and CD4 + T cells are the extensively researched subtypes of TILs. This article examines the functions and processes of several subtypes of TILs in HCC. Emerging T cell-based therapies, including TILs and chimeric antigen receptor (CAR)-T cell therapy, have shown tumor regression in several clinical and preclinical studies. Herein, it also delves into the existing T cell-based immunotherapies in HCC, with emphasis on TILs and CAR-T cells.
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Affiliation(s)
- Thikra Majid Muhammed
- Biology Department, College of Education for Pure Sciences, University of Anbar, Anbar, Iraq
| | - Saade Abdalkareem Jasim
- Medical Laboratory Techniques Department, College of Health and Medical Technology, University of Al-Maarif, Anbar, Iraq.
| | - Ahmed Hussein Zwamel
- Department of Medical Analysis, Medical Laboratory Technique College, The Islamic University, Najaf, Iraq
- Department of Medical Analysis, Medical Laboratory Technique College, The Islamic University of Al Diwaniyah, Al Diwaniyah, Iraq
- Department of Medical Analysis, Medical Laboratory Technique College, The Islamic University of Babylon, Babylon, Iraq
| | - Safia Obaidur Rab
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, King Khalid University, Abha, Saudi Arabia
| | - Suhas Ballal
- Department of Chemistry and Biochemistry, School of Sciences, JAIN (Deemed to Be University), Bangalore, Karnataka, India
| | - Abhayveer Singh
- Centre for Research Impact & Outcome, Chitkara University Institute of Engineering and Technology, Chitkara University, Rajpura, 140401, Punjab, India
| | - Anima Nanda
- Department of Biomedical, Sathyabama Institute of Science and Technology, Chennai, Tamil Nadu, India
| | - Subhashree Ray
- Department of Biochemistry, IMS and SUM Hospital, Siksha 'O' Anusandhan (Deemed to Be University), Bhubaneswar, Odisha, 751003, India
| | - Ahmed Hjazi
- Department of Medical Laboratory, College of Applied Medical Sciences, Prince Sattam Bin Abdulaziz University, Al-Kharj, Saudi Arabia.
| | - Hatif Abdulrazaq Yasin
- Department of Medical Laboratories Technology, Al-Nisour University College, Nisour Seq. Karkh, Baghdad, Iraq
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17
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Yi Z, Li X, Li Y, Wang R, Zhang W, Wang H, Ji Y, Zhao J, Song J. Multi-cohort validation based on a novel prognostic signature of anoikis for predicting prognosis and immunotherapy response of esophageal squamous cell carcinoma. Front Oncol 2025; 15:1530035. [PMID: 40165896 PMCID: PMC11955476 DOI: 10.3389/fonc.2025.1530035] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2024] [Accepted: 02/24/2025] [Indexed: 04/02/2025] Open
Abstract
Immunotherapy is recognized as an effective and promising treatment modality that offers a new approach to cancer treatment. However, identifying responsive patients remains challenging. Anoikis, a distinct form of programmed cell death, plays a crucial role in cancer progression and metastasis. Thus, we aimed to investigate prognostic biomarkers based on anoikis and their role in guiding immunotherapy decisions for esophageal squamous cell carcinoma (ESCC). By consensus clustering, the GSE53624 cohort of ESCC patients was divided into two subgroups based on prognostic anoikis-related genes (ARGs), with significant differences in survival outcomes between the two subgroups. Subsequently, we constructed an ARGs signature with four genes, and its reliability and accuracy were validated both internally and externally. Additional, different risk groups showed notable variances in terms of immunotherapy response, tumor infiltration, functional enrichment, immune function, and tumor mutation burden. Notably, the effectiveness of the signature in predicting immunotherapy response was confirmed across multiple cohorts, including GSE53624, GSE53625, TCGA-ESCC, and IMvigor210, highlighting its potential utility in predicting immunotherapy response. In conclusion, the ARGs signature has the potential to serve as an innovative and dependable prognostic biomarker for ESCC, facilitating personalized treatment strategies in this field, and may represent a valuable new tool for guiding ESCC immunotherapy decision-making.
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Affiliation(s)
- Zhongquan Yi
- Department of Central Laboratory, Affiliated Hospital 6 of Nantong University, Yancheng Third People's Hospital, Yancheng, China
| | - Xia Li
- Department of General Medicine, Affiliated Hospital 6 of Nantong University, Yancheng Third People's Hospital, Yancheng, China
| | - Yangyang Li
- Department of Cardiothoracic Surgery, Affiliated Hospital 6 of Nantong University, Yancheng Third People’s Hospital, Yancheng, China
| | - Rui Wang
- Department of Cardiothoracic Surgery, Affiliated Hospital 6 of Nantong University, Yancheng Third People’s Hospital, Yancheng, China
| | - Weisong Zhang
- Department of Cardiothoracic Surgery, Affiliated Hospital 6 of Nantong University, Yancheng Third People’s Hospital, Yancheng, China
| | - Hao Wang
- Department of Cardiothoracic Surgery, Affiliated Hospital 6 of Nantong University, Yancheng Third People’s Hospital, Yancheng, China
| | - Yanan Ji
- Department of Central Laboratory, Affiliated Hospital 6 of Nantong University, Yancheng Third People's Hospital, Yancheng, China
| | - Jing Zhao
- Department of Central Laboratory, Affiliated Hospital 6 of Nantong University, Yancheng Third People's Hospital, Yancheng, China
| | - JianXiang Song
- Department of Cardiothoracic Surgery, Affiliated Hospital 6 of Nantong University, Yancheng Third People’s Hospital, Yancheng, China
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18
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Vafadar A, Younesi M, Babadi S, Alizadeh M, Movahedpour A, Savardashtaki A. Exosome biosensors for detection of liver cancer. Clin Chim Acta 2025; 570:120199. [PMID: 39961411 DOI: 10.1016/j.cca.2025.120199] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2024] [Revised: 02/14/2025] [Accepted: 02/14/2025] [Indexed: 02/22/2025]
Abstract
Liver cancer is a significant global health concern due to its poor prognosis, often resulting from late-stage diagnosis and limited treatment options. While non-invasive methods such as ultrasound, blood tests (like AFP and PIVKA-II), CT scans, and MRIs are commonly employed in liver cancer diagnosis, they can occasionally be limited in sensitivity or associated with high costs. This has heightened the demand for innovative, non-invasive biomarkers that enable early and accurate diagnosis, leading to increased interest in the potential of exosomes. Exosomes are small vesicles released by cells and have the potential to serve as biomarkers for liver cancer. They contain a variety of biomolecules, including nucleic acids, proteins, and lipids, which can offer important information about cell health and disease progression. Developing fast, accurate, sensitive, and reliable techniques for detecting exosomes is essential. Biosensors, analytical tools for biological samples, have emerged as powerful instruments for analyzing exosomes. This review focuses on recent advancements in biosensor technology for exosome detection and explores future perspectives. The goal is to promote the development of innovative biosensor-based methods for detecting exosomes to enable earlier diagnosis and better clinical management of liver cancer.
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Affiliation(s)
- Asma Vafadar
- Student Research Committee, Shiraz University of Medical Sciences, Shiraz, Iran; Department of Medical Biotechnology, School of Advanced Medical Sciences and Technologies, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Mohammad Younesi
- Department of Medical Biotechnology, School of Advanced Medical Sciences and Technologies, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Sepideh Babadi
- Department of Medical Biotechnology, School of Advanced Medical Sciences and Technologies, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Mehdi Alizadeh
- Department of Clinical Biochemistry, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Ahmad Movahedpour
- Cellular and Molecular Research Center, Yasuj University of Medical Sciences, Yasuj, Iran.
| | - Amir Savardashtaki
- Department of Medical Biotechnology, School of Advanced Medical Sciences and Technologies, Shiraz University of Medical Sciences, Shiraz, Iran; Infertility Research Center, Shiraz University of Medical Sciences, Shiraz, Iran.
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19
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Zheng H, Xu B, Fan Y, Tuekprakhon A, Stamataki Z, Wang F. The role of immune regulation in HBV infection and hepatocellular carcinogenesis. Front Immunol 2025; 16:1506526. [PMID: 40160817 PMCID: PMC11949809 DOI: 10.3389/fimmu.2025.1506526] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2024] [Accepted: 02/19/2025] [Indexed: 04/02/2025] Open
Abstract
Hepatitis B virus (HBV) infection is a well-documented independent risk factor for developing hepatocellular carcinoma (HCC). Consequently, extensive research has focused on elucidating the mechanisms by which HBV induces hepatocarcinogenesis. The majority of studies are dedicated to understanding how HBV DNA integration into the host genome, viral RNA expression, and the resulting protein transcripts affect cellular processes and promote the malignant transformation of hepatocytes. However, considering that most acute HBV infections are curable, immune suppression potentially contributes to the critical challenges in the treatment of chronic infections. Regulatory T cells (Tregs) are crucial in immune tolerance. Understanding the interplay of Tregs within the liver microenvironment following HBV infection could offer novel therapeutic approaches for treating HBV infections and preventing HBV-related HCC. Two viewpoints to targeting Tregs in the liver microenvironment include means of reducing their inhibitory function and decreasing Treg frequency. As these strategies may disrupt the immune balance and lead to autoimmune responses, careful and comprehensive profiling of the patient's immunological status and genetic factors is required to successfully employ this promising therapeutic approach.
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Affiliation(s)
- Hailong Zheng
- Department of Hepatobiliary, Pancreatic, and Spleen Surgery, Affiliated Hospital of Inner Mongolia Medical University, Inner Mongolia Medical University, Hohhot, Inner Mongolia Autonomous Region, China
| | - Bingchen Xu
- Department of Hepatobiliary, Pancreatic, and Spleen Surgery, Affiliated Hospital of Inner Mongolia Medical University, Inner Mongolia Medical University, Hohhot, Inner Mongolia Autonomous Region, China
| | - Yiyu Fan
- Centre for Liver and Gastrointestinal Research, School of Infection, Inflammation & Immunology, College of Medicine and Health, University of Birmingham, Birmingham, United Kingdom
| | - Aekkachai Tuekprakhon
- Department of Hepatobiliary, Pancreatic, and Spleen Surgery, Affiliated Hospital of Inner Mongolia Medical University, Inner Mongolia Medical University, Hohhot, Inner Mongolia Autonomous Region, China
- Centre for Liver and Gastrointestinal Research, School of Infection, Inflammation & Immunology, College of Medicine and Health, University of Birmingham, Birmingham, United Kingdom
| | - Zania Stamataki
- Centre for Liver and Gastrointestinal Research, School of Infection, Inflammation & Immunology, College of Medicine and Health, University of Birmingham, Birmingham, United Kingdom
| | - Fei Wang
- Department of Hepatobiliary, Pancreatic, and Spleen Surgery, Affiliated Hospital of Inner Mongolia Medical University, Inner Mongolia Medical University, Hohhot, Inner Mongolia Autonomous Region, China
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20
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Zhang L, Zhuge Y, Ni J. BUB1 serves as a biomarker for poor prognosis in liver hepatocellular carcinoma. BMC Immunol 2025; 26:20. [PMID: 40069598 PMCID: PMC11895216 DOI: 10.1186/s12865-025-00698-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2024] [Accepted: 02/27/2025] [Indexed: 03/15/2025] Open
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) is the most frequent kind of liver cancer with high morbidity and mortality rates worldwide. Altered expression of BUB1 (budding uninhibited by benzimidazole 1) gene leads to chromosome instability and aneuploidy. This study investigated the expression of BUB1 and its prognostic value as well as its correlation with immune cell infiltration and immune checkpoints in HCC. RESULTS Using the Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) databases, we found that BUB1 was up-regulated in HCC, thus prompting us to validate this observation by immunohistochemistry on 57 HCC paraffin embedded tissues from Wuxi No.2 People's Hospital. Kaplan-Meier survival analysis revealed that HCC patients with high BUB1 expression had shorter overall survival (OS) time as well as progression-free interval (PFI), and disease-specific survival (DSS) time compared to the patients with low BUB1 expression. Besides, STRING database showed that the top 10 co-expression genes were mainly involved in the regulation of cell division during the mitosis. Gene Ontology (GO) analysis and the Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis showed that BUB1 had a connection to cancer related pathways. Lastly, The Tumor Immune Estimation Resource (TIMER) analysis found that BUB1 was positively related to immune cell infiltration and some immune checkpoint gene in HCC. CLINICAL TRIAL NUMBER Not applicable. CONCLUSIONS Our present study demonstrated that BUB1 is a potential prognostic biomarker, and BUB1 may play a role in the tumor immune microenvironment in HCC.
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Affiliation(s)
- Lili Zhang
- Department of Gastroenterology, Nanjing Drum Tower Hospital Clinical College of Nanjing Medical University, Nanjing, Jiangsu Province, China.
- Department of Gastroenterology, Jiangnan University Medical Center, Wuxi No.2 People's Hospital, Wuxi, Jiangsu Province, China.
| | - Yuzheng Zhuge
- Department of Gastroenterology, Nanjing Drum Tower Hospital Clinical College of Nanjing Medical University, Nanjing, Jiangsu Province, China.
| | - Jingbin Ni
- Department of Gastroenterology, Jiangnan University Medical Center, Wuxi No.2 People's Hospital, Wuxi, Jiangsu Province, China
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21
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Pan S, Wang J, Tian J, Wang Y, Wang S, Yu Y, Li F, Jiao YM, Shen Y, Yang L, Liu X, Qiu Q, Luan J, Wang FS, Meng F. Safety and efficacy of PD-1 inhibitors plus tyrosine kinase inhibitors combination therapy in patients with advanced hepatocellular carcinoma combined with hyperbilirubinemia: a retrospective cohort study. Front Immunol 2025; 16:1530477. [PMID: 40134422 PMCID: PMC11932989 DOI: 10.3389/fimmu.2025.1530477] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2024] [Accepted: 02/21/2025] [Indexed: 03/27/2025] Open
Abstract
Background Programmed death-1 (PD-1) inhibitors plus tyrosine kinase inhibitors (TKIs) combination therapy are considered as a first-line treatment recommendation for advanced hepatocellular carcinoma (HCC). However, patients with hyperbilirubinemia are excluded from this therapeutic option due to limitations in indications. There is a notable absence of published studies evaluating the safety and efficacy of the PD-1 inhibitors plus TKIs combination therapy in patients with HCC combined with hyperbilirubinemia. Methods Patients with HCC complicated with hyperbilirubinemia who received combination therapy with PD-1 inhibitors and TKIs were retrospectively analyzed. Adverse events, tumor response, and laboratory parameters were recorded to assess the safety and efficacy of the treatment, as well as to identify potential risk factors influencing survival. Results A total of 108 participants were included in the study, with 56 patients (51.9%) reporting at least one adverse event, the majority of which were mild. The objective response rate (ORR) for the enrolled participants was 11.9%, and the disease control rate(DCR) reached 61.2%. The median overall survival (OS) for the entire cohort was 5.03 months, while the median progression-free survival (PFS) was 3.63 months. Multifactorial analysis showed that MELD score >18 and increased total bilirubin (TBIL) levels within one week were significant risk factors for OS. Patients with a decrease in TBIL levels within one week had significantly prolonged median OS (not reached vs 3.3months, P =0.013) and median PFS (7.03 months vs 2.77 months, P =0.010). Conclusion Combination therapy demonstrated favorable safety and tolerability among patients with HCC combined with hyperbilirubinemia. Patients who experienced a rapid decline in TBIL levels during the early phase of treatment with PD-1 inhibitors and TKIs were observed to derive clinical benefits. Early initiation of aggressive interventions aimed at reducing TBIL levels is recommended to optimize treatment outcomes.
