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Lereim RR, Dunn C, Aamdal E, Chauhan SK, Straume O, Guren TK, Kyte JA. Plasma protein dynamics during ipilimumab treatment in metastatic melanoma: associations with tumor response, adverse events and survival. Oncoimmunology 2025; 14:2440967. [PMID: 39703053 DOI: 10.1080/2162402x.2024.2440967] [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: 04/30/2024] [Revised: 11/30/2024] [Accepted: 12/05/2024] [Indexed: 12/21/2024] Open
Abstract
The immune checkpoint inhibitor ipilimumab provides long term survival in some metastatic melanoma patients, but the majority has no benefit, and may experience serious side effects. Here, we investigated the dynamics of plasma cytokine concentrations and their potential utility for predicting treatment response, adverse events and overall survival (OS) in patients with metastatic melanoma undergoing ipilimumab monotherapy. A cohort of 148 patients was examined, with plasma samples collected prior to treatment initiation and at the end of the first and second treatment cycles. Concentrations of 48 plasma proteins were measured using a multiplex immunoassay. The results revealed a general increase in cytokine levels following the first ipilimumab dose, consistent with immune activation. Patients not responding to treatment exhibited significantly elevated baseline levels of G-CSF, IL-2RA, MIP-1a, and SCF, compared to tumor responders (p < 0.05). Furthermore, high levels of IL-2RA, IFNγ, PDGF-bb and MIG were linked to inferior OS, while high concentrations of MIF and RANTES were associated with improved OS (p < 0.05). A multivariate model containing CRP, LDH, ECOG, IL-2RA and PDGF-bb identified a subgroup of patients with poor OS. Patients who experienced severe immune-related adverse events within three months of treatment initiation had higher baseline concentrations of several cytokines, indicating a potential association between preexisting inflammation and adverse events. These findings indicate that the first dose of ipilimumab induces a systemic response with increased levels of circulating cytokines and suggest candidate biomarkers for clinical response, immune-mediated toxicity and survival. Further studies in independent patient cohorts are required to confirm the findings.
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Affiliation(s)
| | - Claire Dunn
- Department of Cancer Immunology, Oslo University Hospital, Oslo, Norway
| | - Elin Aamdal
- Department of Clinical Cancer Research, Oslo University Hospital, Oslo, Norway
- Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway
| | | | - Oddbjørn Straume
- Department of Oncology and Medical Physics, Haukeland University Hospital, Bergen, Norway
- Centre for Cancer Biomarkers, Department of Clinical Science, University of Bergen, Bergen, Norway
| | - Tormod Kyrre Guren
- Department of Clinical Cancer Research, Oslo University Hospital, Oslo, Norway
| | - Jon Amund Kyte
- Department of Cancer Immunology, Oslo University Hospital, Oslo, Norway
- Department of Clinical Cancer Research, Oslo University Hospital, Oslo, Norway
- Faculty of Health Sciences, Oslo Metropolitan University, Oslo, Norway
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Castagnino PA, Haas DA, Musante L, Tancler NA, Tran BV, Kean R, Steck AR, Martinez LA, Mostaghel EA, Hooper DC, Kim FJ. Sigma1 inhibitor suppression of adaptive immune resistance mechanisms mediated by cancer cell derived extracellular vesicles. Cancer Biol Ther 2025; 26:2455722. [PMID: 39863992 PMCID: PMC11776462 DOI: 10.1080/15384047.2025.2455722] [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: 08/07/2024] [Revised: 12/28/2024] [Accepted: 01/15/2025] [Indexed: 01/27/2025] Open
Abstract
Adaptive immune resistance in cancer describes the various mechanisms by which tumors adapt to evade anti-tumor immune responses. IFN-γ induction of programmed death-ligand 1 (PD-L1) was the first defined and validated adaptive immune resistance mechanism. The endoplasmic reticulum (ER) is central to adaptive immune resistance as immune modulatory secreted and integral membrane proteins are dependent on ER. Sigma1 is a unique ligand-regulated integral membrane scaffolding protein enriched in the ER of cancer cells. PD-L1 is an integral membrane glycoprotein that is translated into the ER and processed through the cellular secretory pathway. At the cell surface, PD-L1 is an immune checkpoint molecule that binds PD-1 on activated T-cells and blocks anti-tumor immunity. PD-L1 can also be incorporated into cancer cell-derived extracellular vesicles (EVs), and EV-associated PD-L1 can inactivate T-cells within the tumor microenvironment. Here, we demonstrate that a selective small molecule inhibitor of Sigma1 can block IFN-γ mediated adaptive immune resistance in part by altering the incorporation of PD-L1 into cancer cell-derived EVs. Sigma1 inhibition blocked post-translational maturation of PD-L1 downstream of IFN-γ/STAT1 signaling. Subsequently, EVs released in response to IFN-γ stimulation were significantly less potent suppressors of T-cell activation. These results suggest that by reducing tumor derived immune suppressive EVs, Sigma1 inhibition may promote antitumor immunity. Sigma1 modulation presents a novel approach to regulating the tumor immune microenvironment by altering the content and production of EVs. Altogether, these data support the notion that Sigma1 may play a role in adaptive immune resistance in the tumor microenvironment.
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Affiliation(s)
- Paola A. Castagnino
- Department of Pharmacology, Physiology, and Cancer Biology, Thomas Jefferson University, Philadelphia, PA, USA
- Sidney Kimmel Comprehensive Cancer Center at Jefferson, Philadelphia, PA, USA
| | - Derick A. Haas
- Department of Pharmacology, Physiology, and Cancer Biology, Thomas Jefferson University, Philadelphia, PA, USA
- Sidney Kimmel Comprehensive Cancer Center at Jefferson, Philadelphia, PA, USA
| | - Luca Musante
- University of Pennsylvania School of Veterinary Medicine, Philadelphia, PA, USA
| | - Nathalia A. Tancler
- Department of Pharmacology, Physiology, and Cancer Biology, Thomas Jefferson University, Philadelphia, PA, USA
- Sidney Kimmel Comprehensive Cancer Center at Jefferson, Philadelphia, PA, USA
| | - Bach V. Tran
- Department of Pharmacology, Physiology, and Cancer Biology, Thomas Jefferson University, Philadelphia, PA, USA
- Sidney Kimmel Comprehensive Cancer Center at Jefferson, Philadelphia, PA, USA
| | - Rhonda Kean
- Department of Pharmacology, Physiology, and Cancer Biology, Thomas Jefferson University, Philadelphia, PA, USA
- Sidney Kimmel Comprehensive Cancer Center at Jefferson, Philadelphia, PA, USA
| | - Alexandra R. Steck
- Department of Pharmacology, Physiology, and Cancer Biology, Thomas Jefferson University, Philadelphia, PA, USA
- Sidney Kimmel Comprehensive Cancer Center at Jefferson, Philadelphia, PA, USA
| | - Luis A. Martinez
- Department of Pharmacology, Physiology, and Cancer Biology, Thomas Jefferson University, Philadelphia, PA, USA
- Sidney Kimmel Comprehensive Cancer Center at Jefferson, Philadelphia, PA, USA
| | - Elahe A. Mostaghel
- Geriatric Research, Education and Clinical Center, U.S. Department of Veterans Affairs Puget Sound Health Care System, Seattle, WA, USA
| | - D. Craig Hooper
- Department of Pharmacology, Physiology, and Cancer Biology, Thomas Jefferson University, Philadelphia, PA, USA
- Sidney Kimmel Comprehensive Cancer Center at Jefferson, Philadelphia, PA, USA
| | - Felix J. Kim
- Department of Pharmacology, Physiology, and Cancer Biology, Thomas Jefferson University, Philadelphia, PA, USA
- Sidney Kimmel Comprehensive Cancer Center at Jefferson, Philadelphia, PA, USA
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Yuan D, Gao Y, Xia L, Liu H, Wu X, Ding X, Huang Y, Deng C, Li J, Dai W, Liu J, Ma J. Discovery of novel biphenyl compounds bearing hydroxamic acid moiety as the first PD-L1/class I HDACs dual inhibitors. J Enzyme Inhib Med Chem 2025; 40:2461190. [PMID: 39912413 PMCID: PMC11803765 DOI: 10.1080/14756366.2025.2461190] [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: 11/29/2024] [Revised: 01/06/2025] [Accepted: 01/27/2025] [Indexed: 02/07/2025] Open
Abstract
Herein, we firstly reported a series of biphenyl compounds bearing hydroxamic acid moiety as PD-L1/class I HDACs dual inhibitors. Among them, compound 14 displayed the strongest inhibitory activity in vitro against HDAC2 and HDAC3 with IC50 values of 27.98 nM and 14.47 nM, and had an IC50 value of 88.10 nM for PD-1/PD-L1 interaction. Importantly, 14 could upregulate the expression of PD-L1 and CXCL10 in a PD-L1 low-expression cancer cell line (MCF-7), highlighting the potential to enhance efficacy by recruiting T-cell infiltration into TME and improving the response of PD-1/PD-L1 inhibitor associated with PD-L1 low-expression. Besides, we identified another compound, 22, which possessed the strongest inhibitory activity against PD-1/PD-L1 interaction with an IC50 value of 12.47 nM, and effectively inhibited the proliferation of three cancer cell lines. Our results suggest that compounds 14 and 22 can be served as lead compounds of PD-L1/class I HDACs dual inhibitors for further optimisation.