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Affiliation(s)
- Shida Pan
- Beijing Ditan Hospital, Capital Medical University, Beijing, China
- Senior Department of Infectious Diseases, The Fifth Medical Center of Chinese People's Liberation Army (PLA) General Hospital, Beijing, China
| | - Jianing Wang
- Senior Department of Infectious Diseases, The Fifth Medical Center of Chinese People's Liberation Army (PLA) General Hospital, Beijing, China
- Peking University 302 Clinical Medical School, Beijing, China
| | - Jiahe Tian
- Senior Department of Infectious Diseases, The Fifth Medical Center of Chinese People's Liberation Army (PLA) General Hospital, Beijing, China
- Peking University 302 Clinical Medical School, Beijing, China
| | - Yilin Wang
- Senior Department of Infectious Diseases, The Fifth Medical Center of Chinese People's Liberation Army (PLA) General Hospital, Beijing, China
- Chinese People's Liberation Army (PLA) Medical School, Beijing, China
| | - Siyu Wang
- Senior Department of Infectious Diseases, The Fifth Medical Center of Chinese People's Liberation Army (PLA) General Hospital, Beijing, China
| | - Yingying Yu
- Senior Department of Infectious Diseases, The Fifth Medical Center of Chinese People's Liberation Army (PLA) General Hospital, Beijing, China
- The First Affiliated Hospital of University of Science and Technology of China (USTC), Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
| | - Fengyi Li
- Senior Department of Infectious Diseases, The Fifth Medical Center of Chinese People's Liberation Army (PLA) General Hospital, Beijing, China
| | - Yan-Mei Jiao
- Senior Department of Infectious Diseases, The Fifth Medical Center of Chinese People's Liberation Army (PLA) General Hospital, Beijing, China
| | - Yingjuan Shen
- Senior Department of Infectious Diseases, The Fifth Medical Center of Chinese People's Liberation Army (PLA) General Hospital, Beijing, China
| | - Luo Yang
- Senior Department of Infectious Diseases, The Fifth Medical Center of Chinese People's Liberation Army (PLA) General Hospital, Beijing, China
| | - Xiaomeng Liu
- Senior Department of Infectious Diseases, The Fifth Medical Center of Chinese People's Liberation Army (PLA) General Hospital, Beijing, China
| | - Qin Qiu
- Senior Department of Infectious Diseases, The Fifth Medical Center of Chinese People's Liberation Army (PLA) General Hospital, Beijing, China
| | - Junqing Luan
- Senior Department of Infectious Diseases, The Fifth Medical Center of Chinese People's Liberation Army (PLA) General Hospital, Beijing, China
| | - Fu-Sheng Wang
- Beijing Ditan Hospital, Capital Medical University, Beijing, China
- Senior Department of Infectious Diseases, The Fifth Medical Center of Chinese People's Liberation Army (PLA) General Hospital, Beijing, China
- Peking University 302 Clinical Medical School, Beijing, China
- Chinese People's Liberation Army (PLA) Medical School, Beijing, China
| | - Fanping Meng
- Senior Department of Infectious Diseases, The Fifth Medical Center of Chinese People's Liberation Army (PLA) General Hospital, Beijing, China
- Peking University 302 Clinical Medical School, Beijing, China
- Chinese People's Liberation Army (PLA) Medical School, Beijing, China
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22
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Meier C, Brieger A. The role of IL-8 in cancer development and its impact on immunotherapy resistance. Eur J Cancer 2025; 218:115267. [PMID: 39899909 DOI: 10.1016/j.ejca.2025.115267] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2024] [Revised: 01/28/2025] [Accepted: 01/28/2025] [Indexed: 02/05/2025]
Abstract
Tumors are structures of high complexity. Plurality of their structural and functional components - heterogeneity, diversity, directionality, interdependence and integration of signaling pathways - seem to follow isolated local rules, whereby a superordinate structure remains largely unknown. Understanding the complexity of cancer is the mainstay in finding determinants and developing effective therapies. Interleukin 8 (IL-8) is a potent pro-inflammatory chemokine that is significantly elevated in many different tumor entities. In contrast to its initially postulated anti-tumor properties, an increasing number of studies have been published in recent years linking this chemokine with tumor-promoting features and poor prognosis. This review summarizes the current state and diversity of the role of IL-8 in the development of cancer.
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Affiliation(s)
- Clara Meier
- Goethe University Frankfurt, University Hospital, Medical Clinic 1, Biomedical Research Laboratory, Frankfurt am Main, Germany
| | - Angela Brieger
- Goethe University Frankfurt, University Hospital, Medical Clinic 1, Biomedical Research Laboratory, Frankfurt am Main, Germany.
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23
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Tu Y, Wu H, Zhong C, Liu Y, Xiong Z, Chen S, Wang J, Wong PPC, Yang W, Liang Z, Lu J, Chen S, Zhang L, Feng Y, Si-Tou WWY, Yin B, Lin Y, Liang J, Liang L, Vong JSL, Ren W, Kwong TT, Leung H, To KF, Ma S, Tong M, Sun H, Xia Q, Zhou J, Kerr D, La Thangue N, Sung JJY, Chan SL, Cheng ASL. Pharmacological activation of STAT1-GSDME pyroptotic circuitry reinforces epigenetic immunotherapy for hepatocellular carcinoma. Gut 2025; 74:613-627. [PMID: 39486886 DOI: 10.1136/gutjnl-2024-332281] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/24/2024] [Accepted: 10/02/2024] [Indexed: 11/04/2024]
Abstract
BACKGROUND Genomic screening uncovered interferon-gamma (IFNγ) pathway defects in tumours refractory to immune checkpoint blockade (ICB). However, its non-mutational regulation and reversibility for therapeutic development remain less understood. OBJECTIVE We aimed to identify ICB resistance-associated druggable histone deacetylases (HDACs) and develop a readily translatable combination approach for patients with hepatocellular carcinoma (HCC). DESIGN We correlated the prognostic outcomes of HCC patients from a pembrolizumab trial (NCT03419481) with tumourous cell expressions of all HDAC isoforms by single-cell RNA sequencing. We investigated the therapeutic efficacy and mechanism of action of selective HDAC inhibition in 4 ICB-resistant orthotopic and spontaneous models using immune profiling, single-cell multiomics and chromatin immunoprecipitation-sequencing and verified by genetic modulations and co-culture systems. RESULTS HCC patients showing higher HDAC1/2/3 expressions exhibited deficient IFNγ signalling and poorer survival on ICB therapy. Transient treatment of a selective class-I HDAC inhibitor CXD101 resensitised HDAC1/2/3high tumours to ICB therapies, resulting in CD8+T cell-dependent antitumour and memory T cell responses. Mechanistically, CXD101 synergised with ICB to stimulate STAT1-driven antitumour immunity through enhanced chromatin accessibility and H3K27 hyperacetylation of IFNγ-responsive genes. Intratumoural recruitment of IFNγ+GZMB+cytotoxic lymphocytes further promoted cleavage of CXD101-induced Gasdermin E (GSDME) to trigger pyroptosis in a STAT1-dependent manner. Notably, deletion of GSDME mimicked STAT1 knockout in abolishing the antitumour efficacy and survival benefit of CXD101-ICB combination therapy by thwarting both pyroptotic and IFNγ responses. CONCLUSION Our immunoepigenetic strategy harnesses IFNγ-mediated network to augment the cancer-immunity cycle, revealing a self-reinforcing STAT1-GSDME pyroptotic circuitry as the mechanistic basis for an ongoing phase-II trial to tackle ICB resistance (NCT05873244).
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Affiliation(s)
- Yalin Tu
- School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong, China
| | - Haoran Wu
- School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong, China
| | - Chengpeng Zhong
- School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong, China
- Department of Liver Surgery, Renji Hospital Affiliated to Shanghai Jiao Tong University, School of Medicine, Shanghai, China
| | - Yan Liu
- School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong, China
| | - Zhewen Xiong
- School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong, China
| | - Siyun Chen
- School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong, China
| | - Jing Wang
- School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong, China
| | - Patrick Pak-Chun Wong
- School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong, China
| | - Weiqin Yang
- School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong, China
| | - Zhixian Liang
- School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong, China
| | - Jiahuan Lu
- School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong, China
| | - Shufen Chen
- School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong, China
| | - Lingyun Zhang
- School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong, China
| | - Yu Feng
- School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong, China
| | - Willis Wai-Yiu Si-Tou
- School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong, China
| | - Baoyi Yin
- School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong, China
| | - Yingnan Lin
- School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong, China
| | - Jianxin Liang
- School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong, China
| | - Liying Liang
- Department of Clinical Pharmacy, Guangzhou Medical University, Guangzhou, China
| | - Joaquim S L Vong
- School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong, China
| | - Weida Ren
- School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong, China
| | - Tsz Tung Kwong
- Department of Clinical Oncology, The Chinese University of Hong Kong, Hong Kong, China
| | - Howard Leung
- Department of Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Hong Kong, China
| | - Ka Fai To
- Department of Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Hong Kong, China
| | - Stephanie Ma
- School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China
| | - Man Tong
- School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong, China
| | - Hanyong Sun
- Department of Liver Surgery, Renji Hospital Affiliated to Shanghai Jiao Tong University, School of Medicine, Shanghai, China
| | - Qiang Xia
- Department of Liver Surgery, Renji Hospital Affiliated to Shanghai Jiao Tong University, School of Medicine, Shanghai, China
| | - Jingying Zhou
- School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong, China
| | - David Kerr
- Nuffield Division of Clinical and Laboratory Sciences, University of Oxford, Oxford, UK
| | - Nick La Thangue
- Department of Oncology, The University of Oxford, Oxford, UK
| | - Joseph J Y Sung
- Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore
- State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Hong Kong, China
| | - Stephen Lam Chan
- Department of Clinical Oncology, The Chinese University of Hong Kong, Hong Kong, China
| | - Alfred Sze-Lok Cheng
- School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong, China
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Lv J, Gan FY, Li MH, Yin QJ. Silencing NCAPD3 Inhibits Tumor Growth and Metastasis in Hepatocellular Carcinoma by Suppressing PI3K-AKT Signalling Pathway. Curr Med Sci 2025:10.1007/s11596-025-00026-2. [PMID: 40029498 DOI: 10.1007/s11596-025-00026-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2024] [Revised: 01/23/2025] [Accepted: 01/26/2025] [Indexed: 03/05/2025]
Abstract
OBJECTIVE To evaluate the expression pattern of non-SMC condensin II complex subunit D3 (NCAPD3) in hepatocellular carcinoma (HCC) tissues, assess its association with clinical characteristics, and explore the effects of NCAPD3 on HCC cells and the potential underlying mechanisms. METHODS NCAPD3 expression in HCC tumors and adjacent noncancerous tissues was quantified via quantitative PCR. Patients were divided into high- and low-expression groups on the basis of NCAPD3 levels, and associations with clinical parameters were assessed. The effects of NCAPD3 knockdown and the phosphatidylinositol-3-kinase (PI3K) agonist Y-P 740 on cell functions were examined via cell proliferation, Transwell migration, and invasion assays. Differentially expressed genes following NCAPD3 knockdown in SMMC-7721 cells were identified via mRNA sequencing. Western blotting was performed to measure NCAPD3, AKT serine/threonine kinase 1 (AKT1), and phosphorylated AKT1 levels. RESULTS NCAPD3 mRNA expression was notably upregulated in HCC tissues as compared with that in adjacent noncancer tissues. A positive correlation was observed between NCAPD3 expression and both lymphatic and distant metastases in patients with HCC. NCAPD3 knockdown reduced the proliferation and metastasis of SMMC-7721 and Huh-7 cells. mRNA sequencing revealed 140 downregulated genes and 125 upregulated genes. Further validation experiments confirmed that NCAPD3 modulated the PI3K-AKT signalling pathway and that the PI3K agonist Y-P 740 counteracted the effects of NCAPD3 knockdown. CONCLUSIONS Elevated NCAPD3 expression was strongly correlated with HCC metastasis. NCAPD3 inhibition impedes HCC cell growth and metastatic potential by suppressing the PI3K-AKT signalling pathway.
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Affiliation(s)
- Jun Lv
- Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, China.
| | - Fu-Yuan Gan
- Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, China
| | - Ming-Hao Li
- Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, China
| | - Qing-Jun Yin
- Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, China
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25
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Hosseini Shabanan S, Shobeiri P, Behnoush AH, Haghshomar M, Fowler KJ, Lewandowski RJ. 90Y-Transarterial Radioembolization Combined with Immune Checkpoint Inhibitors in Hepatocellular Carcinoma: A Systematic Review. J Gastrointest Cancer 2025; 56:73. [PMID: 40025380 DOI: 10.1007/s12029-025-01189-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/03/2025] [Indexed: 03/04/2025]
Abstract
BACKGROUND Transarterial radioembolization with yttrium-90 (90Yt-TARE) and immune checkpoint inhibitors (ICIs) are emerging as treatment modalities for intermediate to advanced hepatocellular carcinoma (HCC) based on randomized controlled trials. Herein, we systematically reviewed the published literature on the effects of 90Yt-TARE and ICIs combined on clinical outcomes of HCC. METHODS Medical databases of PubMed, Embase, and Cochrane Library were systematically searched for all studies assessing the use of concomitant immunotherapy of ICI with TARE in patients with HCC. Patient characteristics, treatment protocols, treatment outcomes, treatment adverse events, and survival outcomes were extracted after the screening phase. The primary outcomes were overall survival (OS) and patient-free survival (PFS), while the secondary outcomes were imaging objective response (OR) and adverse events. RESULTS Among 3432 reviewed, ten studies were included in this systematic review, including four randomized controlled trials and six retrospective studies. These consisted of 413 patients with HCC, and seven studies included patients with Child-Pugh A or B7 scores. Most studies allowed advanced or intermediate HCC stages, but only two specified BCLC stages (B and C). Median tumor sizes ranged from 56 to 78.5 mm. Various agents with different administration schedules were used as ICIs for immunotherapy by different studies for the combination of 90Yt-TARE with ICIs. Median OS ranged from 16.2 to 27 months between different studies while the PFS also ranged from 5.6 to 13.3 months. The OR rates according to imaging-based response assessments were reported between 31 and 89%, and the incidence rate of any grade toxicities was between 50 and 80%. CONCLUSION Concomitant treatment with 90Yt-TARE and ICIs has shown promising results in the treatment of patients with HCC. Further studies are required to reach a consensus on the optimal treatment protocol and the outcome of these treatments for patients with intermediate to advanced HCC.
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Affiliation(s)
| | - Parnian Shobeiri
- Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA
| | - Amir Hossein Behnoush
- Department of Radiology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
| | - Maryam Haghshomar
- Department of Radiology, Northwestern University Feinberg School of Medicine, 676 N. Saint Clair Street, Arkes Family Pavilion, Suite 800, Chicago, IL, 60611, USA
| | - Kathryn J Fowler
- Department of Radiology, University of California, San Diego, CA, USA
| | - Robert J Lewandowski
- Department of Radiology, Section of Interventional Radiology, Northwestern University, Chicago, IL, USA
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26
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Deng M, Zhao R, Zou H, Guan R, Wang J, Lee C, He B, Zhou J, Li S, Wei W, Cai H, Guo R. Oxaliplatin induces pyroptosis in hepatoma cells and enhances antitumor immunity against hepatocellular carcinoma. Br J Cancer 2025; 132:371-383. [PMID: 39748129 PMCID: PMC11832738 DOI: 10.1038/s41416-024-02908-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2024] [Revised: 11/03/2024] [Accepted: 11/08/2024] [Indexed: 01/04/2025] Open
Abstract
BACKGROUND Pyroptosis is closely associated with chemotherapeutic drugs and immune response. Here, we investigated whether oxaliplatin, a key drug in FOLFOX-hepatic artery infusion chemotherapy (FOLFOX-HAIC), induces pyroptosis in hepatoma cells and enhances antitumor immunity after tumor cell death. METHODS Hepatoma cells were treated with oxaliplatin. Pyroptosis and immunoreactivity were evaluated in vitro and in vivo. RESULTS Oxaliplatin activated caspase-3-mediated gasdermin E (GSDME) cleavage and induced pyroptosis in Hep G2 and SK-Hep-1 cells in vitro. Liver cancer cells with high levels of GSDME expression are prone to pyroptosis. Bioinformatic analysis revealed that pyrolysis-related genes are closely related to immunity. In vivo experiments revealed that oxaliplatin exhibited superior antitumor efficacy in mice with normal immune function and more pronounced inhibitory effect on hepatocellular carcinoma with high GSDME levels. Higher levels of cytokines and greater CD8+ T cell infiltration were observed in tumor tissues with better efficacy. Furthermore, an in vitro coculture assay confirmed that oxaliplatin-induced pyroptosis in Hep G2 cells overexpressing GSDME and activated the p38/MAPK signaling pathway to improve the cytotoxicity of CD8+ T cells. Analysis of clinical samples of HCC suggested that the efficacy of FOLFOX-HAIC in patients with high GSDME expression was better than that in patients with low GSDME expression. CONCLUSIONS Oxaliplatin induced pyroptosis in hepatoma cells by activating caspase-3-mediated cleavage of GSDME, which enhanced the cytotoxicity of CD8+ T cells by regulating the p38/MAPK signaling pathway. These results suggest that GSDME level may be used as a marker to predict the efficacy of FOLFOX-HAIC.
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Affiliation(s)
- Min Deng
- Department of Liver Surgery, Sun Yat-sen University Cancer Center, Guangzhou, China
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
- Department of General Surgery, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, China
| | - Rongce Zhao
- Department of Liver Surgery, Sun Yat-sen University Cancer Center, Guangzhou, China
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - Hao Zou
- Department of Liver Surgery, Sun Yat-sen University Cancer Center, Guangzhou, China
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - Renguo Guan
- Department of General Surgery, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, China
| | - Jiongliang Wang
- Department of Liver Surgery, Sun Yat-sen University Cancer Center, Guangzhou, China
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - Carol Lee
- School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong Special Administrative Region, Hong Kong, China
| | - Benyi He
- Department of Liver Surgery, Sun Yat-sen University Cancer Center, Guangzhou, China
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - Jing Zhou
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
- Department of Pathology, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Shaohua Li
- Department of Liver Surgery, Sun Yat-sen University Cancer Center, Guangzhou, China
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - Wei Wei
- Department of Liver Surgery, Sun Yat-sen University Cancer Center, Guangzhou, China
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - Hao Cai
- Department of General Surgery, Department of Transplantation, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.
| | - Rongping Guo
- Department of Liver Surgery, Sun Yat-sen University Cancer Center, Guangzhou, China.
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China.
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He Y, Du B, Liao W, Wang W, Su J, Guo C, Zhang K, Shi Z. Construction and evaluation of a prognostic model of autophagy-related genes in hepatocellular carcinoma. Biochem Biophys Rep 2025; 41:101893. [PMID: 39760097 PMCID: PMC11700244 DOI: 10.1016/j.bbrep.2024.101893] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2024] [Revised: 12/05/2024] [Accepted: 12/05/2024] [Indexed: 01/07/2025] Open
Abstract
Background Hepatocellular carcinoma (HCC) is a globally prevalent disease. Our article evaluates risk models based on autophagy- and HCC-related genes and their prognostic value by bioinformatics analytical methods to provide a scientific basis for clinical treatment. Methods Prognostic genes were identified by univariate and multivariate Cox analyses, and risk scores were calculated. The value of risk models was analysed by receiver operating characteristic curve (ROC), immune microenvironment and drug sensitivity. Prognostic gene-related regulatory mechanisms based on network database. Results We screened four prognosis-related genes (SQSTM1, GABARAPL1, CDKN2A, HSPB8) for model construction. The AUC for 1-, 2- and 3-year survival was higher than 0.6 in both the training and validation sets. The nomogram constructed based on risk scores, pathologic_T predicted the outcome better. There were differences in the tumour microenvironment between the high and low risk groups, as evidenced by differences in the distribution of immune cells and differences in the expression of immune checkpoints. Conclusion Our results illustrate that models, nomograms and risk scores were valuable for tumour progression. Clinical trial number Not applicable.
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Affiliation(s)
| | | | | | - Wei Wang
- Department of Hepatobiliary and Pancreatic Surgery, The Second Affiliated Hospital of Kunming Medical University, No.374 Yunnan-Burma Road, Kunming, Yunnan, 650101, China
| | - Jifeng Su
- Department of Hepatobiliary and Pancreatic Surgery, The Second Affiliated Hospital of Kunming Medical University, No.374 Yunnan-Burma Road, Kunming, Yunnan, 650101, China
| | - Chen Guo
- Department of Hepatobiliary and Pancreatic Surgery, The Second Affiliated Hospital of Kunming Medical University, No.374 Yunnan-Burma Road, Kunming, Yunnan, 650101, China
| | - Kai Zhang
- Department of Hepatobiliary and Pancreatic Surgery, The Second Affiliated Hospital of Kunming Medical University, No.374 Yunnan-Burma Road, Kunming, Yunnan, 650101, China
| | - Zhitian Shi
- Department of Hepatobiliary and Pancreatic Surgery, The Second Affiliated Hospital of Kunming Medical University, No.374 Yunnan-Burma Road, Kunming, Yunnan, 650101, China
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Gao H, Qu L, Li M, Guan X, Zhang S, Deng X, Wang J, Xing F. Unlocking the potential of chimeric antigen receptor T cell engineering immunotherapy: Long road to achieve precise targeted therapy for hepatobiliary pancreatic cancers. Int J Biol Macromol 2025; 297:139829. [PMID: 39814310 DOI: 10.1016/j.ijbiomac.2025.139829] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2024] [Revised: 01/03/2025] [Accepted: 01/11/2025] [Indexed: 01/18/2025]
Abstract
Innovative therapeutic strategies are urgently needed to address the ongoing global health concern of hepatobiliary pancreatic malignancies. This review summarizes the latest and most comprehensive research of chimeric antigen receptor (CAR-T) cell engineering immunotherapy for treating hepatobiliary pancreatic cancers. Commencing with an exploration of the distinct anatomical location and the immunosuppressive, hypoxic tumor microenvironment (TME), this review critically assesses the limitations of current CAR-T therapy in hepatobiliary pancreatic cancers and proposes corresponding solutions. Various studies aim at enhancing CAR-T cell efficacy in these cancers through improving T cell persistence, enhancing antigen specificity and reducing tumor heterogeneity, also modulating the immunosuppressive and hypoxic TME. Additionally, the review examines the application of emerging nanoparticles and biotechnologies utilized in CAR-T therapy for these cancers. The results suggest that constructing optimized CAR-T cells to overcome physical barrier, manipulating the TME to relieve immunosuppression and hypoxia, designing CAR-T combination therapies, and selecting the most suitable delivery strategies, all together could collectively enhance the safety of CAR-T engineering and advance the effectiveness of adaptive cell therapy for hepatobiliary pancreatic cancers.
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Affiliation(s)
- Hongli Gao
- Department of Oncology, Shengjing Hospital of China Medical University, Shenyang 110004, China
| | - Lianyue Qu
- Department of Pharmacy, The First Hospital of China Medical University, Shenyang 110001, China
| | - Mu Li
- Department of General Surgery, Shengjing Hospital of China Medical University, Shenyang 110004, China
| | - Xin Guan
- Department of Gastroenterology, Shengjing Hospital of China Medical University, Shenyang 110004, China
| | - Shuang Zhang
- Department of General Surgery, Shengjing Hospital of China Medical University, Shenyang 110004, China
| | - Xin Deng
- Department of General Surgery, Shengjing Hospital of China Medical University, Shenyang 110004, China.
| | - Jin Wang
- Department of Medical Oncology, The First Hospital of China Medical University, Shenyang 110001, China.
| | - Fei Xing
- Department of Oncology, Shengjing Hospital of China Medical University, Shenyang 110004, China.
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29
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Sun Y, Li T, Ding L, Wang J, Chen C, Liu T, Liu Y, Li Q, Wang C, Huo R, Wang H, Tian T, Zhang C, Pan B, Zhou J, Fan J, Yang X, Yang W, Wang B, Guo W. Platelet-mediated circulating tumor cell evasion from natural killer cell killing through immune checkpoint CD155-TIGIT. Hepatology 2025; 81:791-807. [PMID: 38779918 DOI: 10.1097/hep.0000000000000934] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/15/2023] [Accepted: 04/23/2024] [Indexed: 05/25/2024]
Abstract
BACKGROUND AND AIMS Circulating tumor cells (CTCs) are precursors of cancer metastasis. However, how CTCs evade immunosurveillance during hematogenous dissemination remains unclear. APPROACH AND RESULTS We identified CTC-platelet adhesions by single-cell RNA sequencing and multiplex immunofluorescence of blood samples from multiple cancer types. Clinically, CTC-platelet aggregates were associated with significantly shorter progression-free survival and overall survival in patients with HCC. In vitro, ex vivo, and in vivo assays demonstrated direct platelet adhesions gifted cancer cells with an evasive ability from NK cell killing by upregulating inhibitory checkpoint CD155 (PVR cell adhesion molecule), therefore facilitating distant metastasis. Mechanistically, CD155 was transcriptionally regulated by the FAK/JNK/c-Jun cascade in a platelet contact-dependent manner. Further competition assays and cytotoxicity experiments revealed that CD155 on CTCs inhibited NK-cell cytotoxicity only by engaging with immune receptor TIGIT, but not CD96 and DNAM1, another 2 receptors for CD155. Interrupting the CD155-TIGIT interactions with a TIGIT antibody restored NK-cell immunosurveillance on CTCs and markedly attenuated tumor metastasis. CONCLUSIONS Our results demonstrated CTC evasion from NK-cell-mediated innate immunosurveillance mainly through immune checkpoint CD155-TIGIT, potentially offering an immunotherapeutic strategy for eradicating CTCs.
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MESH Headings
- Killer Cells, Natural/immunology
- Killer Cells, Natural/metabolism
- Humans
- Neoplastic Cells, Circulating/immunology
- Neoplastic Cells, Circulating/metabolism
- Neoplastic Cells, Circulating/pathology
- Receptors, Immunologic/metabolism
- Blood Platelets/immunology
- Blood Platelets/metabolism
- Tumor Escape/immunology
- Receptors, Virus/metabolism
- Liver Neoplasms/immunology
- Liver Neoplasms/pathology
- Carcinoma, Hepatocellular/immunology
- Carcinoma, Hepatocellular/pathology
- Male
- Mice
- Female
- Animals
- Cell Line, Tumor
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Affiliation(s)
- Yunfan Sun
- Department of Liver Surgery & Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University; Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, China
| | - Tong Li
- Department of Laboratory Medicine, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Lin Ding
- Department of Laboratory Medicine, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Jiyan Wang
- Department of Laboratory Medicine, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Chen Chen
- Department of Cell Biology, Shanghai Dunwill Medical Technology Company, Shanghai, China
| | - Te Liu
- Shanghai Geriatric Institute of Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Yu Liu
- Department of Laboratory Medicine, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Qian Li
- Department of Laboratory Medicine, Zhongshan Hospital, Fudan University, Shanghai, China
- Department of Laboratory Medicine, Wusong Branch, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Chuyu Wang
- Department of Laboratory Medicine, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Ran Huo
- Department of Laboratory Medicine, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Hao Wang
- Department of Laboratory Medicine, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Tongtong Tian
- Department of Laboratory Medicine, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Chunyan Zhang
- Department of Laboratory Medicine, Zhongshan Hospital, Fudan University, Shanghai, China
- Department of Laboratory Medicine, Xiamen Branch, Zhongshan Hospital, Fudan University, Xiamen, China
| | - Baishen Pan
- Department of Laboratory Medicine, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Jian Zhou
- Department of Liver Surgery & Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University; Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, China
| | - Jia Fan
- Department of Liver Surgery & Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University; Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, China
| | - Xinrong Yang
- Department of Liver Surgery & Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University; Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, China
| | - Wenjing Yang
- Department of Laboratory Medicine, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Beili Wang
- Department of Laboratory Medicine, Zhongshan Hospital, Fudan University, Shanghai, China
- Department of Laboratory Medicine, Wusong Branch, Zhongshan Hospital, Fudan University, Shanghai, China
- Department of Laboratory Medicine, Shanghai Geriatric Medical Center, Shanghai, China
| | - Wei Guo
- Department of Laboratory Medicine, Zhongshan Hospital, Fudan University, Shanghai, China
- Department of Laboratory Medicine, Wusong Branch, Zhongshan Hospital, Fudan University, Shanghai, China
- Department of Laboratory Medicine, Xiamen Branch, Zhongshan Hospital, Fudan University, Xiamen, China
- Department of Laboratory Medicine, Shanghai Geriatric Medical Center, Shanghai, China
- Cancer Center, Zhongshan Hospital, Fudan University, Shanghai, China
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30
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Yu X, Qian J, Ding L, Pan C, Liu X, Wu Q, Wang S, Liu J, Shang M, Su R, Guo D, Xie H, Yin S, Zhou L, Zheng S. Galectin-1-Induced Tumor Associated Macrophages Repress Antitumor Immunity in Hepatocellular Carcinoma Through Recruitment of Tregs. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2025; 12:e2408788. [PMID: 39853961 PMCID: PMC11923918 DOI: 10.1002/advs.202408788] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/29/2024] [Revised: 12/12/2024] [Indexed: 01/26/2025]
Abstract
Tumor-associated macrophages (TAMs) are commonly considered accomplices in tumorigenesis and tumor development. However, the precise mechanism by which tumor cells prompt TAMs to aid in evading immune surveillance remains to be further investigated. Here, it is elucidated that tumor-secreted galectin-1 (Gal1) conferred immunosuppressive properties to TAMs. Specifically, patient specimens and a public database is first used to analyze the clinical relevance of Gal1 in hepatocellular carcinoma (HCC). Then, it is demonstrated that TAMs functioned as a critical mediator in the Gal1-induced progression of HCC and the establishment of an immunosuppressive tumor microenvironment. Furthermore, RNA-sequencing determined that Gal1 promoted the upregulation of chemokine (C-C motif) ligand 20 (CCL20) in TAMs via activating the PI3K/AKT/NF-κB pathway. Employing an anti-CCL20 neutralizing antibody and Foxp3DTR mice, it is demonstrated that CCR6+Foxp3+ regulatory T cells (Tregs) recruited by Gal1-induced TAMs contributed to reduced infiltration and dysfunctional state of CD8+ T cells, subsequently facilitating tumor progression. Targeting Gal1 dampened the secretion of CCL20 and inhibits the recruitment of Tregs, thereby activating anti-tumor immunity and ameliorating anti-PD-1 resistance. Together, this findings revealed that Gal1-induced TAMs recruited Tregs through the CCL20-CCR6 axis. Inhibition of Gal1 improves the effectiveness of anti-PD1 therapy, shedding important new light on the combination immunotherapy of HCC.