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Affiliation(s)
- Dandan Yuan
- School of Medicine, Huaqiao University, Quanzhou, China
| | - Yali Gao
- Pharmacy Department, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, China
| | - Lin Xia
- Fujian Provincial Key Laboratory of Innovative Drug Target Research, School of Pharmaceutical Sciences, Xiamen University, Xiamen, China
| | - Han Liu
- School of Medicine, Huaqiao University, Quanzhou, China
| | - Xingye Wu
- School of Medicine, Huaqiao University, Quanzhou, China
| | - Xueyan Ding
- School of Medicine, Huaqiao University, Quanzhou, China
| | - Yudan Huang
- School of Medicine, Huaqiao University, Quanzhou, China
| | | | - Jin Li
- School of Medicine, Huaqiao University, Quanzhou, China
| | - Wenqi Dai
- School of Medicine, Huaqiao University, Quanzhou, China
| | - Jieqing Liu
- School of Medicine, Huaqiao University, Quanzhou, China
| | - Junjie Ma
- School of Medicine, Huaqiao University, Quanzhou, China
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Xu JX, Su YX, Chen YY, Huang YY, Chen ZS, Peng YC, Qi LN. Immune infiltration landscape and potential drug-targeted implications for hepatocellular carcinoma with 'progression/hyper-progression' recurrence. Ann Med 2025; 57:2456113. [PMID: 39865865 PMCID: PMC11774162 DOI: 10.1080/07853890.2025.2456113] [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: 01/03/2024] [Revised: 12/20/2024] [Accepted: 01/08/2025] [Indexed: 01/30/2025] Open
Abstract
BACKGROUND AND AIMS Hepatocellular carcinoma (HCC) recurrence was previously characterized into four types, and patients with progression/hyper-progression recurrence (type III-IV) have an extremely poor prognosis. However, the immune background of resectable HCC, particularly in patients who experience recurrence, remains underexplored. Therefore, this study aimed to describe the immune landscape of resectable HCC, especially postoperative type III-IV recurrent HCC, and explore potential immune-targeted anti-relapse strategies for treated populations. METHODS The differences in gene expression in patients with recurrent HCC (type I-II (solitary or multi-intrahepatic oligo recurrence) vs. type III-IV) were investigated using bulk sequencing. Multiple immune infiltration methods (single-sample gene set enrichment analysis (GSEA), Microenvironment Cell Populations-counter and ESTIMATE) were used, and patients were divided into four groups to identify four distinct immune subtypes: immune-enrichment/matrix-poor (IE1), immune-enrichment/matrix-rich (IE2), immune intermediate/matrix-rich (ITM) and immune desert/matrix-poor (ID). Co-expression and protein interaction analyses were used to identify characteristic genes in ITM closely associated with type III-IV recurrence, which was matched with drug targets for Huaier granules (HG) and lenvatinib. Virtual docking was used to identify potential therapeutic targets, and the results were verified using single-nuclei RNA sequencing and histological analysis. RESULTS ITM was closely related to type III-IV recurrence and exhibited immunotherapy potential. The potential efficacy of inhibiting CCNA2, VEGFA, CXCL8, PLK2, TIMP1, ITGB2, ALDOA, ANXA5 and CSK in ITM reversal was determined. Molecular docking demonstrated that the proteins of these genes could bind to HG or lenvatinib. The immunohistochemical findings demonstrated differential VEGFA (p < .01) and PLK2 (p < .001) expression in ITM type and ID in type III-IV recurrent HCC. CONCLUSIONS Three primary immunotypes of resectable HCC (IE2, ITM and ID) were identified, and HG and lenvatinib could potentially overcome immune checkpoint blockade (ICB) resistance in ITM patients with HCC, particularly those classified as type III-IV.
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Affiliation(s)
- Jing-Xuan Xu
- Department of Hepatobiliary Surgery, Guangxi Medical University Cancer Hospital, Nanning, China
- Key Laboratory of Early Prevention and Treatment for Regional High Frequency Tumour, Ministry of Education, Nanning, China
| | - Yue-Xiang Su
- Department of Hepatobiliary Surgery, Guangxi Medical University Cancer Hospital, Nanning, China
- Key Laboratory of Early Prevention and Treatment for Regional High Frequency Tumour, Ministry of Education, Nanning, China
| | - Yuan-Yuan Chen
- Department of Ultrasound, First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Yi-Yue Huang
- Department of Hepatobiliary Surgery, Guangxi Medical University Cancer Hospital, Nanning, China
- Key Laboratory of Early Prevention and Treatment for Regional High Frequency Tumour, Ministry of Education, Nanning, China
| | - Zu-Shun Chen
- Department of Hepatobiliary Surgery, Guangxi Medical University Cancer Hospital, Nanning, China
| | - Yu-Chong Peng
- Department of General Surgery, Chongqing Hospital of Traditional Chinese Medicine, Chongqing, China
| | - Lu-Nan Qi
- Department of Hepatobiliary Surgery, Guangxi Medical University Cancer Hospital, Nanning, China
- Key Laboratory of Early Prevention and Treatment for Regional High Frequency Tumour, Ministry of Education, Nanning, China
- Guangxi Liver Cancer Diagnosis and Treatment Engineering and Technology Research Center, Nanning, China
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Zhang C, Wang Y, Yu Y, Pang Y, Xiao X, Hao L. Overexpression of ST8Sia1 inhibits tumor progression by TGF-β1 signaling in rectal adenocarcinoma and promotes the tumoricidal effects of CD8 + T cells by granzyme B and perforin. Ann Med 2025; 57:2439539. [PMID: 39656552 PMCID: PMC11633436 DOI: 10.1080/07853890.2024.2439539] [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: 02/09/2024] [Revised: 05/23/2024] [Accepted: 10/29/2024] [Indexed: 12/12/2024] Open
Abstract
BACKGROUND Rectal adenocarcinoma (READ) involves the dysregulated expression of alpha 2,8-Sialyltransferase1 (ST8Sia1) although its role during READ's progression is unclear. METHODS The mRNA level of ST8Sia1 was analyzed based on The Cancer Genome Atlas (TCGA), Gene Expression Omnibus (GEO), and Tumor Immune Estimation Resource (TIMER) 2.0. Furthermore, the prognostic and significance of ST8Sia1 in READ was assessed through Kaplan-Meier curve, univariate, multivariate Cox regression, and receiver operating characteristic (ROC) methods. The role of ST8Sia1 in the READ immune microenvironment was explored using ESTIMATE analysis and TIMER databases. Furthermore, the expression of ST8Sia1 in tissues was analyzed using real-time quantitative polymerase chain reaction (RT-qPCR), western blotting (WB), and immunohistochemistry (IHC). Perforin and Granzyme B secretion by CD8+ T cells, as well as tumor cell apoptosis, were detected after co-culturing CD8+ T cells with READ tumor cells and ST8Sia1-overexpression (ST8Sia1-OE) tumor cells. Furthermore, we examined the interaction between ST8Sia1 and TGF-β1 in READ cells. RESULTS ST8Sia1 exhibited excellent diagnostic capability for READ, with positive correlations to immune response and negative correlations to tumor purity. Increased levels of perforin and Granzyme B from CD8+ T cells were observed in vitro, enhancing tumor cell apoptosis. ST8Sia1 interacts with TGF-β1, mediating its inhibitory effects on READ development. CONCLUSIONS ST8Sia1 is a potential diagnostic biomarker and therapeutic target for READ, enhancing CD8+ T cell function and possibly improving patient outcomes through cellular immunotherapy.
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Affiliation(s)
- Chang Zhang
- Department of Anorectal, The Affiliated Yantai Yuhuangding Hospital of Qingdao University, Yantai City, Shandong Province, China
| | - Yeli Wang
- Department of Anorectal, The Affiliated Yantai Yuhuangding Hospital of Qingdao University, Yantai City, Shandong Province, China
| | - Yao Yu
- Department of General Pediatric Surgery, The Affiliated Yantai Yuhuangding Hospital of Qingdao University, Yantai City, Shandong Province, China
| | - Yanchao Pang
- Department of Anorectal, The Affiliated Yantai Yuhuangding Hospital of Qingdao University, Yantai City, Shandong Province, China
| | - Xiao Xiao
- Department of Neurology, The Affiliated Yantai Yuhuangding Hospital of Qingdao University, Yantai City, Shandong Province, China
| | - Leilei Hao
- Department of Anorectal, The Affiliated Yantai Yuhuangding Hospital of Qingdao University, Yantai City, Shandong Province, China
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Huang R, Yu J, Zhang B, Li X, Liu H, Wang Y. Emerging COX-2 inhibitors-based nanotherapeutics for cancer diagnosis and treatment. Biomaterials 2025; 315:122954. [PMID: 39549439 DOI: 10.1016/j.biomaterials.2024.122954] [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: 10/27/2024] [Accepted: 11/07/2024] [Indexed: 11/18/2024]
Abstract
Increasing evidence has showed that tumorigenesis is closely linked to inflammation, regulated by multiple signaling pathways. Among these, the cyclooxygenase-2/prostaglandin E2 (COX-2/PGE2) axis plays a crucial role in the progression of both inflammation and cancer. Inhibiting the activity of COX-2 can reduce PGE2 secretion, thereby suppressing tumor growth. Therefore, COX-2 inhibitors are considered potential therapeutic agents for cancers. However, their clinical applications are greatly hindered by poor physicochemical properties and serious adverse effects. Fortunately, the advent of nanotechnology offers solutions to these limitations, enhancing drug delivery efficiency and mitigating adverse effects. Given the considerable progress in this area, it is timely to review emerging COX-2 inhibitors-based nanotherapeutics for cancer diagnosis and therapy. In this review, we first outline the various antineoplastic mechanisms of COX-2 inhibitors, then comprehensively summarize COX-2 inhibitors-based nanotherapeutics for cancer monotherapy, combination therapy, and diagnosis. Finally, we highlight and discuss future perspectives and challenges in the development of COX-2 inhibitors-based nanomedicine.
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Affiliation(s)
- Ruiping Huang
- Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang, Liaoning, 110016, PR China
| | - Jiang Yu
- Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang, Liaoning, 110016, PR China
| | - Baoyue Zhang
- Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang, Liaoning, 110016, PR China
| | - Xin Li
- Department of Respiratory Medicine, First Affiliated Hospital of Jinzhou Medical University, Jinzhou, 121001, PR China
| | - Hongzhuo Liu
- Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang, Liaoning, 110016, PR China; Joint International Research Laboratory of Intelligent Drug Delivery Systems, Ministry of Education, Shenyang Pharmaceutical University, Shenyang, Liaoning, 110016, PR China.
| | - Yongjun Wang
- Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang, Liaoning, 110016, PR China; Joint International Research Laboratory of Intelligent Drug Delivery Systems, Ministry of Education, Shenyang Pharmaceutical University, Shenyang, Liaoning, 110016, PR China.
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Zhang T, Tang D, Wu P, Jiang S, Zhang Y, Naeem A, Li Y, Li C, Hu B, Guo S, Sun C, Xiao H, Yan R, Weng Y, Huang Y. NIR-II photo-accelerated polymer nanoparticles boost tumor immunotherapy via PD-L1 silencing and immunogenic cell death. Bioact Mater 2025; 46:285-300. [PMID: 39811466 PMCID: PMC11732249 DOI: 10.1016/j.bioactmat.2024.12.018] [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: 08/12/2024] [Revised: 12/16/2024] [Accepted: 12/17/2024] [Indexed: 01/16/2025] Open
Abstract
Immune checkpoint blockade (ICB) therapy is a widely favored anti-tumor treatment, but it shows limited response to non-immunogenic "cold" tumors and suffers from drug resistance. Photodynamic therapy (PDT), as a powerful localized treatment approach, can convert a "cold tumor" into a "hot tumor" by inducing immunogenic cell death (ICD) in tumor cells, thereby enhancing tumor immunogenicity and promoting tumor immunotherapy. However, the effectiveness of PDT is largely hindered by the limited penetration depth into tumor tissues. To address these issues, we proposed an all-in-one drug system with NIR-II photo-accelerated PDT effects, efficient immune checkpoint gene silencing, and a facile manufacturing process. The so-called all-in-one drug system comprises a multi-modal designed polymer PPNP and siRNA. PPNP is an amphipathic polymer that includes the near infrared-II (NIR-II) photosensitizer Aza-boron-dipyrromethene (Aza-BODIPY), a glutathione (GSH)-cleavable linker, and a cationic monomer derived from cholesterol. PPNP can self-assemble and efficiently load siRNA. Under laser irradiation, PPNP triggers a potent ICD cascade, causing the on-demand release of siPD-L1, reshaping the tumor's immunosuppressive microenvironment, effectively inhibiting the growth of various tumors, and stimulating the immune memory. This study represents a generalized platform for PDT and gene silencing, designed to modulate immune-related signaling pathways for improved anticancer therapy.
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Affiliation(s)
- Tian Zhang
- School of Life Science, Advanced Research Institute of Multidisciplinary Science, Aerospace Center Hospital, Key Laboratory of Molecular Medicine and Biotherapy, Key Laboratory of Medical Molecule Science and Pharmaceutics Engineering, Beijing Institute of Technology, Beijing, 100081, China
| | - Dongsheng Tang
- Beijing National Laboratory for Molecular Science Laboratory of Polymer Physics and Chemistry Institute of Chemistry Chinese Academy of Science Beijing 100190, China
| | - Pengfei Wu
- School of Life Science, Advanced Research Institute of Multidisciplinary Science, Aerospace Center Hospital, Key Laboratory of Molecular Medicine and Biotherapy, Key Laboratory of Medical Molecule Science and Pharmaceutics Engineering, Beijing Institute of Technology, Beijing, 100081, China
| | - Shaoping Jiang
- School of Life Science, Advanced Research Institute of Multidisciplinary Science, Aerospace Center Hospital, Key Laboratory of Molecular Medicine and Biotherapy, Key Laboratory of Medical Molecule Science and Pharmaceutics Engineering, Beijing Institute of Technology, Beijing, 100081, China
| | - Yuquan Zhang
- School of Life Science, Advanced Research Institute of Multidisciplinary Science, Aerospace Center Hospital, Key Laboratory of Molecular Medicine and Biotherapy, Key Laboratory of Medical Molecule Science and Pharmaceutics Engineering, Beijing Institute of Technology, Beijing, 100081, China
| | - Abid Naeem
- School of Life Science, Advanced Research Institute of Multidisciplinary Science, Aerospace Center Hospital, Key Laboratory of Molecular Medicine and Biotherapy, Key Laboratory of Medical Molecule Science and Pharmaceutics Engineering, Beijing Institute of Technology, Beijing, 100081, China
| | - Yong Li
- School of Life Science, Advanced Research Institute of Multidisciplinary Science, Aerospace Center Hospital, Key Laboratory of Molecular Medicine and Biotherapy, Key Laboratory of Medical Molecule Science and Pharmaceutics Engineering, Beijing Institute of Technology, Beijing, 100081, China
| | - Chunhui Li
- School of Life Science, Advanced Research Institute of Multidisciplinary Science, Aerospace Center Hospital, Key Laboratory of Molecular Medicine and Biotherapy, Key Laboratory of Medical Molecule Science and Pharmaceutics Engineering, Beijing Institute of Technology, Beijing, 100081, China
| | - Bo Hu
- School of Life Science, Advanced Research Institute of Multidisciplinary Science, Aerospace Center Hospital, Key Laboratory of Molecular Medicine and Biotherapy, Key Laboratory of Medical Molecule Science and Pharmaceutics Engineering, Beijing Institute of Technology, Beijing, 100081, China
| | - Shuai Guo
- School of Life Science, Advanced Research Institute of Multidisciplinary Science, Aerospace Center Hospital, Key Laboratory of Molecular Medicine and Biotherapy, Key Laboratory of Medical Molecule Science and Pharmaceutics Engineering, Beijing Institute of Technology, Beijing, 100081, China
| | - Caixia Sun
- School of Chemistry, Chemical Engineering & Biotechnology, Nanyang Technological University, 637371, Singapore
| | - Haihua Xiao
- Beijing National Laboratory for Molecular Science Laboratory of Polymer Physics and Chemistry Institute of Chemistry Chinese Academy of Science Beijing 100190, China
| | - Ran Yan
- Key Laboratory of Biomedical Functional Materials, School of Science, China Pharmaceutical University, Nanjing, 211198, China
| | - Yuhua Weng
- School of Life Science, Advanced Research Institute of Multidisciplinary Science, Aerospace Center Hospital, Key Laboratory of Molecular Medicine and Biotherapy, Key Laboratory of Medical Molecule Science and Pharmaceutics Engineering, Beijing Institute of Technology, Beijing, 100081, China
- Advanced Research Institute of Multidisciplinary Science, Beijing Institute of Technology (BIT), Zhuhai 519088, China
- Advanced Technology Research Institute, Beijing Institute of Technology (BIT), Jinan 250101, China
| | - Yuanyu Huang
- School of Life Science, Advanced Research Institute of Multidisciplinary Science, Aerospace Center Hospital, Key Laboratory of Molecular Medicine and Biotherapy, Key Laboratory of Medical Molecule Science and Pharmaceutics Engineering, Beijing Institute of Technology, Beijing, 100081, China
- Advanced Research Institute of Multidisciplinary Science, Beijing Institute of Technology (BIT), Zhuhai 519088, China
- Advanced Technology Research Institute, Beijing Institute of Technology (BIT), Jinan 250101, China
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Chen L, Li L, Zhao H, Li H, Li J, Li C, Zhou Y, Yang L, Liang J, Zhang H, Li J, Xu P, Yuan C, Liu Z, Huang M, Jiang L. Integration of EMAP-II-targeted anti-angiogenesis and photodynamic therapy using zinc phthalocyanine nanosystem for enhanced cancer treatment. Colloids Surf B Biointerfaces 2025; 248:114493. [PMID: 39778222 DOI: 10.1016/j.colsurfb.2024.114493] [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: 10/03/2024] [Revised: 12/17/2024] [Accepted: 12/31/2024] [Indexed: 01/11/2025]
Abstract
Angiogenesis provides essential nutrients and oxygen to tumors during tumorigenesis, facilitating invasion and metastasis. Consequently, inhibiting tumor angiogenesis is an established strategy in anti-cancer therapy. In this study, we engineered a dual-function nanosystem with both antiangiogenic and photodynamic properties. We transformed the hydrophobic photosensitizer zinc phthalocyanine (PS) into a hydrophilic form via protein renaturation, resulting in a novel photosensitizer: Monocyte-Activating Polypeptide-II (EMAP-II:PS@NPs). Characterization through dynamic light scattering (DLS) and UV-vis spectroscopy showed that these nanoparticles exhibited uniform size and stability, and enhanced solubility. We further demonstrated that EMAP-II:PS@NPs effectively target tumor vascular endothelia causing intracellular photodynamic cytotoxicity. Notably, EMAP-II:PS@NPs achieved effective ablation of solid tumors at significantly reduced dosages of drugs compared to conventional therapies, due to their potent apoptotic effects on light-exposed cells. This study highlights the potential of combining anti-angiogenic activity with phototherapy, paving the way for innovative cancer treatment strategies.
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Affiliation(s)
- Liyun Chen
- College of Chemistry, Fuzhou University, Fuzhou, Fujian 350116, China
| | - Linlin Li
- College of Chemistry, Fuzhou University, Fuzhou, Fujian 350116, China
| | - Hailong Zhao
- College of Chemistry, Fuzhou University, Fuzhou, Fujian 350116, China
| | - Hao Li
- College of Chemistry, Fuzhou University, Fuzhou, Fujian 350116, China
| | - Jiahui Li
- College of Chemistry, Fuzhou University, Fuzhou, Fujian 350116, China
| | - Chao Li
- College of Chemistry, Fuzhou University, Fuzhou, Fujian 350116, China
| | - Yang Zhou
- College of Chemistry, Fuzhou University, Fuzhou, Fujian 350116, China
| | - Luxuan Yang
- College of Chemistry, Fuzhou University, Fuzhou, Fujian 350116, China
| | - Jun Liang
- College of Chemistry, Fuzhou University, Fuzhou, Fujian 350116, China
| | - Honglian Zhang
- College of Chemistry, Fuzhou University, Fuzhou, Fujian 350116, China
| | - Juan Li
- College of Chemistry, Fuzhou University, Fuzhou, Fujian 350116, China
| | - Peng Xu
- College of Biological Science and Engineering, Fuzhou University, Fuzhou, Fujian 350116, China; The National & Local Joint Engineering Research Center on Biopharmaceutical and Photodynamic Therapy Technologies, Fuzhou University, Fuzhou, Fujian 350116, China
| | - Cai Yuan
- College of Biological Science and Engineering, Fuzhou University, Fuzhou, Fujian 350116, China; The National & Local Joint Engineering Research Center on Biopharmaceutical and Photodynamic Therapy Technologies, Fuzhou University, Fuzhou, Fujian 350116, China
| | - Zhenhua Liu
- Department of Oncology, Fuzhou University Affiliated Provincial Hospital, Fujian Provincial Hospital, Fuzhou, Fujian 350001, China.
| | - Mingdong Huang
- College of Chemistry, Fuzhou University, Fuzhou, Fujian 350116, China; The National & Local Joint Engineering Research Center on Biopharmaceutical and Photodynamic Therapy Technologies, Fuzhou University, Fuzhou, Fujian 350116, China.
| | - Longguang Jiang
- College of Chemistry, Fuzhou University, Fuzhou, Fujian 350116, China; The National & Local Joint Engineering Research Center on Biopharmaceutical and Photodynamic Therapy Technologies, Fuzhou University, Fuzhou, Fujian 350116, China.
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Yuan Z, Wang JH, Cui H, Wang SY, Wei B, Cui JX. Mapping the landscape of gastric cancer immunotherapy: Bibliometric insights into advances and hotspots. World J Gastrointest Oncol 2025; 17:100997. [DOI: 10.4251/wjgo.v17.i3.100997] [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: 09/01/2024] [Revised: 12/11/2024] [Accepted: 12/31/2024] [Indexed: 02/14/2025] Open
Abstract
BACKGROUND Immunotherapy has surfaced as a promising therapeutic modality for gastric cancer (GC). A comprehensive review of advancements, current status, and research trends in GC immunotherapy is essential to inform future investigative efforts.