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Affiliation(s)
- Xizhi Yu
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310003, China
- NHC Key Laboratory of Combined Multi-organ Transplantation, Key Laboratory of Organ Transplantation, Zhejiang, 310003, China
- Key Laboratory of the diagnosis and treatment of organ Transplantation, Research Unit of Collaborative Diagnosis and Treatment for Hepatobiliary and Pancreatic Cancer, Chinese Academy of Medical Sciences (2019RU019), Hangzhou, 310003, China
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Hangzhou, 310003, China
| | - Junjie Qian
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310003, China
- NHC Key Laboratory of Combined Multi-organ Transplantation, Key Laboratory of Organ Transplantation, Zhejiang, 310003, China
- Key Laboratory of the diagnosis and treatment of organ Transplantation, Research Unit of Collaborative Diagnosis and Treatment for Hepatobiliary and Pancreatic Cancer, Chinese Academy of Medical Sciences (2019RU019), Hangzhou, 310003, China
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Hangzhou, 310003, China
| | - Limin Ding
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310003, China
- NHC Key Laboratory of Combined Multi-organ Transplantation, Key Laboratory of Organ Transplantation, Zhejiang, 310003, China
- Key Laboratory of the diagnosis and treatment of organ Transplantation, Research Unit of Collaborative Diagnosis and Treatment for Hepatobiliary and Pancreatic Cancer, Chinese Academy of Medical Sciences (2019RU019), Hangzhou, 310003, China
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Hangzhou, 310003, China
| | - Caixu Pan
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310003, China
- NHC Key Laboratory of Combined Multi-organ Transplantation, Key Laboratory of Organ Transplantation, Zhejiang, 310003, China
- Key Laboratory of the diagnosis and treatment of organ Transplantation, Research Unit of Collaborative Diagnosis and Treatment for Hepatobiliary and Pancreatic Cancer, Chinese Academy of Medical Sciences (2019RU019), Hangzhou, 310003, China
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Hangzhou, 310003, China
| | - Xi Liu
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310003, China
- NHC Key Laboratory of Combined Multi-organ Transplantation, Key Laboratory of Organ Transplantation, Zhejiang, 310003, China
- Key Laboratory of the diagnosis and treatment of organ Transplantation, Research Unit of Collaborative Diagnosis and Treatment for Hepatobiliary and Pancreatic Cancer, Chinese Academy of Medical Sciences (2019RU019), Hangzhou, 310003, China
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Hangzhou, 310003, China
| | - Qinchuan Wu
- NHC Key Laboratory of Combined Multi-organ Transplantation, Key Laboratory of Organ Transplantation, Zhejiang, 310003, China
- Key Laboratory of the diagnosis and treatment of organ Transplantation, Research Unit of Collaborative Diagnosis and Treatment for Hepatobiliary and Pancreatic Cancer, Chinese Academy of Medical Sciences (2019RU019), Hangzhou, 310003, China
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Hangzhou, 310003, China
| | - Shuai Wang
- Department of Hepatobiliary and Pancreatic Surgery, Department of Liver Transplantation, Shulan (Hangzhou) Hospital Affiliated to Zhejiang Shuren University Shulan International Medical College, Hangzhou, 310000, China
| | - Jianpeng Liu
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310003, China
- NHC Key Laboratory of Combined Multi-organ Transplantation, Key Laboratory of Organ Transplantation, Zhejiang, 310003, China
- Key Laboratory of the diagnosis and treatment of organ Transplantation, Research Unit of Collaborative Diagnosis and Treatment for Hepatobiliary and Pancreatic Cancer, Chinese Academy of Medical Sciences (2019RU019), Hangzhou, 310003, China
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Hangzhou, 310003, China
| | - Mingge Shang
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310003, China
- NHC Key Laboratory of Combined Multi-organ Transplantation, Key Laboratory of Organ Transplantation, Zhejiang, 310003, China
- Key Laboratory of the diagnosis and treatment of organ Transplantation, Research Unit of Collaborative Diagnosis and Treatment for Hepatobiliary and Pancreatic Cancer, Chinese Academy of Medical Sciences (2019RU019), Hangzhou, 310003, China
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Hangzhou, 310003, China
| | - Rong Su
- NHC Key Laboratory of Combined Multi-organ Transplantation, Key Laboratory of Organ Transplantation, Zhejiang, 310003, China
- Key Laboratory of the diagnosis and treatment of organ Transplantation, Research Unit of Collaborative Diagnosis and Treatment for Hepatobiliary and Pancreatic Cancer, Chinese Academy of Medical Sciences (2019RU019), Hangzhou, 310003, China
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Hangzhou, 310003, China
| | - Danjing Guo
- NHC Key Laboratory of Combined Multi-organ Transplantation, Key Laboratory of Organ Transplantation, Zhejiang, 310003, China
- Key Laboratory of the diagnosis and treatment of organ Transplantation, Research Unit of Collaborative Diagnosis and Treatment for Hepatobiliary and Pancreatic Cancer, Chinese Academy of Medical Sciences (2019RU019), Hangzhou, 310003, China
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Hangzhou, 310003, China
| | - Haiyang Xie
- NHC Key Laboratory of Combined Multi-organ Transplantation, Key Laboratory of Organ Transplantation, Zhejiang, 310003, China
- Key Laboratory of the diagnosis and treatment of organ Transplantation, Research Unit of Collaborative Diagnosis and Treatment for Hepatobiliary and Pancreatic Cancer, Chinese Academy of Medical Sciences (2019RU019), Hangzhou, 310003, China
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Hangzhou, 310003, China
| | - Shengyong Yin
- NHC Key Laboratory of Combined Multi-organ Transplantation, Key Laboratory of Organ Transplantation, Zhejiang, 310003, China
- Key Laboratory of the diagnosis and treatment of organ Transplantation, Research Unit of Collaborative Diagnosis and Treatment for Hepatobiliary and Pancreatic Cancer, Chinese Academy of Medical Sciences (2019RU019), Hangzhou, 310003, China
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Hangzhou, 310003, China
| | - Lin Zhou
- NHC Key Laboratory of Combined Multi-organ Transplantation, Key Laboratory of Organ Transplantation, Zhejiang, 310003, China
- Key Laboratory of the diagnosis and treatment of organ Transplantation, Research Unit of Collaborative Diagnosis and Treatment for Hepatobiliary and Pancreatic Cancer, Chinese Academy of Medical Sciences (2019RU019), Hangzhou, 310003, China
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Hangzhou, 310003, China
| | - Shusen Zheng
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310003, China
- NHC Key Laboratory of Combined Multi-organ Transplantation, Key Laboratory of Organ Transplantation, Zhejiang, 310003, China
- Key Laboratory of the diagnosis and treatment of organ Transplantation, Research Unit of Collaborative Diagnosis and Treatment for Hepatobiliary and Pancreatic Cancer, Chinese Academy of Medical Sciences (2019RU019), Hangzhou, 310003, China
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Hangzhou, 310003, China
- Department of Hepatobiliary and Pancreatic Surgery, Department of Liver Transplantation, Shulan (Hangzhou) Hospital Affiliated to Zhejiang Shuren University Shulan International Medical College, Hangzhou, 310000, China
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Xu J, Liu Y. Nanomaterials for liver cancer targeting: research progress and future prospects. Front Immunol 2025; 16:1496498. [PMID: 40092984 PMCID: PMC11906451 DOI: 10.3389/fimmu.2025.1496498] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2024] [Accepted: 01/07/2025] [Indexed: 03/19/2025] Open
Abstract
The incidence and mortality rates of liver cancer in China remain elevated. Although early-stage liver cancer is amenable to surgical resection, a significant proportion of patients are diagnosed at advanced stages. Currently, in addition to surgical resection for hepatocellular carcinoma, the primary treatment modalities predominantly include chemotherapy. The widespread use of chemotherapy, which non-selectively targets both malignant and healthy cells, often results in substantial immunosuppression. Simultaneously, the accumulation of chemotherapeutic agents can readily induce drug resistance upon reaching the physiological threshold, thereby diminishing the efficacy of these treatments. Besides chemotherapy, there exist targeted therapy, immunotherapy and other therapeutic approaches. Nevertheless, the development of drug resistance remains an inevitable challenge. To address these challenges, we turn to nanomedicine, an emerging and widely utilized discipline that significantly influences medical imaging, antimicrobial strategies, drug delivery systems, and other related areas. Stable and safe nanomaterials serve as effective carriers for delivering anticancer drugs. They enhance the precision of drug targeting, improve bioavailability, and minimize damage to healthy cells. This review focuses on common nanomaterial carriers used in hepatocellular carcinoma (HCC) treatment over the past five years. The following is a summary of the three drugs: Sorafenib, Gefitinib, and lenvatinib. Each drug employs distinct nanomaterial delivery systems, which result in varying levels of bioavailability, drug release rates, and therapeutic efficacy.
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Affiliation(s)
- Jiahong Xu
- Department of Hepatopancreatobiliary Surgery, Cancer Hospital of Dalian University of Technology, Liaoning Cancer Hospital and Institute, Shenyang, China
| | - Yefu Liu
- Department of Hepatopancreatobiliary Surgery, Cancer Hospital of Dalian University of Technology, Liaoning Cancer Hospital and Institute, Shenyang, China
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Zhou Y, Wang J, Chen Y, Lin W, Zhou R, Zhao L, Wang H. NRIR promotes immune escape in hepatocellular cancer by regulating IFNγ-induced PD-L1 expression. J Adv Res 2025:S2090-1232(25)00133-X. [PMID: 40023249 DOI: 10.1016/j.jare.2025.02.034] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2024] [Revised: 11/25/2024] [Accepted: 02/25/2025] [Indexed: 03/04/2025] Open
Abstract
INTRODUCTION Hepatocellular carcinoma (HCC) is one of the most common malignant tumors worldwide, with insensitive treatment and poor prognosis; in recent years, breakthroughs in IFN signaling pathway and PDL1/PD1 signaling pathway in HCC immunotherapy research. OBJECTIVES This study aimed to investigate the molecular mechanisms controlling the immune response and immune evasion. METHODS NRIR was identified as a differential gene affecting the IFN signaling pathway and PDL1/PD1 signaling pathway in HCC by bioinformatics, and the function of NRIR was investigated in the HCC cell model and the xenograft mouse model. Quantitative Real-time PCR (qRT-PCR) was used to detect NRIR and PD-L1 mRNAs in hepatocellular carcinoma tissues, and dual luciferase reporter gene assay, fluorescence in situ hybridization, western blot and RNA immunoprecipitation (RIP) to explore the molecular mechanisms between NRIR and target genes. RESULTS In this study, we observed a significant positive correlation between NRIR and PD-L1 expression in HCC, and NRIR upregulated PD-L1 expression in HCC by modulating the IFNγ signaling pathway. We demonstrated that NRIR recruited the transcription factor ZNF384 to initiate CMPK2 transcription. Furthermore, CMPK2 regulates ATP production to modulate STAT1 activation to affect PD-L1 expression. CONCLUSION Our findings revealed the important players of NRIR in regulating PD-L1 expression in HCC and provided new insights for the clinical application of immune-targeted therapies.
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Affiliation(s)
- Yan Zhou
- Department of Medical Oncology, Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou, China; Department of Pathology & Guangdong Province Key Laboratory of Molecular Tumor Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China
| | - Jing Wang
- Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, China; Department of Pathology & Guangdong Province Key Laboratory of Molecular Tumor Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China
| | - Yuanhang Chen
- Department of Medical Oncology, Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou, China; Department of Pathology & Guangdong Province Key Laboratory of Molecular Tumor Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China
| | - Wandie Lin
- Department of Pathology & Guangdong Province Key Laboratory of Molecular Tumor Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China
| | - Rui Zhou
- Department of Pathology & Guangdong Province Key Laboratory of Molecular Tumor Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China
| | - Liang Zhao
- Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, China; Department of Pathology & Guangdong Province Key Laboratory of Molecular Tumor Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China.
| | - Hui Wang
- Department of Medical Oncology, Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou, China.
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Bu J, Li Z, Hu D, Lan L, Huang J, Wang X, Li Q, Zhou J, Zeng Y. Enhanced efficacy of immune checkpoint inhibitors combined locoregional therapy and tyrosine kinase inhibitors in the treatment of unresectable hepatocellular carcinoma: A single - center retrospective study. Front Oncol 2025; 15:1554711. [PMID: 40071095 PMCID: PMC11893395 DOI: 10.3389/fonc.2025.1554711] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2025] [Accepted: 02/04/2025] [Indexed: 03/14/2025] Open
Abstract
Background Unresectable hepatocellular carcinoma (HCC) presents significant treatment challenges. While locoregional therapies (LT) and tyrosine kinase inhibitors (TKI) offer some benefits, prognosis remains poor. Immune checkpoint inhibitors (ICI) have shown promise in other oncological settings, suggesting potential benefits in HCC treatment regimens. Methods This retrospective study analyzed 232 patients diagnosed with unresectable HCC at West China Hospital from January 2019 to December 2023. Patients were categorized into two treatment groups: LT+TKI and LT+TKI+ICI. All patients underwent standardized locoregional treatments and first-line TKIs, with the latter group also receiving ICIs. The primary endpoints measured were overall survival (OS) and progression-free survival (PFS). Survival analysis utilized Kaplan-Meier estimates and Cox regression models. Results The LT+TKI+ICI group demonstrated significantly improved survival outcomes compared to the LT+TKI group. Median OS was 28 ± 3.9 months in the LT+TKI+ICI group versus 21 ± 3.0 months in the LT+TKI group, with corresponding 6-, 12-, and 24-month OS rates of 96.8%, 79.3%, and 59.4% versus 85.8%, 71.5%, and 44.1%, respectively (HR, 0.64; 95% CI, 0.449-0.913; P = 0.014). Median PFS also favored the LT+TKI+ICI group (11 ± 1.1 months vs. 7 ± 0.76 months; HR, 0.60; 95% CI, 0.452-0.805; P<0.001). Multivariable analysis identified LT+TKI, vascular invasion, and metastasis as independent risk factors for poorer survival outcomes. Conclusions Adding ICI to LT and TKI significantly extends both OS and PFS in patients with unresectable HCC. These findings suggest that integrating ICI into treatment protocols could be beneficial in managing unresectable HCC, particularly for patients with vascular invasion.