AIM To delineate the trends, advancements, and focal points in immunotherapy for GC.
METHODS We performed a bibliometric analysis of 2906 articles in English concerning GC immunotherapy published from 2000 to December 20, 2023, indexed in the Web of Science Core Collection. Data analysis and visualization were facilitated by CiteSpace (6.1.6R), VOSviewer v.1.6.17, and GraphPad Prism v8.0.2.
RESULTS There has been an increase in the annual publication rate of GC immunotherapy research. China leads in publication volume, while the United States demonstrates the highest citation impact. Fudan University is notable for its citation frequency and publication output. Co-citation analysis and keyword frequency revealed and highlighted a focus on GC prognosis, the tumor microenvironment (TME), and integrative immunotherapy with targeted therapy. Emerging research areas include gastroesophageal junction cancer, adoptive immunotherapy, and the role of Treg cell in immunotherapy.
CONCLUSION GC immunotherapy research is an expanding field attracting considerable scientific interest. With the clinical adoption of immunotherapy in GC, the primary goals are to enhance treatment efficacy and patient outcomes. Unlike hematological malignancies, GC's solid TME presents distinct immunological challenges that may attenuate the cytotoxic effects of immune cells on cancer cells. For instance, although CAR-T therapy is effective in hematological malignancies, it has underperformed in GC settings. Current research is centered on overcoming immunosuppression within the TME, with a focus on combinations of targeted therapy, adoptive immunotherapy, Treg cell dynamics, and precise prognosis prediction in immunotherapy. Additionally, immunotherapy's role in treating gastroesophageal junction cancer has become a novel research focus.
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Affiliation(s)
- Zhen Yuan
- School of Medicine, Nankai University, Tianjin 300071, China
- Department of General Surgery, The First Medical Center, Chinese PLA General Hospital, Beijing 100853, China
| | - Jing-Hang Wang
- School of Medicine, Nankai University, Tianjin 300071, China
- Department of General Surgery, The First Medical Center, Chinese PLA General Hospital, Beijing 100853, China
| | - Hao Cui
- School of Medicine, Nankai University, Tianjin 300071, China
- Department of General Surgery, The First Medical Center, Chinese PLA General Hospital, Beijing 100853, China
| | - Shu-Yuan Wang
- School of Medicine, Nankai University, Tianjin 300071, China
| | - Bo Wei
- Department of General Surgery, The First Medical Center, Chinese PLA General Hospital, Beijing 100853, China
| | - Jian-Xin Cui
- Department of General Surgery, The First Medical Center, Chinese PLA General Hospital, Beijing 100853, China
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10
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Tang X, Wen Y, Zhang Z, Song X, Zhu J, Tian X, Li J. A β-cyclodextrin-based supramolecular modular system creating micellar carriers for codelivery of doxorubicin and siRNA for potential combined chemotherapy and immunotherapy. Carbohydr Polym 2025; 352:123202. [PMID: 39843103 DOI: 10.1016/j.carbpol.2024.123202] [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: 11/04/2024] [Revised: 12/22/2024] [Accepted: 12/29/2024] [Indexed: 01/24/2025]
Abstract
The combination of chemotherapy and gene therapy holds promise in treating cancer. A key strategy is to use small interfering RNAs (siRNAs) to silence programmed death-ligand 1 (PD-L1) expression in cancer cells, disrupting tumor immune evasion and enhancing anticancer treatments, particularly when used in conjunction with chemotherapy drugs such as doxorubicin (Dox). However, effective codelivery of drugs and genes requires carefully designed carriers and complex synthesis procedures. To address this challenge, we propose a convenient modular self-assembly system for creating multifunctional micellar carriers that can efficiently codeliver both Dox and siRNA, where micelles are formed by cationic amphiphilic supramolecular architectures that are constructed through host-guest interactions between β-cyclodextrin (β-CD) and adamantane (Ad) to incorporate various functional polymer segments, such as low-molecular-weight polyethylenimine (oligoethylenimine, OEI), poly(ethylene glycol) (PEG), and polycaprolactone (PCL), at adjustable ratios. The supramolecular micellar carrier systems can be easily optimized to achieve excellent structural stability, drug and gene loading, and delivery efficiency, resulting in significant anticancer effects from Dox delivery and simultaneous inhibition of PD-L1 due to the siRNA delivery. Therefore, this modular supramolecular strategy offers a sophisticated, adaptable, and straightforward approach to creating multifunctional micellar carriers, with potential for drug- and gene-based immune-assisted cancer therapy.
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Affiliation(s)
- Xichuan Tang
- Department of Biomedical Engineering, College of Design and Engineering, National University of Singapore, 15 Kent Ridge Crescent, Singapore 119276, Singapore
| | - Yuting Wen
- Department of Biomedical Engineering, College of Design and Engineering, National University of Singapore, 15 Kent Ridge Crescent, Singapore 119276, Singapore; National University of Singapore (Suzhou) Research Institute, Suzhou, Jiangsu 215123, China; National University of Singapore (Chongqing) Research Institute, Yubei, Chongqing 401120, China.
| | - Zhongxing Zhang
- Department of Biomedical Engineering, College of Design and Engineering, National University of Singapore, 15 Kent Ridge Crescent, Singapore 119276, Singapore
| | - Xia Song
- Department of Biomedical Engineering, College of Design and Engineering, National University of Singapore, 15 Kent Ridge Crescent, Singapore 119276, Singapore
| | - Jingling Zhu
- Department of Biomedical Engineering, College of Design and Engineering, National University of Singapore, 15 Kent Ridge Crescent, Singapore 119276, Singapore; NUS Environmental Research Institute (NERI), National University of Singapore, 5A Engineering Drive 1, Singapore 117411, Singapore
| | - Xuehao Tian
- Department of Biomedical Engineering, College of Design and Engineering, National University of Singapore, 15 Kent Ridge Crescent, Singapore 119276, Singapore
| | - Jun Li
- Department of Biomedical Engineering, College of Design and Engineering, National University of Singapore, 15 Kent Ridge Crescent, Singapore 119276, Singapore; National University of Singapore (Suzhou) Research Institute, Suzhou, Jiangsu 215123, China; National University of Singapore (Chongqing) Research Institute, Yubei, Chongqing 401120, China; NUS Environmental Research Institute (NERI), National University of Singapore, 5A Engineering Drive 1, Singapore 117411, Singapore.
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11
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Wu Q, Wu Q, Lin H, Zhang C, You Z, Kang S, Xu Y, Chen X, Yang C, Song Y, Zhu L. Microfluidic Replication and Phenotypic Profiling of Extracellular Vesicles from the Tumor Microenvironment Using Dual-Switch Aptamer Logic Gates. Anal Chem 2025; 97:5313-5323. [PMID: 40012368 DOI: 10.1021/acs.analchem.5c00234] [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: 02/28/2025]
Abstract
The phenotypic profiling of extracellular vesicles (EVs) within the tumor microenvironment (TME) provides critical insights into the intercellular communication mechanisms of EVs underlying tumor physiology. However, conventional methods typically isolate EVs from the extracellular space through tissue fragmentation, which compromises tissue viability, and neglects the spatial organization of the tissue and the dynamic nature of EV secretion. Herein, we introduce an innovative microfluidic platform to cultivate intact tumor tissues while preserving their spatial architecture and facilitating natural EV secretion. This system enables the direct replication of EVs onto the chip for high-fidelity phenotypic analysis. Utilizing a combinatorial-aptamer-induced dual-switch logic gate methodology, this approach allows for the precise subtyping of EVs derived from both tumor cells and immune cells within the TME. Specifically, aptamers targeting EpCAM and PD-L1, along with the connector probe, were employed to induce a dual-switch signal to identify distinct EV populations. This strategy enables noninvasive, real-time capture and phenotypic profiling of EVs directly within the microfluidic environment. Furthermore, our findings indicate that immunotherapy with PD-1 antibodies significantly enhances the secretion of EVs by immune cells within the TME, underscoring the potential role of EVs as mediators of therapeutic responses. Overall, we have developed a robust, noninvasive method for the phenotypic profiling of EVs in the TME, offering a powerful tool for investigating the biological functions and implications of EVs in tumor pathophysiology.
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Affiliation(s)
- Qiaoyi Wu
- Department of Trauma Center and Emergency Surgery, The First Affiliated Hospital of Fujian Medical University, Department of Trauma Center & Emergency Surgery, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou 350005, P. R. China
| | - Qiuyue Wu
- The MOE Key Laboratory of Spectrochemical Analysis and Instrumentation, State Key Laboratory of Physical Chemistry of Solid Surfaces, Department of Chemical Biology, College of Chemistry and Chemical Engineering, Xiamen University, Xiamen 361005, P. R. China
| | - Haoting Lin
- The MOE Key Laboratory of Spectrochemical Analysis and Instrumentation, State Key Laboratory of Physical Chemistry of Solid Surfaces, Department of Chemical Biology, College of Chemistry and Chemical Engineering, Xiamen University, Xiamen 361005, P. R. China
| | - Chi Zhang
- The MOE Key Laboratory of Spectrochemical Analysis and Instrumentation, State Key Laboratory of Physical Chemistry of Solid Surfaces, Department of Chemical Biology, College of Chemistry and Chemical Engineering, Xiamen University, Xiamen 361005, P. R. China
| | - Zhenlong You
- The MOE Key Laboratory of Spectrochemical Analysis and Instrumentation, State Key Laboratory of Physical Chemistry of Solid Surfaces, Department of Chemical Biology, College of Chemistry and Chemical Engineering, Xiamen University, Xiamen 361005, P. R. China
| | - Siyin Kang
- The MOE Key Laboratory of Spectrochemical Analysis and Instrumentation, State Key Laboratory of Physical Chemistry of Solid Surfaces, Department of Chemical Biology, College of Chemistry and Chemical Engineering, Xiamen University, Xiamen 361005, P. R. China
| | - Yuanfeng Xu
- The MOE Key Laboratory of Spectrochemical Analysis and Instrumentation, State Key Laboratory of Physical Chemistry of Solid Surfaces, Department of Chemical Biology, College of Chemistry and Chemical Engineering, Xiamen University, Xiamen 361005, P. R. China
| | - Xiaofeng Chen
- The MOE Key Laboratory of Spectrochemical Analysis and Instrumentation, State Key Laboratory of Physical Chemistry of Solid Surfaces, Department of Chemical Biology, College of Chemistry and Chemical Engineering, Xiamen University, Xiamen 361005, P. R. China
- School of Environmental Science and Engineering, Hainan University, Haikou 570228, P. R. China
| | - Chaoyong Yang
- The MOE Key Laboratory of Spectrochemical Analysis and Instrumentation, State Key Laboratory of Physical Chemistry of Solid Surfaces, Department of Chemical Biology, College of Chemistry and Chemical Engineering, Xiamen University, Xiamen 361005, P. R. China
- Institute of Molecular Medicine, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, P. R. China
| | - Yanling Song
- The MOE Key Laboratory of Spectrochemical Analysis and Instrumentation, State Key Laboratory of Physical Chemistry of Solid Surfaces, Department of Chemical Biology, College of Chemistry and Chemical Engineering, Xiamen University, Xiamen 361005, P. R. China
| | - Lin Zhu
- The MOE Key Laboratory of Spectrochemical Analysis and Instrumentation, State Key Laboratory of Physical Chemistry of Solid Surfaces, Department of Chemical Biology, College of Chemistry and Chemical Engineering, Xiamen University, Xiamen 361005, P. R. China
- School of Environmental Science and Engineering, Hainan University, Haikou 570228, P. R. China
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12
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Huang YJ, Ngiow SF, Baxter AE, Manne S, Park SL, Wu JE, Khan O, Giles JR, Wherry EJ. Continuous expression of TOX safeguards exhausted CD8 T cell epigenetic fate. Sci Immunol 2025; 10:eado3032. [PMID: 40053604 DOI: 10.1126/sciimmunol.ado3032] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2024] [Accepted: 02/06/2025] [Indexed: 03/09/2025]
Abstract
Although checkpoint blockade temporarily improves exhausted CD8 T (Tex) cell function, the underlying Tex epigenetic landscape remains largely unchanged, preventing durable Tex "reinvigoration" in cancer and chronic infections. The transcription factor TOX initiates Tex epigenetic programming, yet it remains unclear whether TOX continually preserves Tex biology after Tex establishment. Here, we demonstrated that induced TOX ablation in committed Tex cells resulted in apoptotic-driven loss of Tex cells, reduced expression of inhibitory receptors, and decreased terminal differentiation. Gene expression and epigenetic profiling revealed a critical role for TOX in maintaining chromatin accessibility and transcriptional patterns in committed Tex cells. Moreover, TOX removal endows established Tex cells with greater fate flexibility to differentiate into more functional effector-like T cells. Thus, continuous TOX expression in established Tex cells acts as a durable epigenetic barrier reinforcing the Tex developmental fate. TOX manipulation even after Tex establishment could therefore provide therapeutic opportunities to rewire Tex cells in chronic infections or cancer.
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Affiliation(s)
- Yinghui J Huang
- Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
- Institute for Immunology and Immune Health, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
- Parker Institute for Cancer Immunotherapy at University of Pennsylvania, Philadelphia, PA, USA
| | - Shin Foong Ngiow
- Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
- Institute for Immunology and Immune Health, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
- Parker Institute for Cancer Immunotherapy at University of Pennsylvania, Philadelphia, PA, USA
| | - Amy E Baxter
- Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
- Institute for Immunology and Immune Health, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Sasikanth Manne
- Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
- Institute for Immunology and Immune Health, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Simone L Park
- Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
- Institute for Immunology and Immune Health, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Jennifer E Wu
- Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
- Institute for Immunology and Immune Health, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
- Parker Institute for Cancer Immunotherapy at University of Pennsylvania, Philadelphia, PA, USA
| | - Omar Khan
- Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
- Institute for Immunology and Immune Health, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Josephine R Giles
- Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
- Institute for Immunology and Immune Health, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
- Parker Institute for Cancer Immunotherapy at University of Pennsylvania, Philadelphia, PA, USA
| | - E John Wherry
- Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
- Institute for Immunology and Immune Health, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
- Parker Institute for Cancer Immunotherapy at University of Pennsylvania, Philadelphia, PA, USA
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13
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Zang H, Liu T, Wang X, Cheng S, Zhu X, Huang C, Duan L, Zhao X, Guo F, Wang X, Zhang C, Yang F, Gu Y, Hu H, Gao S. PD-1 IR2 promotes tumor evasion via deregulating CD8 + T cell function. J Immunother Cancer 2025; 13:e010529. [PMID: 40050045 PMCID: PMC11887316 DOI: 10.1136/jitc-2024-010529] [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: 09/07/2024] [Accepted: 02/22/2025] [Indexed: 03/09/2025] Open
Abstract
BACKGROUND The programmed cell death 1 (PD-1) is an immune checkpoint that mediates immune evasion of tumors. Alternative splicing (AS) such as intron retention (IR) plays a crucial role in the immune-related gene processing and its function. However, it is not clear whether PDCD1 encoding PD-1 exists as an IR splicing isoform and what underlying function of such isoform plays in tumor evasion. METHODS An AS isoform of human PDCD1, characterized by the second IR and named PD-1IR2, was identified by reverse transcription-PCR (RT-PCR) and Sanger sequencing. The expression profile of PD1IR2 was assessed by quantitative RT-PCR and flow cytometry, while its function was evaluated through immune cell proliferation, cytokine interleukin 2 secretion, and tumor cell killing assays. PDCD1IR2 CKI mice which specifically conditional knock-in PDCD1IR2 in T cells and humanized peripheral blood mononuclear cells (PBMC)-NOG (NOD.Cg-PrkdcscidIL2rgtm1Sug/JicCrl) mice were utilized to further confirm the physiological function of PD-1IR2 in vivo. RESULTS PD-1IR2 is expressed in a variety of human leukemia cell lines and tumor-infiltrating lymphocytes. PD-1IR2 expression is induced on T cell activation and regulated by the RNA-binding protein hnRNPLL. PD-1IR2 negatively regulates the immune function of CD8+ T cells, indicated by inhibiting T cell proliferation, cytokine production, and tumor cell killing in vitro. PD-1IR2+ CD8+ T cells show impaired antitumor function, which consequently promote tumor evasion in a conditional knock-in mouse model and a PBMC-engrafted humanized NOG mouse model. PD-1IR2 mice exhibit resistance to anti-PD-L1 therapy compared with wild-type mice. CONCLUSIONS PD-1IR2 is a potential immune checkpoint that may mediate potential resistance to immune checkpoint therapy.
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Affiliation(s)
- Haojing Zang
- Department of Microbiology and Immunology, Shanxi Medical University, Taiyuan, Shanxi, China
- Shanxi Academy of Advanced Research and Innovation, Taiyuan, Shanxi, China
| | - Tongfeng Liu
- School of Life Sciences and Technology, Advanced Institute for Life and Health, Southeast University Zhongda Hospital, Nanjing, Jiangsu, China
- Medical College, Guizhou University, Guiyang, Guizhou, China
| | - Xiaodong Wang
- School of Life Sciences and Technology, Advanced Institute for Life and Health, Southeast University Zhongda Hospital, Nanjing, Jiangsu, China
- School of Biomedical Engineering (Suzhou), Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China
| | - Shuwen Cheng
- School of Life Sciences and Technology, Advanced Institute for Life and Health, Southeast University Zhongda Hospital, Nanjing, Jiangsu, China
- Medical School of Nanjing University, Nanjing, Jiangsu, China
| | - Xiaofeng Zhu
- School of Life Sciences and Technology, Advanced Institute for Life and Health, Southeast University Zhongda Hospital, Nanjing, Jiangsu, China
- Medical College, Guizhou University, Guiyang, Guizhou, China
| | - Chang Huang
- School of Life Sciences and Technology, Advanced Institute for Life and Health, Southeast University Zhongda Hospital, Nanjing, Jiangsu, China
- Medical College, Guizhou University, Guiyang, Guizhou, China
| | - Liqiang Duan
- Shanxi Academy of Advanced Research and Innovation, Taiyuan, Shanxi, China
- School of Life Sciences and Technology, Advanced Institute for Life and Health, Southeast University Zhongda Hospital, Nanjing, Jiangsu, China
| | - Xujie Zhao
- School of Life Sciences and Technology, Advanced Institute for Life and Health, Southeast University Zhongda Hospital, Nanjing, Jiangsu, China
| | - Fang Guo
- School of Life Sciences and Technology, Advanced Institute for Life and Health, Southeast University Zhongda Hospital, Nanjing, Jiangsu, China
- The Key Laboratory of Medical Molecular Cell Biology of Shanxi Province, Institutes of Biomedical Sciences, Shanxi University, Taiyuan, Shanxi, China
| | - Xuetong Wang
- School of Life Sciences and Technology, Advanced Institute for Life and Health, Southeast University Zhongda Hospital, Nanjing, Jiangsu, China
- School of Biomedical Engineering (Suzhou), Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China
| | - Chang Zhang
- School of Life Sciences and Technology, Advanced Institute for Life and Health, Southeast University Zhongda Hospital, Nanjing, Jiangsu, China
- Department of oncology, The Key Laboratory of Advanced Interdisciplinary Studies, First Affiliated Hospital of Guangzhou Medical University State Key Laboratory of Respiratory Disease, Guangzhou, Guangdong, China
| | - Facai Yang
- School of Life Sciences and Technology, Advanced Institute for Life and Health, Southeast University Zhongda Hospital, Nanjing, Jiangsu, China
| | - Yinmin Gu
- The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
- School of Medicine, Southeast University, Nanjing, Jiangsu, China
| | - Hongbo Hu
- Center for Immunology and Hematology, Department of Biotherapy and Cancer Center, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China
| | - Shan Gao
- Department of Microbiology and Immunology, Shanxi Medical University, Taiyuan, Shanxi, China
- School of Life Sciences and Technology, Advanced Institute for Life and Health, Southeast University Zhongda Hospital, Nanjing, Jiangsu, China
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14
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Moore J, Gkantalis J, Guix I, Chou W, Yuen K, Lazar AA, Spitzer M, Combes A, Barcellos-Hoff MH. Identification of a conserved subset of cold tumors responsive to immune checkpoint blockade. J Immunother Cancer 2025; 13:e010528. [PMID: 40050047 PMCID: PMC11887281 DOI: 10.1136/jitc-2024-010528] [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: 09/06/2024] [Accepted: 02/03/2025] [Indexed: 03/09/2025] Open
Abstract
BACKGROUND The efficacy of immune checkpoint blockade (ICB) depends on restoring immune recognition of cancer cells that have evaded immune surveillance. Transforming growth factor-beta (TGFβ) is associated with immune-poor, so-called cold tumors whereas loss of its signaling promotes DNA misrepair that could stimulate immune response. METHODS We analyzed transcriptomic data from IMvigor210, The Cancer Genome Atlas, and Tumor Immune Syngeneic MOuse data sets to evaluate the predictive value of high βAlt, a score representing low expression of a signature consisting of TGFβ targets and high expression of genes involved in error-prone DNA repair. The immune context of βAlt was assessed by evaluating tumor-educated immune signatures. An ICB-resistant, high βAlt preclinical tumor model was treated with a TGFβ inhibitor, radiation, and/or ICB and assessed for immune composition and tumor control. RESULTS We found that a high βAlt score predicts ICB response yet is paradoxically associated with an immune-poor tumor microenvironmentcancer in both human and mouse tumors. We postulated that high βAlt cancers consist of cancer cells in which loss of TGFβ signaling generates a TGFβ rich, immunosuppressive tumor microenvironment. Accordingly, preclinical modeling showed that TGFβ inhibition followed by radiotherapy could convert an immune-poor, high βAlt tumor to an immune-rich, ICB-responsive tumor. Mechanistically, TGFβ inhibition increased activated natural killer (NK) cells, which were required to recruit lymphocytes to respond to ICB in irradiated tumors. NK cell activation signatures were also increased in high βAlt, cold mouse and human tumors that responded to ICB. CONCLUSIONS These studies indicate that loss of TGFβ signaling competency and gain of error-prone DNA repair identifies a subset of cold tumors that are responsive to ICB. Our mechanistic studies show that inhibiting TGFβ activity can convert a high βAlt, cold tumor into ICB-responsive tumors via NK cells. A biomarker consisting of combined TGFβ, DNA repair, and immune context signatures is a means to prospectively identify patients whose cancers may be converted from cold to hot with appropriate therapy.