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Affiliation(s)
- Junfeng Bu
- Department of Liver Surgery, West China Hospital, Sichuan University, Chengdu, China
| | - Zihan Li
- West China School of Medicine, Sichuan University, Chengdu, China
| | - Die Hu
- Department of Liver Surgery, West China Hospital, Sichuan University, Chengdu, China
| | - Ling Lan
- Department of Liver Surgery, West China Hospital, Sichuan University, Chengdu, China
| | - Jiwei Huang
- Department of Liver Surgery, West China Hospital, Sichuan University, Chengdu, China
| | - Xin Wang
- Department of Radiation Oncology, West China Hospital, Sichuan University, Chengdu, China
| | - Qiu Li
- Department of Medical Oncology, West China Hospital, Sichuan University, Chengdu, China
| | - Jin Zhou
- Department of Liver Surgery, West China Hospital, Sichuan University, Chengdu, China
| | - Yong Zeng
- Department of Liver Surgery, West China Hospital, Sichuan University, Chengdu, China
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Hu X, Zhu H, Shen Y, Rao L, Li J, He X, Xu X. Metal-organic framework nanoparticles activate cGAS-STING pathway to improve radiotherapy sensitivity. J Nanobiotechnology 2025; 23:131. [PMID: 39979917 PMCID: PMC11844015 DOI: 10.1186/s12951-025-03229-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2024] [Accepted: 02/11/2025] [Indexed: 02/22/2025] Open
Abstract
Tumor immunotherapy aims to harness the immune system to identify and eliminate cancer cells. However, its full potential is hindered by the immunosuppressive nature of tumors. Radiotherapy remains a key treatment modality for local tumor control and immunomodulation within the tumor microenvironment. Yet, the efficacy of radiotherapy is often limited by tumor radiosensitivity, and traditional radiosensitizers have shown limited effectiveness in hepatocellular carcinoma (HCC). To address these challenges, we developed a novel multifunctional nanoparticle system, ZIF-8@MnCO@DOX (ZMD), designed to enhance drug delivery to tumor tissues. In the tumor microenvironment, Zn²⁺ and Mn²⁺ ions released from ZMD participate in a Fenton-like reaction, generating reactive oxygen species (ROS) that promote tumor cell death and improve radiosensitivity. Additionally, the release of doxorubicin (DOX)-an anthracycline chemotherapeutic agent-induces DNA damage and apoptosis in cancer cells. The combined action of metal ions and double-stranded DNA (dsDNA) from damaged tumor cells synergistically activates the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway, thereby initiating a robust anti-tumor immune response. Both in vitro and in vivo experiments demonstrated that ZMD effectively activates the cGAS-STING pathway, promotes anti-tumor immune responses, and exerts a potent tumor-killing effect in combination with radiotherapy, leading to regression of both primary tumors and distant metastases. Our work provides a straightforward, safe, and effective strategy for combining immunotherapy with radiotherapy to treat advanced cancer.
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Affiliation(s)
- Xinyao Hu
- Cancer Center, Renmin Hospital of Wuhan University, NO. 99 Zhang Zhidong Road, Wuchang District, Wuhan, 430060, China
- Institute of Chemical Biology, Shenzhen Bay Laboratory, Shenzhen, 518132, China
| | - Hua Zhu
- Department of Neurosurgery, Renmin Hospital of Wuhan University, Wuhan, 430060, China
| | - Yang Shen
- Cancer Center, Renmin Hospital of Wuhan University, NO. 99 Zhang Zhidong Road, Wuchang District, Wuhan, 430060, China
| | - Lang Rao
- Institute of Chemical Biology, Shenzhen Bay Laboratory, Shenzhen, 518132, China
| | - Jiayi Li
- Cancer Center, Renmin Hospital of Wuhan University, NO. 99 Zhang Zhidong Road, Wuchang District, Wuhan, 430060, China
| | - Xiaoqin He
- Cancer Center, Renmin Hospital of Wuhan University, NO. 99 Zhang Zhidong Road, Wuchang District, Wuhan, 430060, China.
| | - Ximing Xu
- Cancer Center, Renmin Hospital of Wuhan University, NO. 99 Zhang Zhidong Road, Wuchang District, Wuhan, 430060, China.
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Xu K, Zhang H, Dai H, Mao W. Machine learning and multi-omics characterization of SLC2A1 as a prognostic factor in hepatocellular carcinoma: SLC2A1 is a prognostic factor in HCC. Gene 2025; 938:149178. [PMID: 39681148 DOI: 10.1016/j.gene.2024.149178] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2024] [Revised: 12/12/2024] [Accepted: 12/13/2024] [Indexed: 12/18/2024]
Abstract
Hepatocellular carcinoma (HCC) is characterized by high incidence, significant mortality, and marked heterogeneity, making accurate molecular subtyping essential for effective treatment. Using multi-omics data from HCC patients, we applied diverse clustering algorithms to identify three HCC subtypes (HSs) with distinct prognostic characteristics. Among these, HS1 emerged as an immune-compromised subtype associated with the poorest prognosis. Additionally, we developed a novel, robust, and highly accurate machine learning-guided prognostic signature (MLPS) by integrating multiple machine learning algorithms and their combinations. Our study also identified SLC2A1, the core gene of MLPS, as being highly expressed during advanced stages of tumor progression. Knockdown experiments demonstrated that reducing SLC2A1 expression significantly suppressed the malignant behavior of HCC cells. Furthermore, SLC2A1 expression was linked to responsiveness to dasatinib and vincristine, suggesting potential therapeutic relevance. MLPS and SLC2A1 offer promising tools for individualized prognosis prediction and targeted therapy in HCC, providing new opportunities to improve patient outcomes.
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Affiliation(s)
- Kangjie Xu
- Zhongda Hospital, Southeast University, Jiangsu Province, Nanjing 210009, PR China; Binhai County People's Hospital, Jiangsu Province, Yancheng 224000, PR China
| | - Houliang Zhang
- Zhongda Hospital, Southeast University, Jiangsu Province, Nanjing 210009, PR China
| | - Hua Dai
- Yangzhou University Clinical Medical College, Jiangsu Key Laboratory of Experimental & Translational Non-coding RNA Research, Jiangsu Province, Yangzhou 225009, PR China.
| | - Weipu Mao
- Zhongda Hospital, Southeast University, Jiangsu Province, Nanjing 210009, PR China; Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA.
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Piao Y, Zhai N, Zhang X, Zhao W, Li M. Post-translational modifications in hepatocellular carcinoma: unlocking new frontiers in immunotherapy. Front Immunol 2025; 16:1554372. [PMID: 40040703 PMCID: PMC11876159 DOI: 10.3389/fimmu.2025.1554372] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2025] [Accepted: 01/31/2025] [Indexed: 03/06/2025] Open
Abstract
Liver cancer, particularly hepatocellular carcinoma (HCC), is one of the most common and aggressive malignancies worldwide. Immunotherapy has shown promising results in treating HCC, but its efficacy is often limited by complex mechanisms of immune evasion. Post-translational modifications (PTMs) of proteins play a critical role in regulating the immune responses within the tumor microenvironment (TME). These modifications influence protein function, stability, and interactions, which either promote or inhibit immune cell activity in cancer. In this mini-review, we explore the diverse PTMs that impact immune evasion in liver cancer, including glycosylation, phosphorylation, acetylation, and ubiquitination. We focus on how these PTMs regulate key immune checkpoint molecules such as PD-L1, CTLA-4, and the TCR complex. Furthermore, we discuss the potential of targeting PTMs in combination with existing immunotherapies to enhance the effectiveness of treatment in HCC. Understanding the role of PTMs in immune regulation may lead to the development of novel therapeutic strategies to overcome resistance to immunotherapy in liver cancer.
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Affiliation(s)
- Yuexian Piao
- Department of Interventional Therapy, First Hospital of Jilin University, Changchun, China
| | - Naicui Zhai
- Core Facility of First Hospital of Jilin University, Changchun, China
| | - Xiaoling Zhang
- Key Laboratory of Organ Regeneration and Transplantation of Ministry of Education, First Hospital of Jilin University, Changchun, China
- National-Local Joint Engineering Laboratory of Animal Models for Human Disease, First Hospital of Jilin University, Changchun, China
| | - Wenjie Zhao
- Key Laboratory of Organ Regeneration and Transplantation of Ministry of Education, First Hospital of Jilin University, Changchun, China
- National-Local Joint Engineering Laboratory of Animal Models for Human Disease, First Hospital of Jilin University, Changchun, China
| | - Min Li
- Department of Interventional Therapy, First Hospital of Jilin University, Changchun, China
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Xiao H, Wang B, Xiong S, Li C, Ding Y, Chao D, Mei B, Shen N, Luo G. Comprehensive Analysis of the Role of Heat Shock Proteins in the Immune Microenvironment and Clinical Significance of Hepatocellular Carcinoma. J Hepatocell Carcinoma 2025; 12:325-342. [PMID: 39991516 PMCID: PMC11844299 DOI: 10.2147/jhc.s495151] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2024] [Accepted: 02/08/2025] [Indexed: 02/25/2025] Open
Abstract
Purpose Hepatocellular carcinoma (HCC) is a prevalent malignancy that not only imposes a substantial financial burden but also significantly impacts the quality of life and overall survival of affected individuals. Heat shock proteins (HSPs) are a protein class with significant involvement in safeguarding and restoring cellular integrity. They help restore proper protein structure by binding to and refolding denatured proteins. However, the specific role of HSPs in HCC requires further investigation. Methods We analyzed the genomic characteristics of HSPs in liver cancer in the TCGA and ICGC databases, and functional enriched analysis of HSPs. Construction of an HSPs-Related Prognostic Model for patients with hepatocellular carcinoma. HSP-related risk score (HRRS) was identified as an independent prognostic factor in patients with hepatocellular carcinoma, and the clinical pathological characteristics and immune microenvironment of high-risk and low-risk groups were compared. Further, we studied HRRS-based liver cancer treatment strategies and confirmed the protein expression of HSPD1 and DNAJC5 in normal liver tissues and hepatocellular carcinoma tissues by collecting human hepatocellular carcinoma tissues. Results We observed elevated expression levels of most HSPs across HCC tissues. In addition, 14 hSPs were found to be related to prognostic significance among HCC patients and utilized to develop HRRS prognostic model for prognosis prediction and risk stratification. The prognostic and immunotherapeutic response predictive value of HRRS was validated utilizing data from TCGA and GEO cohorts. Moreover, we created a nomogram to assess HRRS clinical utility and verified its efficiency through various methods. Through IHC was found that HSPD1 and DNAJC5 were significantly overexpressed in hepatocellular carcinoma tissues. Conclusion Our results lead us to conclude that HCC's development and progression are intimately associated with HSPs, and the HRRS model represents a potentially robust prognostic model that could assist in clinical decision-making regarding chemotherapy and immunotherapy for HCC patients. Moreover, HSPD1 and DNAJC5 have the potential to serve as therapeutic targets for HCC.
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Affiliation(s)
- Han Xiao
- Department of Hepato-Biliary-Pancreatic Surgery, The First Hospital of Jiujiang City, Jiujiang, Jiangxi Province, 332000, People’s Republic of China
- Jiujiang City Key Laboratory of Cell Therapy, The First Hospital of Jiujiang City, Jiujiang, Jiangxi Province, 332000, People’s Republic of China
| | - Ben Wang
- Department of General Surgery, No. 215 hospital of Shaanxi Nuclear Industry, Xianyang, Shannxi Province, 712000, People’s Republic of China
| | - Shaomin Xiong
- Department of Hepato-Biliary-Pancreatic Surgery, The First Hospital of Jiujiang City, Jiujiang, Jiangxi Province, 332000, People’s Republic of China
- Jiujiang City Key Laboratory of Cell Therapy, The First Hospital of Jiujiang City, Jiujiang, Jiangxi Province, 332000, People’s Republic of China
| | - Chunbo Li
- Department of General Surgery, No. 215 hospital of Shaanxi Nuclear Industry, Xianyang, Shannxi Province, 712000, People’s Republic of China
| | - Yanbao Ding
- Department of Hepato-Biliary-Pancreatic Surgery, The First Hospital of Jiujiang City, Jiujiang, Jiangxi Province, 332000, People’s Republic of China
- Jiujiang City Key Laboratory of Cell Therapy, The First Hospital of Jiujiang City, Jiujiang, Jiangxi Province, 332000, People’s Republic of China
| | - Dai Chao
- Department of Hepato-Biliary-Pancreatic Surgery, The First Hospital of Jiujiang City, Jiujiang, Jiangxi Province, 332000, People’s Republic of China
- Jiujiang City Key Laboratory of Cell Therapy, The First Hospital of Jiujiang City, Jiujiang, Jiangxi Province, 332000, People’s Republic of China
| | - Baohua Mei
- Department of Hepato-Biliary-Pancreatic Surgery, The First Hospital of Jiujiang City, Jiujiang, Jiangxi Province, 332000, People’s Republic of China
- Jiujiang City Key Laboratory of Cell Therapy, The First Hospital of Jiujiang City, Jiujiang, Jiangxi Province, 332000, People’s Republic of China
| | - Naiying Shen
- Department of General Surgery, No. 215 hospital of Shaanxi Nuclear Industry, Xianyang, Shannxi Province, 712000, People’s Republic of China
| | - Gang Luo
- Department of Hepato-Biliary-Pancreatic Surgery, The First Hospital of Jiujiang City, Jiujiang, Jiangxi Province, 332000, People’s Republic of China
- Jiujiang City Key Laboratory of Cell Therapy, The First Hospital of Jiujiang City, Jiujiang, Jiangxi Province, 332000, People’s Republic of China
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Guo X, Nie H, Zhang W, Li J, Ge J, Xie B, Hu W, Zhu Y, Zhong N, Zhang X, Zhao X, Wang X, Sun Q, Wei K, Chen X, Ni L, Zhang T, Lu S, Zhang L, Dong C. Contrasting cytotoxic and regulatory T cell responses underlying distinct clinical outcomes to anti-PD-1 plus lenvatinib therapy in cancer. Cancer Cell 2025; 43:248-268.e9. [PMID: 39889705 DOI: 10.1016/j.ccell.2025.01.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/20/2023] [Revised: 09/04/2024] [Accepted: 01/06/2025] [Indexed: 02/03/2025]
Abstract
Combination of anti-PD-1 with lenvatinib showed clinical efficacy in multiple cancers, yet the underlying immunological mechanisms are unclear. Here, we compared T cells in hepatocellular carcinoma (HCC) patients before and after combination treatment using single-cell transcriptomics and T cell receptor (scTCR) clonotype analyses. We found that tumor-infiltrating GZMK+ CD8+ effector/effector memory T (Teff/Tem) cells, showing a favorable response to combination therapy, comprise progenitor exhausted T (Tpex) cells and also unappreciated circulating Tem (cTem) cells enriched with hepatitis B virus (HBV) specificity. Further integrated analyses revealed that cTem cells are specifically associated with responsiveness to the combination therapy, whereas Tpex cells contribute to responses in both combination therapy and anti-PD-1 monotherapy. Notably, an underexplored KIR+ CD8+ T cell subset in the tumor and FOXP3+ CD4+ regulatory T cells are specifically enriched in non-responders after the combination therapy. Our study thus elucidated T cell subsets associated with clinical benefits and resistance in cancer immunotherapy.