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Affiliation(s)
- Jade Moore
- Department of Radiation Oncology, University of California San Francisco, San Francisco, California, USA
| | - Jim Gkantalis
- Department of Radiation Oncology, University of California San Francisco, San Francisco, California, USA
| | - Ines Guix
- Department of Radiation Oncology, University of California San Francisco, San Francisco, California, USA
| | - William Chou
- Department of Radiation Oncology, University of California San Francisco, San Francisco, California, USA
| | - Kobe Yuen
- Oncology Biomarker Development, Genentech, South San Francisco, California, USA
| | - Ann A Lazar
- Division of Oral Epidemiology and Division of Biostatistics, University of California San Francisco, San Francisco, California, USA
| | - Matthew Spitzer
- Depts of Otolaryngology-Head and Neck Surgery and of Microbiology and Immunology, University of California San Francisco, San Francisco, California, USA
| | - Alexis Combes
- Department of Pathology, University of California San Francisco, San Francisco, California, USA
| | - Mary Helen Barcellos-Hoff
- Department of Radiation Oncology, University of California San Francisco, San Francisco, California, USA
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15
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Choi AS, Moon TJ, Bhalotia A, Rajan A, Ogunnaike L, Hutchinson DW, Hwang I, Gokhale A, Kim JN, Ma T, Karathanasis E. Lipid Nanoparticles and PEG: Time Frame of Immune Checkpoint Blockade Can Be Controlled by Adjusting the Rate of Cellular Uptake of Nanoparticles. Mol Pharm 2025. [PMID: 40035231 DOI: 10.1021/acs.molpharmaceut.4c01039] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/05/2025]
Abstract
The engineerability of lipid nanoparticles (LNPs) and their ability to deliver nucleic acids make LNPs attractive tools for cancer immunotherapy. LNP-based gene delivery can be employed for various approaches in cancer immunotherapy, including encoding tumor-associated antigens and silencing of negative immune checkpoint proteins. For example, LNPs carrying small interfering RNAs can offer several advantages, including sustained and durable inhibition of an immune checkpoint protein. Due to their tunable design, modifying the lipid composition of LNPs can regulate the rate of their uptake by immune cells and the rate of gene silencing. Controlling the kinetics of LNP uptake provides additional flexibility and strategies to generate appropriate immunomodulation in the tumor microenvironment. Here, we evaluated the effects of polyethylene glycol (PEG) content ranging from 0.5 to 6 mol % on the cellular uptake of LNPs by immune cells and gene silencing of PD-L1 after intratumoral administration. We evaluated the cellular uptake and PD-L1 blockade in vitro in cell studies and in vivo using the YUMM1.7 melanoma tumor model. Cell studies showed that the rate of cell uptake was inversely correlated to an increasing mol % of PEG in a linear relationship. In the in vivo studies, 0.5% PEG LNP initiated an immediate effect in the tumor with a significant decrease in the PD-L1 expression of immune cells observed within 24 h. In comparison, the gene silencing effect of 6% PEG LNP was delayed, with a significant decrease of PD-L1 expression in immune cell subsets being observed 72 h after administration. Notably, performance of the 6% PEG LNP at 72 h was comparable to that of the 0.5% PEG LNP at 24 h. Overall, this study suggests that PEG modifications and intratumoral administration of LNPs can be a promising strategy for an effective antitumor immune response.
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Affiliation(s)
- Andrew S Choi
- Department of Biomedical Engineering, School of Medicine, Case Western Reserve University, Cleveland, Ohio 44106, United States
| | - Taylor J Moon
- Department of Biomedical Engineering, School of Medicine, Case Western Reserve University, Cleveland, Ohio 44106, United States
| | - Anubhuti Bhalotia
- Department of Biomedical Engineering, School of Medicine, Case Western Reserve University, Cleveland, Ohio 44106, United States
| | - Aarthi Rajan
- Department of Biomedical Engineering, School of Medicine, Case Western Reserve University, Cleveland, Ohio 44106, United States
| | - Laolu Ogunnaike
- Department of Biomedical Engineering, School of Medicine, Case Western Reserve University, Cleveland, Ohio 44106, United States
| | - Diarmuid W Hutchinson
- Department of Biomedical Engineering, School of Medicine, Case Western Reserve University, Cleveland, Ohio 44106, United States
| | - Inga Hwang
- Department of Biomedical Engineering, School of Medicine, Case Western Reserve University, Cleveland, Ohio 44106, United States
| | - Aaditya Gokhale
- Department of Biomedical Engineering, School of Medicine, Case Western Reserve University, Cleveland, Ohio 44106, United States
| | - Justin N Kim
- Department of Biomedical Engineering, School of Medicine, Case Western Reserve University, Cleveland, Ohio 44106, United States
| | - Timothy Ma
- Department of Biomedical Engineering, School of Medicine, Case Western Reserve University, Cleveland, Ohio 44106, United States
| | - Efstathios Karathanasis
- Department of Biomedical Engineering, School of Medicine, Case Western Reserve University, Cleveland, Ohio 44106, United States
- Case Comprehensive Cancer Center, School of Medicine, Case Western Reserve University, Cleveland, Ohio 44106, United States
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16
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Majocchi S, Lloveras P, Nouveau L, Legrand M, Viandier A, Malinge P, Charreton M, Raymond C, Pace EA, Millard BL, Svensson LA, Kelpšas V, Anceriz N, Salgado-Pires S, Daubeuf B, Magistrelli G, Gueneau F, Moine V, Masternak K, Shang L, Fischer N, Ferlin WG. NI-3201 Is a Bispecific Antibody Mediating PD-L1-Dependent CD28 Co-stimulation on T Cells for Enhanced Tumor Control. Cancer Immunol Res 2025; 13:365-383. [PMID: 39760515 DOI: 10.1158/2326-6066.cir-24-0298] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2024] [Revised: 09/02/2024] [Accepted: 11/26/2024] [Indexed: 01/07/2025]
Abstract
Despite advances in cancer immunotherapy, such as targeting the PD-1/PD-L1 axis, a substantial number of patients harbor tumors that are resistant or relapse. Selective engagement of T-cell co-stimulatory molecules with bispecific antibodies may offer novel therapeutic options by enhancing signal 1-driven activation occurring via T-cell receptor engagement. In this study, we report the development and preclinical characterization of NI-3201, a PD-L1×CD28 bispecific antibody generated on the κλ-body platform that was designed to promote T-cell activity and antitumor function through a dual mechanism of action. We confirmed that NI-3201 blocks the PD-L1/PD-1 immune checkpoint pathway and conditionally provides T-cell co-stimulation via CD28 (signal 2) when engaging PD-L1+ tumors or immune cells. In systems with signal 1-primed T cells, NI-3201 enhanced potent effector functionality: in vitro through antigen-specific recall assays with cytomegalovirus-specific T cells and in vivo by inducing tumor regression and immunologic memory in tumor-associated antigen-expressing MC38 syngeneic mouse models. When T-cell engagers were used to provide synthetic signal 1, the combination with NI-3201 resulted in synergistic T cell-dependent cytotoxicity and potent antitumor activity in two humanized mouse tumor models. Nonhuman primate safety assessments showed favorable tolerability and pharmacokinetics at pharmacologically active doses. Quantitative systems pharmacology modeling predicted that NI-3201 exposure results in antitumor activity in patients, but this remains to be investigated. Overall, this study suggests that by combining PD-L1 blockade with safe and effective CD28 co-stimulation, NI-3201 has the potential to improve cancer immunotherapy outcomes, and the clinical development of NI-3201 for PD-L1+ solid tumors is planned.
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Affiliation(s)
- Sara Majocchi
- Light Chain Bioscience - Novimmune SA, Geneva, Switzerland
| | | | - Lise Nouveau
- Light Chain Bioscience - Novimmune SA, Geneva, Switzerland
| | | | | | | | - Maud Charreton
- Light Chain Bioscience - Novimmune SA, Geneva, Switzerland
| | - Cecile Raymond
- Light Chain Bioscience - Novimmune SA, Geneva, Switzerland
| | | | | | | | | | - Nadia Anceriz
- Light Chain Bioscience - Novimmune SA, Geneva, Switzerland
| | | | - Bruno Daubeuf
- Light Chain Bioscience - Novimmune SA, Geneva, Switzerland
| | | | - Franck Gueneau
- Light Chain Bioscience - Novimmune SA, Geneva, Switzerland
| | - Valéry Moine
- Light Chain Bioscience - Novimmune SA, Geneva, Switzerland
| | | | - Limin Shang
- Light Chain Bioscience - Novimmune SA, Geneva, Switzerland
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17
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Bader KB, Padilla F, Haworth KJ, Ellens N, Dalecki D, Miller DL, Wear KA. Overview of Therapeutic Ultrasound Applications and Safety Considerations: 2024 Update. JOURNAL OF ULTRASOUND IN MEDICINE : OFFICIAL JOURNAL OF THE AMERICAN INSTITUTE OF ULTRASOUND IN MEDICINE 2025; 44:381-433. [PMID: 39526313 PMCID: PMC11796337 DOI: 10.1002/jum.16611] [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: 08/11/2024] [Revised: 10/11/2024] [Accepted: 10/19/2024] [Indexed: 11/16/2024]
Abstract
A 2012 review of therapeutic ultrasound was published to educate researchers and physicians on potential applications and concerns for unintended bioeffects (doi: 10.7863/jum.2012.31.4.623). This review serves as an update to the parent article, highlighting advances in therapeutic ultrasound over the past 12 years. In addition to general mechanisms for bioeffects produced by therapeutic ultrasound, current applications, and the pre-clinical and clinical stages are outlined. An overview is provided for image guidance methods to monitor and assess treatment progress. Finally, other topics relevant for the translation of therapeutic ultrasound are discussed, including computational modeling, tissue-mimicking phantoms, and quality assurance protocols.
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Affiliation(s)
| | - Frederic Padilla
- Gene Therapy ProgramFocused Ultrasound FoundationCharlottesvilleVirginiaUSA
- Department of RadiologyUniversity of Virginia Health SystemCharlottesvilleVirginiaUSA
| | - Kevin J. Haworth
- Department of PediatricsUniversity of CincinnatiCincinnatiOhioUnited States
- Department of Internal MedicineUniversity of CincinnatiCincinnatiOhioUSA
- Department of Biomedical EngineeringUniversity of CincinnatiCincinnatiOhioUSA
| | | | - Diane Dalecki
- Department of Biomedical EngineeringUniversity of RochesterRochesterNew YorkUSA
| | - Douglas L. Miller
- Department of RadiologyUniversity of Michigan Health SystemAnn ArborMichiganUSA
| | - Keith A. Wear
- Center for Devices and Radiological HealthU.S. Food and Drug AdministrationSilver SpringMarylandUSA
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18
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Zhang K, Li S, Li J, Zhou X, Qin Y, Wu L, Ling J. Ultra-pH-sensitive nanoplatform for precise tumor therapy. Biomaterials 2025; 314:122858. [PMID: 39366182 DOI: 10.1016/j.biomaterials.2024.122858] [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: 06/21/2024] [Revised: 09/16/2024] [Accepted: 09/26/2024] [Indexed: 10/06/2024]
Abstract
The emergence of precision cancer treatment has triggered a paradigm shift in the field of oncology, facilitating the implementation of more effective and personalized therapeutic approaches that enhance patient outcomes. The pH of the tumor microenvironment (TME) plays a pivotal role in both the initiation and progression of cancer, thus emerging as a promising focal point for precision cancer treatment. By specifically targeting the acidic conditions inherent to the tumor microenvironment, innovative therapeutic interventions have been proposed, exhibiting significant potential in augmenting treatment efficacy and ameliorating patient prognosis. The concept of ultra-pH-sensitive (UPS) nanoplatform was proposed several years ago, demonstrating exceptional pH sensitivity and an adjustable pH transition point. Subsequently, diverse UPS nanoplatforms have been actively explored for biomedical applications, enabling the loading of fluorophores, therapeutic drugs, and photosensitizers. This review aims to elucidate the design strategy and response mechanism of the UPS nanoplatform, with a specific emphasis on its applications in surgical therapy, immunotherapy, drug delivery, photodynamic therapy, and photothermal therapy. The potential and challenges of translating in the clinic on UPS nanoplatforms are finally explored. Thanks to its responsive and easily modifiable nature, the integration of multiple functional units within a UPS nanoplatform holds great promise for future advancements in tumor precision theranositcs.
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Affiliation(s)
- Ke Zhang
- Nantong Key Laboratory of Public Health and Medical Analysis, School of Public Health, Nantong University, Nantong, Jiangsu, 226019, China
| | - Shijie Li
- Nantong Key Laboratory of Public Health and Medical Analysis, School of Public Health, Nantong University, Nantong, Jiangsu, 226019, China
| | - Jiaying Li
- Nantong Key Laboratory of Public Health and Medical Analysis, School of Public Health, Nantong University, Nantong, Jiangsu, 226019, China
| | - Xiaobo Zhou
- Nantong Key Laboratory of Public Health and Medical Analysis, School of Public Health, Nantong University, Nantong, Jiangsu, 226019, China.
| | - Yuling Qin
- Nantong Key Laboratory of Public Health and Medical Analysis, School of Public Health, Nantong University, Nantong, Jiangsu, 226019, China
| | - Li Wu
- Nantong Key Laboratory of Public Health and Medical Analysis, School of Public Health, Nantong University, Nantong, Jiangsu, 226019, China; School of Life Sciences, Nantong University, Nantong, Jiangsu, 226019, China.
| | - Jue Ling
- Key Laboratory of Neuroregeneration of Jiangsu and the Ministry of Education, Co-Innovation Center of Neuroregeneration, Nantong University, Nantong, 226001, China.
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19
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Panja P, Manne U, Awasthi V, Bhattacharya R, Mukherjee P. Interrogation of the tumor microenvironment by nanoparticles. Cancer Lett 2025; 612:217454. [PMID: 39805387 DOI: 10.1016/j.canlet.2025.217454] [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: 10/25/2024] [Revised: 01/08/2025] [Accepted: 01/10/2025] [Indexed: 01/16/2025]
Abstract
The tumor microenvironment (TME) plays a pivotal role in cancer progression by fostering intricate multicellular crosstalk among cancer cells, stromal cells, and immune cells. This review explores the emerging paradigm of utilizing nanoparticles to disrupt this crosstalk within the TME as a therapeutic strategy. Nanoparticles are engineered with precise physicochemical properties to target specific cell types and deliver therapeutic payloads, thereby inhibiting critical signaling pathways involved in tumor growth, invasion, and metastasis. The mechanisms involved include modulation of the immune response, interference with growth factor signaling, and induction of programmed cell death in cancer cells. Challenges such as biocompatibility, efficient delivery, and potential development of resistance are discussed alongside promising advancements in nanoparticle design. Moving forward, integration of nanoparticle-based therapies with existing treatment modalities holds great potential for enhancing therapeutic efficacy and personalized medicine in cancer therapy.
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Affiliation(s)
- Prasanta Panja
- Department of Pathology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, 73104, USA
| | - Upender Manne
- Department of Pathology, University of Alabama at Birmingham, Birmingham, AL, USA; O'Neal Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Vibhudutta Awasthi
- Department of Pharmaceutical Sciences, University of Oklahoma Health Science Center, Suite 309, 1110 N. Stonewall Avenue, Oklahoma City, OK, 73117, USA
| | - Resham Bhattacharya
- Department of Obstetrics and Gynecology, The University of Oklahoma Health Sciences Center, Oklahoma City, OK, 73104, USA; Peggy and Charles Stephenson Cancer Center, The University of Oklahoma Health Sciences Center, Oklahoma City, OK, 73104, USA
| | - Priyabrata Mukherjee
- Department of Pathology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, 73104, USA; Peggy and Charles Stephenson Cancer Center, The University of Oklahoma Health Sciences Center, Oklahoma City, OK, 73104, USA.
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20
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Zhuang AB, Xi Z, Cheng YX, Zhang CH, Li WG. Current status and future perspectives of immunotherapy for abdominal liposarcoma: From basic research to clinical practice. Shijie Huaren Xiaohua Zazhi 2025; 33:81-88. [DOI: 10.11569/wcjd.v33.i2.81] [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: 09/28/2024] [Revised: 11/06/2024] [Accepted: 12/17/2024] [Indexed: 02/28/2025] Open
Abstract
Liposarcoma is a highly heterogeneous type of soft tissue sarcoma originating from adipose tissue, characterized by complex biological behavior and invasiveness. Traditional treatments have shown limited efficacy in high-grade and metastatic liposarcoma, with unsatisfactory patient outcomes. In recent years, the breakthroughs of immunotherapy in various solid tumors have sparked interest in its potential application to liposarcoma. This review systematically examines the progress in basic research and clinical practice of immunotherapy for liposarcoma, discussing the tumor immune microenvironment, mechanisms of immune evasion, the application of immune checkpoint inhibitors, combination therapy strategies, the challenges faced, as well as the future direction, with an aim to provide a theoretical basis for personalized treatment of liposarcoma, promote the development of novel immunotherapy strategies, and ultimately improve patient prognosis and quality of life.
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Affiliation(s)
- Ao-Bo Zhuang
- School of Medicine, Xiamen University, Xiamen 361102, Fujian Province, China
| | - Zhe Xi
- School of Medicine, Xiamen University, Xiamen 361102, Fujian Province, China
| | - Ying-Xue Cheng
- School of Medicine, Xiamen University, Xiamen 361102, Fujian Province, China
| | - Chen-He Zhang
- School of Medicine, Xiamen University, Xiamen 361102, Fujian Province, China
| | - Wen-Gang Li
- Department of Hepatobiliary and Pancreatic Surgery, Xiang'an Hospital of Xiamen University, Xiamen 361102, Fujian Province, China
- Cancer Research Center of Xiamen University, Xiamen 361005, Fujian Province, China
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21
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Silwal AP, Thennakoon SKS, Jahan R, Arya SP, Postema RM, Timilsina HP, Reynolds AM, Kokensparger KB, Tan X. Aptamer-Assisted DNA SELEX: Dual-Site Targeting of a Single Protein. ACS Biomater Sci Eng 2025. [PMID: 40016918 DOI: 10.1021/acsbiomaterials.4c02053] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/01/2025]
Abstract
Heterobivalent fusion aptamers that target a single protein show significant promise for studying protein-protein interactions. However, a major challenge is finding two distinct aptamers that can simultaneously recognize the same protein. In this study, we used a novel technique called Aptamer-Assisted DNA SELEX (AADS) to isolate two distinct aptamers capable of recognizing different sites on the programmed death-ligand 1 (PD-L1) protein. Initially, Aptamer 1 (P1C2) was identified by using conventional DNA SELEX targeting the PD-L1 protein. Subsequently, Aptamer 2 (P1CSC) was obtained via AADS, which was designed to bind to the PD-L1/P1C2 complex. After confirming that both aptamers could simultaneously recognize the PD-L1 protein, we engineered fusion aptamers by optimizing their orientation and linker sequences, resulting in the creation of the optimized fusion aptamer, P1CSC-T7-P1C1. Our fusion aptamer targeting PD-L1 demonstrated remarkable specificity and affinity, effectively inhibiting PD-1/PD-L1 interactions at both the protein and cellular levels. These findings highlight the potential of fusion aptamers via AADS as powerful tools for targeting the PD-L1 protein and cancer cells (A549 cells). This represents a significant advancement in aptamer-based molecular recognition and has the potential to drive innovation as a versatile method for targeting a wide range of proteins.