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Affiliation(s)
- Xinyi Guo
- Shanghai Immune Therapy Institute, New Cornerstone Science Laboratory, Shanghai Jiao Tong University School of Medicine - Affiliated Renji Hospital, Shanghai 200127, China; Institute for Immunology, Tsinghua-Peking Center for Life Sciences, Tsinghua University, Beijing 100084, China
| | - Hu Nie
- Institute of Cancer Research, Shenzhen Bay Laboratory, Shenzhen, Guangdong 518132, China; State Key Laboratory of Chemical Oncogenomics, Shenzhen Key Laboratory of Chemical Genomics, School of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate School, Shenzhen, Guangdong 518055, China
| | - Wenwen Zhang
- Faculty of Hepato-Pancreato-Biliary Surgery, Chinese PLA General Hospital / Key Laboratory of Digital Hepatobiliary Surgery, PLA / Institute of Hepatobiliary Surgery of Chinese PLA, Beijing 100953, China
| | - Jiesheng Li
- Institute of Cancer Research, Shenzhen Bay Laboratory, Shenzhen, Guangdong 518132, China; State Key Laboratory of Chemical Oncogenomics, Shenzhen Key Laboratory of Chemical Genomics, School of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate School, Shenzhen, Guangdong 518055, China
| | - Jing Ge
- Shanghai Immune Therapy Institute, New Cornerstone Science Laboratory, Shanghai Jiao Tong University School of Medicine - Affiliated Renji Hospital, Shanghai 200127, China
| | - Bowen Xie
- Institute for Immunology, Tsinghua-Peking Center for Life Sciences, Tsinghua University, Beijing 100084, China
| | - Wenbo Hu
- Institute for Immunology, Tsinghua-Peking Center for Life Sciences, Tsinghua University, Beijing 100084, China
| | - Yicheng Zhu
- Shanghai Immune Therapy Institute, New Cornerstone Science Laboratory, Shanghai Jiao Tong University School of Medicine - Affiliated Renji Hospital, Shanghai 200127, China
| | - Na Zhong
- Shenzhen Peacock Biotechnology Co., Ltd, Shenzhen, Guangdong 518112, China
| | - Xinmei Zhang
- Shenzhen Peacock Biotechnology Co., Ltd, Shenzhen, Guangdong 518112, China
| | - Xiaohong Zhao
- Institute for Immunology, Tsinghua-Peking Center for Life Sciences, Tsinghua University, Beijing 100084, China
| | - Xiaoshuang Wang
- Shanghai Immune Therapy Institute, New Cornerstone Science Laboratory, Shanghai Jiao Tong University School of Medicine - Affiliated Renji Hospital, Shanghai 200127, China; Institute for Immunology, Tsinghua-Peking Center for Life Sciences, Tsinghua University, Beijing 100084, China
| | - Qinli Sun
- Institute for Immunology, Tsinghua-Peking Center for Life Sciences, Tsinghua University, Beijing 100084, China
| | - Kun Wei
- Institute for Immunology, Tsinghua-Peking Center for Life Sciences, Tsinghua University, Beijing 100084, China
| | - Xiaoyuan Chen
- Tsinghua Clinical Research Institute, School of Medicine, Tsinghua University, Beijing 100084, China
| | - Ling Ni
- Institute for Immunology, Tsinghua-Peking Center for Life Sciences, Tsinghua University, Beijing 100084, China
| | - Ting Zhang
- Shanghai Immune Therapy Institute, New Cornerstone Science Laboratory, Shanghai Jiao Tong University School of Medicine - Affiliated Renji Hospital, Shanghai 200127, China
| | - Shichun Lu
- Faculty of Hepato-Pancreato-Biliary Surgery, Chinese PLA General Hospital / Key Laboratory of Digital Hepatobiliary Surgery, PLA / Institute of Hepatobiliary Surgery of Chinese PLA, Beijing 100953, China.
| | - Lei Zhang
- Institute of Cancer Research, Shenzhen Bay Laboratory, Shenzhen, Guangdong 518132, China; State Key Laboratory of Chemical Oncogenomics, Shenzhen Key Laboratory of Chemical Genomics, School of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate School, Shenzhen, Guangdong 518055, China; Shenzhen Medical Academy of Research and Translation (SMART), Shenzhen, Guangdong 518107, China.
| | - Chen Dong
- Shanghai Immune Therapy Institute, New Cornerstone Science Laboratory, Shanghai Jiao Tong University School of Medicine - Affiliated Renji Hospital, Shanghai 200127, China; Research Unit of Immune Regulation and Immune Diseases (2022RU001), Chinese Academy of Medical Sciences, Shanghai Jiao Tong University School of Medicine - Affiliated Renji Hospital, Shanghai 200127, China; Westlake University School of Medicine, Hangzhou, Zhejiang 310030, China.
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Gao D, Lu Y, Jiang T, Duan Q, Huang Z. To construct and validate a risk score model of angiogenesis-related genes to predict the prognosis of hepatocellular carcinoma. Sci Rep 2025; 15:4660. [PMID: 39920250 PMCID: PMC11806001 DOI: 10.1038/s41598-025-87459-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2024] [Accepted: 01/20/2025] [Indexed: 02/09/2025] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the most common malignant tumors with high morbidity and mortality worldwide. Angiogenesis is essential for HCC progression and metastasis. Some angiogenesis-related genes promote this process, whereas other antiangiogenic genes inhibit HCC growth and metastasis. Therefore, finding new potential biomarkers for HCC prognosis prediction and treatment is essential. Public RNAseq and clinical data from TCGA and GEO database, download angiogenesis-related genes from the GeneCards, MSigDB database, through the single factor analysis of Cox, LASSO build risk score-Cox regression analysis model and external validation verified from the GEO. Cox regression analysis, Kaplan Meier (KM) curve, ROC curve, and decision-curve analysis will be used to evaluate and examine the risk score prediction effect of the model. GSVA analysis was used to assess the variation of gene sets between groups, and ClBERSOFT, ESTIMATE, and TIMER databases were used to analyze the immune infiltration in the single-cell level analysis of gene expression differences between cells. Finally, in the three pairs of HCC tissues and tissue adjacent to carcinoma by real-time fluorescent quantitative PCR (qRT_PCR) and western blotting (WB) to evaluate angiogenesis-related genes (ATP2A3 AEBP1 PNMA1, PLAT) expression level in HCC, and AEBP1 was knocked out in HCCLM3 cells, which is to study AEBP1 biological function in HCC. We established a prognostic risk assessment model based on 13 significant genes associated with HCC prognosis by Cox analysis and LASSO-Cox regression analysis. The median was used to divide these patients into high-risk and low-risk groups, and the prognosis of the high-risk group was worse than that of the low-risk group. Through the multivariate Cox regression analysis, it was found that the risk score was an independent predictor of overall survival (OS). The GSVA analysis suggested that the predicted high-risk population showed higher activity in the purine, pyrimidine, and riboflavin metabolic pathways. Compared with the low-risk group, the tumor microenvironment in the high-risk group showed a reduction in the number of cells promoting anti-tumor immunity and an increase in the number of cells inhibiting anti-tumor immunity, as well as a reduction in overall immune infiltration and matrix components. On the single-cell level, it was confirmed that the key genes (AEBP1, ATP2A3, PLAT, and PNMA1) expressed differently between liver cancer and adjacent tissue cell groups. Finally, qRT_PCR and WB results showed that ATP2A3, AEBP1, PNMA1, and PLAT were highly expressed in liver cancer tissue compared to adjacent tissue, and the proliferation, migration, and invasion of HCCLM3 cells were inhibited after knocking out AEBP1. We constructed novel risk score models as prognostic biomarkers for HCC, which has the potential to guide the development of more personalized treatment strategies for HCC patients. In addition, AEBP1 is a potential therapeutic target for HCC.
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Affiliation(s)
- Duangui Gao
- Department of Interventional Radiology, The Affiliated Hospital of Guizhou Medical University, No. 9 Beijing Road, Guiyang, 550002, China
- Institute of Image, Guizhou Medical University, Guiyang, China
| | - Yuan Lu
- Institute of Image, Guizhou Medical University, Guiyang, China
| | - Tianpeng Jiang
- Department of Interventional Radiology, The Affiliated Hospital of Guizhou Medical University, No. 9 Beijing Road, Guiyang, 550002, China
- Institute of Image, Guizhou Medical University, Guiyang, China
| | - Qinghong Duan
- Institute of Image, Guizhou Medical University, Guiyang, China.
- Department of Radiology, The Affiliated Cancer Hospital of Guizhou Medical University, No. 1 Beijing West Road, Guiyang, 550002, China.
| | - Zhi Huang
- Department of Interventional Radiology, The Affiliated Hospital of Guizhou Medical University, No. 9 Beijing Road, Guiyang, 550002, China.
- Institute of Image, Guizhou Medical University, Guiyang, China.
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Kim DH, Kim EM, Lee JS, Kim MN, Kim BK, Kim SU, Park JY, Choi GH, Ahn SH, Lee HW, Kim DY. Cytokine-Induced Killer Cell Immunotherapy Reduces Recurrence in Patients with Early-Stage Hepatocellular Carcinoma. Cancers (Basel) 2025; 17:566. [PMID: 40002160 PMCID: PMC11853259 DOI: 10.3390/cancers17040566] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2024] [Revised: 02/05/2025] [Accepted: 02/06/2025] [Indexed: 02/27/2025] Open
Abstract
BACKGROUND/OBJECTIVES Cytokine-induced killer (CIK) cell immunotherapy has shown promise in reducing recurrence and improving survival outcomes in hepatocellular carcinoma (HCC). We evaluated the efficacy and safety of CIK cell therapy in a real-world clinical setting. METHODS A retrospective analysis was conducted on 49 patients who received CIK cell therapy after curative resection or radiofrequency ablation, compared with 49 matched control patients via 1:1 propensity score matching. The primary endpoint was recurrence-free survival (RFS), and the secondary endpoint was overall survival (OS). RESULTS The median follow-up durations were 19.1 months for the immune cell group and 67.7 months for the control group. In univariable analysis, the immune cell group demonstrated a prolonged RFS than the control group (hazard ratio [HR], 0.32; 95% CI, 0.15-0.71; log-rank p = 0.001). The median RFS was not reached in the immune cell group but was 48.62 months in the control group. A multivariable Cox regression model identified CIK cell therapy as a significant factor associated with a reduced risk of HCC recurrence (adjusted HR, 0.32; 95% CI, 0.15-0.71; p = 0.005). The median OS was not reached in either group; no significant differences in OS were observed between the immune cell and control groups (log-rank p = 0.082). The overall incidence of adverse events was low, and no Grade 3 or 4 events were reported. CONCLUSIONS Adjuvant CIK cell immunotherapy after curative treatment significantly prolongs RFS in early-stage HCC patients. Further research regarding the broader applications of CIK cell immunotherapy in HCC is warranted.
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Affiliation(s)
- Dong Hyun Kim
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul 03722, Republic of Korea; (D.H.K.); (E.M.K.); (J.S.L.); (M.N.K.); (B.K.K.); (S.U.K.); (J.Y.P.); (S.H.A.)
| | - Eun Min Kim
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul 03722, Republic of Korea; (D.H.K.); (E.M.K.); (J.S.L.); (M.N.K.); (B.K.K.); (S.U.K.); (J.Y.P.); (S.H.A.)
| | - Jae Seung Lee
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul 03722, Republic of Korea; (D.H.K.); (E.M.K.); (J.S.L.); (M.N.K.); (B.K.K.); (S.U.K.); (J.Y.P.); (S.H.A.)
- Institute of Gastroenterology, Yonsei University College of Medicine, Seoul 03722, Republic of Korea
- Yonsei Liver Center, Severance Hospital, Seoul 03722, Republic of Korea
| | - Mi Na Kim
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul 03722, Republic of Korea; (D.H.K.); (E.M.K.); (J.S.L.); (M.N.K.); (B.K.K.); (S.U.K.); (J.Y.P.); (S.H.A.)
- Institute of Gastroenterology, Yonsei University College of Medicine, Seoul 03722, Republic of Korea
- Yonsei Liver Center, Severance Hospital, Seoul 03722, Republic of Korea
| | - Beom Kyung Kim
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul 03722, Republic of Korea; (D.H.K.); (E.M.K.); (J.S.L.); (M.N.K.); (B.K.K.); (S.U.K.); (J.Y.P.); (S.H.A.)
- Institute of Gastroenterology, Yonsei University College of Medicine, Seoul 03722, Republic of Korea
- Yonsei Liver Center, Severance Hospital, Seoul 03722, Republic of Korea
| | - Seung Up Kim
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul 03722, Republic of Korea; (D.H.K.); (E.M.K.); (J.S.L.); (M.N.K.); (B.K.K.); (S.U.K.); (J.Y.P.); (S.H.A.)
- Institute of Gastroenterology, Yonsei University College of Medicine, Seoul 03722, Republic of Korea
- Yonsei Liver Center, Severance Hospital, Seoul 03722, Republic of Korea
| | - Jun Yong Park
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul 03722, Republic of Korea; (D.H.K.); (E.M.K.); (J.S.L.); (M.N.K.); (B.K.K.); (S.U.K.); (J.Y.P.); (S.H.A.)
- Institute of Gastroenterology, Yonsei University College of Medicine, Seoul 03722, Republic of Korea
- Yonsei Liver Center, Severance Hospital, Seoul 03722, Republic of Korea
| | - Gi Hong Choi
- Department of Surgery, Yonsei University College of Medicine, Seoul 03722, Republic of Korea;
| | - Sang Hoon Ahn
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul 03722, Republic of Korea; (D.H.K.); (E.M.K.); (J.S.L.); (M.N.K.); (B.K.K.); (S.U.K.); (J.Y.P.); (S.H.A.)
- Institute of Gastroenterology, Yonsei University College of Medicine, Seoul 03722, Republic of Korea
- Yonsei Liver Center, Severance Hospital, Seoul 03722, Republic of Korea
| | - Hye Won Lee
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul 03722, Republic of Korea; (D.H.K.); (E.M.K.); (J.S.L.); (M.N.K.); (B.K.K.); (S.U.K.); (J.Y.P.); (S.H.A.)
- Institute of Gastroenterology, Yonsei University College of Medicine, Seoul 03722, Republic of Korea
- Yonsei Liver Center, Severance Hospital, Seoul 03722, Republic of Korea
| | - Do Young Kim
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul 03722, Republic of Korea; (D.H.K.); (E.M.K.); (J.S.L.); (M.N.K.); (B.K.K.); (S.U.K.); (J.Y.P.); (S.H.A.)
- Institute of Gastroenterology, Yonsei University College of Medicine, Seoul 03722, Republic of Korea
- Yonsei Liver Center, Severance Hospital, Seoul 03722, Republic of Korea
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Liu X, Pan B, Ding J, Zhai X, Hong J, Zheng J. Identifying potential signatures of immune cells in hepatocellular carcinoma using integrative bioinformatics approaches and machine-learning strategies. Immunol Res 2025; 73:46. [PMID: 39904830 DOI: 10.1007/s12026-024-09585-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2023] [Accepted: 12/24/2024] [Indexed: 02/06/2025]
Abstract
Hepatocellular carcinoma (HCC) is a malignant tumor regulated by the immune system. Immunotherapy using checkpoint inhibitors has shown encouraging outcomes in a subset of HCC patients. The main challenges in checkpoint immunotherapy for HCC are to expand treatment options and to broaden the beneficiary population. Therefore, the search for potential signatures of immune cells is meaningful in the development of immunotherapy for HCC. The HCC related datasets were downloaded from the Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA). Differential expression analysis and functional analysis were performed first. Then support vector machine-recursive feature elimination (SVM-RFE), random forests (RF), least absolute shrinkage and selection operation (LASSO), and weighed gene co-expression network analysis (WGCNA) were employed to screen for critical genes, and receiver operating characteristic (ROC) analysis was performed to compare diagnostic performance. Subsequently, single-sample gene set enrichment analysis (ssGSEA) was used to explore the relationship between signatures and immune cells. Finally, we validated the expression of these biomarkers in human HCC samples. 531 overlapping differentially expressed genes (DEGs) were identified. Furthermore, enrichment analysis revealed pathways associated with immune activation processes, immune cell involvement and inflammatory signaling. After using multiple machine-learning strategies, extracellular matrix protein 1 (ECM1), leukemia inhibitory factor receptor (LIFR), sushi repeat containing protein X-linked (SRPX), and thromboxane A2 receptor (TBXA2R) were identified as critical signatures, and exhibited high expression in tumor-adjacent normal tissues. According to the ssGSEA results, ECM1, LIFR, SRPX and TBXA2R were all significantly associated with diverse immune cells, such as monocytes and neutrophils. Moreover, immunostaining of human HCC samples showed that these critical signatures all colocalized with CD14-positive monocytes. Our findings report the potential signatures of immune cells in HCC and confirm that they localize in monocytes of tumor-adjacent normal tissues. ECM1, LIFR, SRPX and TBXA2R could become new potential targets for predictive diagnosis, early intervention and immunotherapy of HCC in the future.
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Affiliation(s)
- Xingchen Liu
- Department of Pathology, The First Affiliated Hospital of Naval Medical University, Shanghai, 200433, China
| | - Bo Pan
- Department of Integrative Oncology, The First Affiliated Hospital of Naval Medical University, Shanghai, 200433, China
- School of Traditional Chinese Medicine, Naval Medical University, Shanghai, 200433, China
| | - Jie Ding
- Department of Gynecology of Traditional Chinese Medicine, The First Affiliated Hospital of Naval Medical University, Shanghai, 200433, China
| | - Xiaofeng Zhai
- Department of Integrative Oncology, The First Affiliated Hospital of Naval Medical University, Shanghai, 200433, China.
- School of Traditional Chinese Medicine, Naval Medical University, Shanghai, 200433, China.
| | - Jing Hong
- Department of Integration of Chinese and Western Medicine, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, Beijing, 100142, China.
- Department of Integrative Oncology, The First Affiliated Hospital of Naval Medical University, Shanghai, 200433, China.
- School of Traditional Chinese Medicine, Naval Medical University, Shanghai, 200433, China.
| | - Jianming Zheng
- Department of Pathology, The First Affiliated Hospital of Naval Medical University, Shanghai, 200433, China.
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Kim J, Seki E. Inflammation and Immunity in Liver Neoplasms: Implications for Future Therapeutic Strategies. Mol Cancer Ther 2025; 24:188-199. [PMID: 39365846 PMCID: PMC11794036 DOI: 10.1158/1535-7163.mct-23-0726] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2024] [Revised: 07/28/2024] [Accepted: 08/09/2024] [Indexed: 10/06/2024]
Abstract
Over the past two decades, the "hallmarks of cancer" have revolutionized cancer research and highlighted the crucial roles of inflammation and immunity. Protumorigenic inflammation promotes cancer development along with inhibition of antitumor immunity, shaping the tumor microenvironment (TME) toward a tumor-permissive state and further enhancing the malignant potential of cancer cells. This immunosuppressive TME allows tumors to evade immunosurveillance. Thus, understanding the complex interplay between tumors and the immune system within the TME has become pivotal, especially with the advent of immunotherapy. Although immunotherapy has achieved notable success in many malignancies, primary liver cancer, particularly hepatocellular carcinoma, presents unique challenges. The hepatic immunosuppressive environment poses obstacles to the effectiveness of immunotherapy, along with high mortality rates and limited treatment options for patients with liver cancer. In this review, we discuss current understanding of the complex immune-mediated mechanisms underlying liver neoplasms, focusing on hepatocellular carcinoma and liver metastases. We describe the molecular and cellular heterogeneity within the TME, highlighting how this presents unique challenges and opportunities for immunotherapy in liver cancers. By unraveling the immune landscape of liver neoplasms, this review aims to contribute to the development of more effective therapeutic interventions, ultimately improving clinical outcomes for patients with liver cancer.
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Affiliation(s)
- Jieun Kim
- Karsh Division of Gastroenterology Hepatology, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
| | - Ekihiro Seki
- Karsh Division of Gastroenterology Hepatology, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
- Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
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Chen Z, Xie T, Chen S, Li Z, Yao S, Lu X, He W, Tang C, Yang D, Li S, Shi F, Lin H, Li Z, Madabhushi A, Zhao X, Liu Z, Lu C. AI-based tumor-infiltrating lymphocyte scoring system for assessing HCC prognosis in patients undergoing liver resection. JHEP Rep 2025; 7:101270. [PMID: 39927235 PMCID: PMC11803844 DOI: 10.1016/j.jhepr.2024.101270] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/20/2024] [Revised: 10/22/2024] [Accepted: 11/04/2024] [Indexed: 02/11/2025] Open
Abstract
Background & Aims Tumor-infiltrating lymphocytes (TILs), particularly CD8+ TILs, are key prognostic markers in many cancers. However, their prognostic value in hepatocellular carcinoma (HCC) remains controversial, with different evidence. Given the heterogeneous outcomes in patients with HCC undergoing liver resection, this study aims to develop an AI-based system to quantify CD8+ TILs and assess their prognostic value for patients with HCC. Methods We conducted a retrospective multicenter study on patients undergoing liver resection across three cohorts (N = 514). We trained a deep neural network and a random forest model to segment tumor regions and locate CD8+ TILs in H&E and CD8-stained whole-slide images. We quantified CD8+ TIL density and established an Automated CD8+ Tumor-infiltrating Lymphocyte Scoring (ATLS-8) system to assess its prognostic value. Results In the discovery cohort, the 5-year overall survival (OS) rates were 34.05% for ATLS-8 low-score and 65.03% for ATLS-8 high-score groups (hazard ratio [HR] 2.40; 95% CI, 1.37-4.19; p = 0.015). These findings were confirmed in validation cohort 1, which had 5-year OS rates of 28.57% and 68.73% (HR 3.38; 95% CI, 1.27-9.02; p = 0.0098), and validation cohort 2, which had 59.26% and 81.48% (HR 2.74; 95% CI, 1.05-7.15; p = 0.031). ATLS-8 improved the prognostic model based on clinical variables (C-index 0.770 vs. 0.757; 0.769 vs. 0.727; 0.712 vs. 0.642 in three cohorts). Conclusions We developed an automated system using CD8-stained whole-slide images to assess immune infiltration (ATLS-8). In patients with HCC undergoing resection, higher CD8+ TIL density correlates with better OS, as per ATLS-8 assessment. This system is a promising tool for advancing clinical immune microenvironment assessment and outcome prediction. Impact and implications CD8+ tumor-infiltrating lymphocytes (TILs) have been identified as a prognostic factor associated with many cancers. In this study, CD8+ TILs were identified as an independent prognostic factor for overall survival in patients with hepatocellular carcinoma who undergoing liver resection. Therefore, ATLS-8, a novel digital biomarker based on whole-slide image-level CD8+ TILs, could play an important role in the prognostic assessment of patients with HCC and could be integrated into clinicopathological models to participate in the decision-making and prognostic assessment of patients. The scoring system combined with artificial intelligence is essential for automated, quantitative, whole-slide image-level assessment of TILs, which can be widely applied to quantify the immune profile of multi-cancer disease types with the discussion of subsequent immunotherapy.
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Affiliation(s)
- Zhiyang Chen
- Department of Radiology, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, China
- Guangdong Provincial Key Laboratory of Artificial Intelligence in Medical Image Analysis and Application, Guangzhou, China
- School of Clinical Dentistry, University of Sheffield, Sheffield, UK
| | - Tingting Xie
- Medical Imaging Center, Peking University Shenzhen Hospital, Shenzhen, Guangdong, China
| | - Shuting Chen
- Department of Radiology, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, China
| | - Zhenhui Li
- Department of Radiology, The Third Affiliated Hospital of Kunming Medical University, Yunnan Cancer Hospital, Yunnan Cancer Center, Kunming, Yunnan, China
| | - Su Yao
- Department of Pathology, Guangdong Provincial People’s Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, China
| | - Xuanjun Lu
- School of Electronics Engineering, Xi’an Shiyou University, Xi’an, China
| | - Wenfeng He
- Department of Radiology, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, China
- Guangdong Provincial Key Laboratory of Artificial Intelligence in Medical Image Analysis and Application, Guangzhou, China
| | - Chao Tang
- Department of Radiology, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, China
- Guangdong Provincial Key Laboratory of Artificial Intelligence in Medical Image Analysis and Application, Guangzhou, China
- College of Information Engineering, Northwest A&F University, Yangling, Shaanxi, China
| | - Dacheng Yang
- Medical Research Institute, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou China
| | - Shaohua Li
- Department of Liver Surgery, Sun Yat-Sen University Cancer Center, Guangzhou, China
| | - Feng Shi
- Department of Interventional Radiology, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Southern Medical University, Guangzhou, China
| | - Huan Lin
- Department of Radiology, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, China
| | - Zipei Li
- School of Computer Science, University of St Andrews, Fife, UK
| | - Anant Madabhushi
- Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, GA, USA
- Radiology and Imaging Sciences, Biomedical Informatics (BMI) and Pathology, Georgia Institute of Technology and Emory University, Atlanta, GA, USA
- Atlanta Veterans Administration Medical Center, Atlanta, GA, USA
| | - Xiangtian Zhao
- Department of Radiology, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, China
| | - Zaiyi Liu
- Department of Radiology, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, China
- Guangdong Provincial Key Laboratory of Artificial Intelligence in Medical Image Analysis and Application, Guangzhou, China
| | - Cheng Lu
- Department of Radiology, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, China
- Guangdong Provincial Key Laboratory of Artificial Intelligence in Medical Image Analysis and Application, Guangzhou, China
- Medical Research Institute, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou China
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Yu S, Zhao Y, Liu Q, Wang J, Fu J, Li R, Yuan Y, Yan X, Su J. Spermidine synthase promotes liver cancer progression in a paracrine manner by altering the macrophage immunometabolic state. Bioorg Chem 2025; 155:108135. [PMID: 39793221 DOI: 10.1016/j.bioorg.2025.108135] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2024] [Revised: 11/03/2024] [Accepted: 01/03/2025] [Indexed: 01/13/2025]
Abstract
PURPOSE Understanding the molecular mechanisms of adaptive regulation in the tumor microenvironment is crucial for precision therapy in hepatocellular carcinoma (HCC). We hypothesized that cargo proteins carried by extracellular vesicles (EVs) released in a hypoxic microenvironment might promote HCC progression by remodeling tumor-associated macrophages (TAMs). METHODS EV protein analysis by label-free proteomics mass spectrometry of HCC cell lines of different tumor grades was performed. The promotional effect if spermidine synthase（SRM） on M2 polarized TAMs was further investigated using various biological approaches. RESULTS SRM expression was positively correlated with liver cancer progression in HCC cell lines, liver cancer samples, and nude mouse models. In a mouse model, SRM expression was positively correlated with TAM infiltration and liver cancer progression. Pan-cancer dataset analysis confirmed that SRM overexpression in HCC tumors is correlated with poor patient prognosis. However, a hypoxic microenvironment is an internal driving factor for exosomal SRM that participates in microenvironmental modifications. Moreover, we defined a hitherto unknown pattern of microenvironmental crosstalk involving SRM in EVs, whereby macrophages complete the phenotypic fate of M2 tumor-associated macrophages through SRM uptake. CONCLUSION SRM regulation within the immune microenvironment is metabolically driven. By upregulating spermidine, which serves as a substrate for eIF5A hypusination, excessive oxidative phosphorylation (OXPHOS) assembly is achieved. This, in turn, leads to the expression of immunosuppressive marker molecules and ultimately promotes liver cancer progression. SRM, which is enriched in the EVs of HCC cells under hypoxic conditions, acts as a potent regulator linking polyamine and energy metabolism in TAMs, thereby promoting liver cancer progression.
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Affiliation(s)
- Sihang Yu
- Key Laboratory of Pathobiology Ministry of Education Department of Pathophysiology College of Basic Medical Sciences Jilin University Changchun China
| | - Yuanxin Zhao
- Key Laboratory of Pathobiology Ministry of Education Department of Pathophysiology College of Basic Medical Sciences Jilin University Changchun China
| | - Qingqing Liu
- Key Laboratory of Pathobiology Ministry of Education Department of Pathophysiology College of Basic Medical Sciences Jilin University Changchun China
| | - Jian Wang
- Key Laboratory of Pathobiology Ministry of Education Department of Pathophysiology College of Basic Medical Sciences Jilin University Changchun China
| | - Jiaying Fu
- Key Laboratory of Pathobiology Ministry of Education Department of Pathophysiology College of Basic Medical Sciences Jilin University Changchun China
| | - Runyuan Li
- Key Laboratory of Pathobiology Ministry of Education Department of Pathophysiology College of Basic Medical Sciences Jilin University Changchun China
| | - Yuan Yuan
- Key Laboratory of Pathobiology Ministry of Education Department of Pathophysiology College of Basic Medical Sciences Jilin University Changchun China
| | - Xiaoyu Yan
- Key Laboratory of Pathobiology Ministry of Education Department of Pathophysiology College of Basic Medical Sciences Jilin University Changchun China
| | - Jing Su
- Key Laboratory of Pathobiology Ministry of Education Department of Pathophysiology College of Basic Medical Sciences Jilin University Changchun China.
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Li G, Zhang G, Li J, Zhang J, Yang Z, Yang L, Wang J. High mobility group protein N2 inhibits the progression of hepatocellular carcinoma and the related molecular mechanisms. Cytotechnology 2025; 77:20. [PMID: 39676764 PMCID: PMC11638430 DOI: 10.1007/s10616-024-00678-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2024] [Accepted: 12/02/2024] [Indexed: 12/17/2024] Open
Abstract
High mobility group protein N2 (HMGN2) related pathways are involved in chromatin regulation/acetylation. It has been reported to be involved in several types of cancers. A recent sequencing study suggested that HMGN2 might be involved in the progression of hepatocellular carcinoma (HCC). This study aimed to explore the role of HMGN2 in HCC, which has been proven to be involved in the development of HCC. In this study, we collected clinical samples and cultured normal hepatocytes and hepatocellular carcinoma cell lines to detect HMGN2 expression levels using reverse transcriptase quantitative polymerase chain reaction (RT-qPCR) and western blot assay. Subsequently, to determine the role of HMGN2 in HCC, HMGN2 was overexpressed in HCC cell lines. MTT (3-(4,5)-dimethylthiahiazo (-z-y1)-3,5-di- phenytetrazoliumromide) assay was used to detect the cell proliferative capacity, and proliferation-related proteins were detected by RT-qPCR and western blot assay. To observe the effect of HMGN2 on cell migration and invasion capacity, Transwell assay was performed. Then, cell apoptosis was detected by flow cytometry, and caspase3 and cleaved-caspase3 were detected using western blot assay. Finally, EMT (epithelial to mesenchymal transition)-related proteins, and matrix metalloproteinase-2 (MMP-2) and MMP-9 expression were detected by RT-qPCR and western blot assay. HMGN2 expression was decreased in HCC tissues as well as in HCC cell lines. After overexpression of HMGN2, MTT results suggested that cell proliferation was decreased, and flow cytometry results showed that the apoptosis level was increased and ki-67 and proliferating cell nuclear antigen (PCNA) expression levels were decreased. On the contrary, cleaved-caspase 3 expression level was increased. HCC cells overexpressing HMGN2 showed a drastic reduction in the number of migrating and invading cells, and the expression levels of MMP-2 and MMP-9 were significantly decreased. Finally, E-cadherin expression was elevated in HCC cells transfected with the HMGN2-plasmid, while N-cadherin showed the opposite result. HMGN2 expression was significantly decreased in patients with HCC. HMGN2 inhibits the malignant behavior of HCC cells and is a potential therapeutic target for HCC.
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Affiliation(s)
- Gang Li
- Department of Hepatobiliary Vascular Surgery, Chengdu Seventh People’s Hospital, Chengdu, 610000 China
| | - Guanbo Zhang
- Department of Hepatobiliary Vascular Surgery, Chengdu Seventh People’s Hospital, Chengdu, 610000 China
| | - Jinsong Li
- Department of Hepatobiliary Vascular Surgery, Chengdu Seventh People’s Hospital, Chengdu, 610000 China
| | - Jie Zhang
- Department of Hepatobiliary Vascular Surgery, Chengdu Seventh People’s Hospital, Chengdu, 610000 China
| | - Zhi Yang
- Department of Hepatobiliary Vascular Surgery, Chengdu Seventh People’s Hospital, Chengdu, 610000 China
| | - Lin Yang
- Department of Hepatobiliary Vascular Surgery, Chengdu Seventh People’s Hospital, Chengdu, 610000 China
| | - Jiaxing Wang
- Department of Hepatobiliary Vascular Surgery, Chengdu Seventh People’s Hospital, Chengdu, 610000 China
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Chen Y, Wang K, Zhang X, Tao D, Shang Y, Wang P, Li Q, Liu Y. Prognostic model development using novel genetic signature associated with adenosine metabolism and immune status for patients with hepatocellular carcinoma. J Physiol Biochem 2025; 81:157-172. [PMID: 39546272 PMCID: PMC11958414 DOI: 10.1007/s13105-024-01061-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2024] [Accepted: 11/06/2024] [Indexed: 11/17/2024]
Abstract
The high mortality rate of hepatocellular carcinoma (HCC) is partly due to advanced diagnosis, emphasizing the need for effective predictive tools in HCC treatment. The aim of this study is to propose a novel prognostic model for HCC based on adenosine metabolizing genes and explore the potential relationship between them. Regression analysis was performed to identify differentially expressed genes associated with adenosine metabolism in HCC patients using RNA sequencing data obtained from a public database. Adenosine metabolism-related risk score (AMrisk) was derived using the least absolute shrinkage and selection operator (LASSO) Cox regression and verified using another database. Changes in adenosine metabolism in HCC were analyzed using functional enrichment analysis and multiple immune scores. The gene expression levels in patient samples were validated using quantitative reverse transcription polymerase chain reaction. Thirty adenosine metabolism-related differentially expressed genes were identified in HCC, and six genes (ADA, P2RY4, P2RY6, RPIA, SLC6A3, and VEGFA) were used to calculate the AMrisk score; the higher the risk scores, the lower the overall survival. Moreover, immune infiltration activation and immune checkpoints were considerably higher in the high-risk group. Additional in vitro experiments validated the enhanced expression of these six genes in HCC. The established predictive model demonstrated that adenosine metabolism-related genes was significantly associated with prognosis in HCC patients.
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Affiliation(s)
- Yidan Chen
- National Clinical Research Center for Digestive Diseases and Xijing Hospital of Digestive Diseases, Xijing Hospital, Air Force Medical University, Xi'an, China
- School of Basic Medicine, Air Force Medical University, Xi'an, China
| | - Kemei Wang
- National Clinical Research Center for Digestive Diseases and Xijing Hospital of Digestive Diseases, Xijing Hospital, Air Force Medical University, Xi'an, China
| | - Xingyun Zhang
- Department of General Medicine, Xijing Hospital, Air Force Medical University, Xi'an, China
| | - Dongying Tao
- Department of Pediatric, Xijing Hospital, Air Force Medical University, Xi'an, China
| | - Yulong Shang
- National Clinical Research Center for Digestive Diseases and Xijing Hospital of Digestive Diseases, Xijing Hospital, Air Force Medical University, Xi'an, China
| | - Ping Wang
- Department of Gastroenterology, Dongying People's Hospital, Dongying, China.
| | - Qiang Li
- National Clinical Research Center for Digestive Diseases and Xijing Hospital of Digestive Diseases, Xijing Hospital, Air Force Medical University, Xi'an, China.
- Department of General Medicine, Xijing Hospital, Air Force Medical University, Xi'an, China.
| | - Yansheng Liu
- National Clinical Research Center for Digestive Diseases and Xijing Hospital of Digestive Diseases, Xijing Hospital, Air Force Medical University, Xi'an, China.
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Lou Y, Zhang X, Sun P, Chang X. Hepatic Arterial Infusion Chemotherapy Enhances the Efficacy of Lenvatinib Plus PD-1 Inhibitors in Hepatocellular Carcinoma Patients with Tumor Thrombosis in the Inferior Vena Cava and/or Right Atrium. Acad Radiol 2025; 32:787-797. [PMID: 39278760 DOI: 10.1016/j.acra.2024.08.058] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2024] [Revised: 08/23/2024] [Accepted: 08/30/2024] [Indexed: 09/18/2024]
Abstract
RATIONALE AND OBJECTIVES Hepatocellular carcinoma (HCC) with invasion into the inferior vena cava (IVC) or the right atrium (RA) presents significant therapeutic challenges due to its rapid progression and limited available treatments. MATERIALS AND METHODS This retrospective study evaluated the effectiveness of hepatic arterial infusion chemotherapy alongside lenvatinib and PD-1 inhibitors (HAIC-Len-PD1) compared to treatment with only lenvatinib and PD-1 inhibitors (Len-PD1). A total of 115 patients with HCC and IVC or RA invasion were included. We analyzed groups for median overall survival (OS) and progression-free survival (PFS) through the Kaplan-Meier method, along with tumor response rates, disease control rates, and adverse event frequencies. RESULTS The HAIC-Len-PD1 treatment showed a marked improvement in median OS (22.2 vs. 14.4 months; P = 0.007) and median PFS (13.8 vs. 5.1 months; P = 0.001) over the Len-PD1 regimen. There was also a higher overall response rate (68.7% vs. 37.5%; P < 0.05) and disease control rate (92.5% vs. 75%; P < 0.05) observed in the HAIC-Len-PD1 group. A subgroup analysis demonstrated consistent survival benefits across diverse patient demographics. Although the incidence of adverse events was higher in the HAIC-Len-PD1 group, these were generally manageable and well-tolerated. CONCLUSION The combined regimen of HAIC, lenvatinib, and PD-1 inhibitors may improve survival and tumor management in HCC patients with IVC or RA invasion, suggesting a potential therapeutic option for this critically at-risk group. Further research in the form of randomized controlled trials are needed to verify these findings for advanced-stage HCC with vascular compromise.
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Affiliation(s)
- Yidan Lou
- Department of Oncology, Hangzhou First People's Hospital, Hangzhou 310006, China; Zhejiang University School of Medicine, Hangzhou 310006, China
| | - Xiaoling Zhang
- Department of Oncology, Hangzhou First People's Hospital, Hangzhou 310006, China; Key Laboratory of Clinical Cancer Pharmacology and Toxicology Research of Zhejiang Province, Affiliated Hangzhou First People's Hospital, Westlake University, Hangzhou 310006, China
| | - Pengfei Sun
- Department of Hepatological Surgery, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong 250117, China
| | - Xu Chang
- Department of Interventional Therapy II, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, China.
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Bredin P, Galvin Z, O'Kane GM. Role of immunotherapy in managing cancers prior to liver transplantation. Curr Opin Organ Transplant 2025; 30:3-11. [PMID: 39620576 DOI: 10.1097/mot.0000000000001187] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2024]
Abstract
PURPOSE OF REVIEW Immune checkpoint inhibitors (ICIs) have transformed the treatment landscape in advanced hepatocellular carcinoma and increasingly are being evaluated in earlier stage disease. Herein we explore the role of ICIs pre-liver transplant for liver cancers. RECENT FINDINGS Given the high response rates with combination approaches including locoregional treatments, more patients with liver confined disease, without vascular invasion, who have received ICIs are now being rendered eligible for potential liver transplant. This opportunity to expand the population who may benefit from liver transplant has also come with challenges recognizing the global shortage of organs. Post-liver transplant immunosuppression potentially competes with the immune-stimulating effects of ICIs and graft rejection has been a concern. ICIs may provide an opportunity to maintain patients on the waiting list but an understanding of who is likely to benefit is needed, to circumvent possible toxicities. In addition, ICIs are now considered standard of care, in combination with chemotherapy, for advanced cholangiocarcinoma, where the role of liver transplant is evolving. SUMMARY As the eligibility criteria globally for liver transplant in the setting of malignancy continues to expand, the integration of ICIs becomes increasingly important.
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Affiliation(s)
| | - Zita Galvin
- St Vincent's University Hospital, Elm Park
- University College Dublin, Ireland
| | - Grainne M O'Kane
- St Vincent's University Hospital, Elm Park
- University College Dublin, Ireland
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Tabrizian P, Pero A, Schwartz M. Hepatic Resection for Hepatocellular Carcinoma. Clin Liver Dis 2025; 29:59-72. [PMID: 39608958 DOI: 10.1016/j.cld.2024.08.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2024]
Abstract
Hepatic resection has long been considered the preferred treatment for hepatocellular carcinoma (HCC) when feasible, but its role, as well as the outcomes is evolving rapidly. This article explores the impact of the changing demographics of HCC, reviews current criteria for resection, considers the roles of liver transplantation and nonsurgical locoregional therapies vis-a-vis resection, highlights the potential of new systemic therapies (particularly immune checkpoint inhibitors) to improve outcomes, details the common complications associated with resection, and discusses recurrence of HCC after resection and its management.
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Affiliation(s)
- Parissa Tabrizian
- Recanati-Miller Transplantation Institute, Icahn School of Medicine at Mount Sinai, 1 Gustave Levy Place, New York, NY 10029, USA
| | - Adriana Pero
- Icahn School of Medicine at Mount Sinai, 1 Gustave Levy Place, New York, NY 10029, USA
| | - Myron Schwartz
- Recanati-Miller Transplantation Institute, Icahn School of Medicine at Mount Sinai, 1 Gustave Levy Place, New York, NY 10029, USA.
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Ascari S, Chen R, Vivaldi C, Stefanini B, De Sinno A, Dalbeni A, Federico P, Tovoli F. Advancements in immunotherapy for hepatocellular carcinoma. Expert Rev Anticancer Ther 2025; 25:151-165. [PMID: 39913170 DOI: 10.1080/14737140.2025.2461631] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2024] [Revised: 01/28/2025] [Accepted: 01/29/2025] [Indexed: 02/07/2025]
Abstract
INTRODUCTION The advent of immune-based combinations, primarily leveraging immune checkpoint inhibitors, has revolutionized the therapeutic landscape of hepatocellular carcinoma (HCC). The current scenario features multiple therapies that have shown superiority over tyrosine kinase inhibitors; however, the absence of direct comparisons and validated prognostic biomarkers complicates therapeutic decision-making. Additionally, a significant proportion of patients still exhibit primary or secondary resistance to existing immunotherapies, underscoring the ongoing need for novel therapeutic strategies. AREAS COVERED This narrative review discusses current strategies aimed at improving the efficacy of immunotherapy for HCC, focusing on the following aspects: available therapeutic options, identification of prognostic biomarkers, approaches to overcoming resistance (including the development of neoantigen vaccines), and the exploration of adjuvant and neoadjuvant strategies. EXPERT OPINION The future of systemic therapies for HCC is likely to be driven by advancements in immunotherapy. Key areas of exploration for the coming years include the discovery of novel checkpoint inhibitors or complementary agents to enhance tumor response when combined with existing treatments, a shift toward neoadjuvant/perioperative trials instead of traditional adjuvant approaches, and the development of personalized neoantigen vaccines.
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Affiliation(s)
- Sara Ascari
- Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
| | - Rusi Chen
- Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
| | - Caterina Vivaldi
- Unit of Medical Oncology 2, Azienda Ospedaliero- Universitaria Pisana, Pisa, Italy
| | - Bernardo Stefanini
- Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
| | - Andrea De Sinno
- Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
| | - Andrea Dalbeni
- Liver Unit, Medicine Department, University of Verona and University and Hospital Trust (AOUI) of Verona, Verona, Italy
- Unit of General Medicine C, Medicine Department, University of Verona and Hospital Trust (AOUI) of Verona, Verona, Italy
| | | | - Francesco Tovoli
- Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
- Division of Internal Medicine, Hepatobiliary and Immunoallergic Diseases, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
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