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Affiliation(s)
- Achut Prasad Silwal
- Department of Chemistry and Center for Photochemical Sciences, Bowling Green State University, Bowling Green, Ohio 43403, United States
| | | | - Raunak Jahan
- Department of Chemistry and Center for Photochemical Sciences, Bowling Green State University, Bowling Green, Ohio 43403, United States
| | - Satya Prakash Arya
- Department of Chemistry and Center for Photochemical Sciences, Bowling Green State University, Bowling Green, Ohio 43403, United States
| | - Rick Mason Postema
- Department of Chemistry and Center for Photochemical Sciences, Bowling Green State University, Bowling Green, Ohio 43403, United States
| | - Hari Prasad Timilsina
- Department of Chemistry and Center for Photochemical Sciences, Bowling Green State University, Bowling Green, Ohio 43403, United States
| | - Andrew Michael Reynolds
- Department of Chemistry and Center for Photochemical Sciences, Bowling Green State University, Bowling Green, Ohio 43403, United States
| | - Kaytelee Brooke Kokensparger
- Department of Chemistry and Center for Photochemical Sciences, Bowling Green State University, Bowling Green, Ohio 43403, United States
| | - Xiaohong Tan
- Department of Chemistry and Center for Photochemical Sciences, Bowling Green State University, Bowling Green, Ohio 43403, United States
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22
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Mousavi S, Nouri S, Sadeghipour A, Atashi A. Tumor microenvironment as a novel therapeutic target for lymphoid leukemias. Ann Hematol 2025:10.1007/s00277-025-06237-w. [PMID: 39994019 DOI: 10.1007/s00277-025-06237-w] [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: 05/12/2024] [Accepted: 01/29/2025] [Indexed: 02/26/2025]
Abstract
Lymphoid leukemias represent a significant global health burden, leading to substantial morbidity and mortality. The intricate interplay between leukemic cells and their surrounding tumor microenvironment (TME) is pivotal in disease initiation, progression, and therapeutic resistance. Comprising a dynamic milieu of stromal, immune, and leukemic cell populations, the TME orchestrates a complex network of signaling pathways and molecular interactions that foster leukemic cell survival and proliferation while evading immune surveillance. The crosstalk between these diverse cellular components within the TME not only fuels tumor progression but also confers resistance to conventional therapies, including the development of multi-drug resistance (MDR). Recognizing the pivotal role of the TME in shaping disease outcomes, novel therapeutic approaches targeting this dynamic ecosystem have emerged as promising strategies to complement existing anti-leukemic treatments. As a result, drugs that target the TME have been developed as complementary strategies to those that directly attack tumor cells. Thus, a detailed understanding of the TME components and their interactions with tumor cells is critical. Such knowledge can guide the design and implementation of novel targeted therapies for lymphoid leukemias.
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Affiliation(s)
- Shahrzad Mousavi
- Department of Hematology, Faculty of Medical Sciences, Tarbiat Modares University, P.O. Box 14115-111, Tehran, Iran
| | - Soheil Nouri
- Department of Hematology, Faculty of Medical Sciences, Tarbiat Modares University, P.O. Box 14115-111, Tehran, Iran
| | - Arezoo Sadeghipour
- Department of Biochemistry, Faculty of Biological Sciences, Tarbiat Modares University, P.O. Box 14115-175, Tehran, Iran
| | - Amir Atashi
- Department of Medical Laboratory Sciences, Faculty of Allied Medical Sciences, Shahroud University of Medical Sciences, Shahroud, Iran.
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23
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Lyu H, Zhou T, Sun X, Chen H, Li J, Shao M, Li J, Zhang Q, Jiang G, Zhou X. Establishing a prognostic model with immune-related genes and investigating EPHB6 expression pattern in breast cancer. Sci Rep 2025; 15:6630. [PMID: 39994456 PMCID: PMC11850720 DOI: 10.1038/s41598-025-91318-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: 11/03/2024] [Accepted: 02/19/2025] [Indexed: 02/26/2025] Open
Abstract
In breast cancer, the behavior of genes linked to the immune system and their interaction with the tumor's microenvironment suggest new paths for tailored therapies. Utilizing the TCGA-BRCA cohort, we established a robust overall survival prediction model through LASSO regression and Gaussian mixture model based on risk group. We found that low-risk patients responded better to chemotherapy. Single-cell analysis further confirmed expression patterns of signature genes in both healthy and malignant breast samples. Our study, the first to use immunohistochemistry (IHC) to assess EPHB6 expression in benign and malignant breast samples, revealed higher EPHB6 levels in benign tissue and triple-negative cancer. In axillary lymph nodes, EPHB6 was predominantly expressed in stroma cells, with diminished expression in cancerous cells upon infiltration. These insights highlight the significance of immune-related genes in breast cancer.
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Affiliation(s)
- Hui Lyu
- Department of Immunology, College of Basic Medicine, Binzhou Medical University, Yantai, Shandong, China
- Clinical Laboratory, Zibo Maternal and Child Health Hospital, Zibo, Shandong, China
| | - Tao Zhou
- Department of General Surgery, Rizhao People's Hospital, Rizhao, Shandong, China
| | - Xiaoqin Sun
- Department of Pathology, Zibo Maternal and Child Health Hospital, Zibo, Shandong, China
| | - Hui Chen
- Department of Pathology, Zibo Maternal and Child Health Hospital, Zibo, Shandong, China
| | - Jing Li
- Department of Pathology, Zibo Maternal and Child Health Hospital, Zibo, Shandong, China
| | - Mingxiu Shao
- Clinical Laboratory, Zibo Maternal and Child Health Hospital, Zibo, Shandong, China
| | - Jianmei Li
- Clinical Laboratory, Zibo Maternal and Child Health Hospital, Zibo, Shandong, China
| | - Quanmei Zhang
- Department of Ultrasound, Zibo Maternal and Child Health Hospital, Zibo, Shandong, China
| | - Guosheng Jiang
- Department of Immunology, College of Basic Medicine, Binzhou Medical University, Yantai, Shandong, China.
| | - Xin Zhou
- Department of Breast and Thyroid Surgery, Zibo Maternal and Child Health Hospital, Zibo, Shandong, China.
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24
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Zhao WJ, Wang ML, Zhao YF, Zhao WP, Huang QH, Lu ZW, Jia F, Shi JJ, Liu BS, Han WH, Lu HW, Zhang BC, Wang ZX. Pan-cancer analysis reveals SMARCAL1 expression is associated with immune cell infiltration and poor prognosis in various cancers. Sci Rep 2025; 15:6591. [PMID: 39994264 PMCID: PMC11850860 DOI: 10.1038/s41598-025-88955-9] [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: 06/07/2024] [Accepted: 02/03/2025] [Indexed: 02/26/2025] Open
Abstract
Although immune checkpoint inhibition in particular has shown promise in cancer immunotherapy, it is not always efficient. Recent studies suggest that SMARCAL1 may play a role in tumor immune evasion, yet its pan-cancer role is unclear. We conducted a comprehensive analysis of SMARCAL1 using TCGA, GTEx, and CCLE databases, evaluating its expression, genetic alterations, epigenetic modifications, and their clinical correlations across 33 cancer types. Our findings indicate that SMARCAL1 is overexpressed in several cancers, such as Glioma, LUAD, KIRC, and LIHC, impacting prognosis. Elevated SMARCAL1 is linked to poor outcomes in Glioma, LUAD, and LIHC but correlates with better survival in KIRC. We also found significant associations between SMARCAL1 expression and DNA methylation in 13 cancers. Furthermore, SMARCAL1 expression correlates with immune infiltration, suggesting it as a potential therapeutic target in cancer immunotherapy. This study underscores the need for further research on SMARCAL1 to enhance immunotherapeutic strategies.
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Affiliation(s)
- Wu-Jie Zhao
- Department of Neurosurgery and Department of Neuroscience, Fujian Key Laboratory of Brain Tumors Diagnosis and Precision Treatment, Xiamen Key Laboratory of Brain Center, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, 361005, Fujian, China
| | - Meng-Lei Wang
- Department of Digestive Diseases, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, 361005, Fujian, China
| | - Yun-Fang Zhao
- Jitang College of North China University of Science and Technology, Tangshan, 063000, Hebei, China
| | - Wen-Peng Zhao
- Department of Neurosurgery and Department of Neuroscience, Fujian Key Laboratory of Brain Tumors Diagnosis and Precision Treatment, Xiamen Key Laboratory of Brain Center, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, 361005, Fujian, China
| | - Qiong-Hui Huang
- The School of Clinical Medicine, Fujian Medical University, Fuzhou, 350108, Fujian, China
| | - Zhen-Wei Lu
- The School of Clinical Medicine, Fujian Medical University, Fuzhou, 350108, Fujian, China
| | - Fang Jia
- Department of Neurosurgery, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510630, Guangdong, China
| | - Jin-Jin Shi
- Department of Neurosurgery and Department of Neuroscience, Fujian Key Laboratory of Brain Tumors Diagnosis and Precision Treatment, Xiamen Key Laboratory of Brain Center, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, 361005, Fujian, China
| | - Bo-Sen Liu
- Department of Neurosurgery and Department of Neuroscience, Fujian Key Laboratory of Brain Tumors Diagnosis and Precision Treatment, Xiamen Key Laboratory of Brain Center, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, 361005, Fujian, China
| | - Wan-Hong Han
- Department of Neurosurgery and Department of Neuroscience, Fujian Key Laboratory of Brain Tumors Diagnosis and Precision Treatment, Xiamen Key Laboratory of Brain Center, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, 361005, Fujian, China
| | - Han-Wen Lu
- Department of Neurosurgery and Department of Neuroscience, Fujian Key Laboratory of Brain Tumors Diagnosis and Precision Treatment, Xiamen Key Laboratory of Brain Center, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, 361005, Fujian, China
| | - Bing-Chang Zhang
- Department of Neurosurgery and Department of Neuroscience, Fujian Key Laboratory of Brain Tumors Diagnosis and Precision Treatment, Xiamen Key Laboratory of Brain Center, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, 361005, Fujian, China.
| | - Zhan-Xiang Wang
- Department of Neurosurgery and Department of Neuroscience, Fujian Key Laboratory of Brain Tumors Diagnosis and Precision Treatment, Xiamen Key Laboratory of Brain Center, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, 361005, Fujian, China.
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25
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Huang R, Wu Y, Shen F, Chen S, Yang X, Lin Y, Fang Y, Shen J. Manganese-coordinated nanoparticles loaded with CHK1 inhibitor dually activate cGAS-STING pathway and enhance efficacy of immune checkpoint therapy. Biomaterials 2025; 319:123199. [PMID: 40009899 DOI: 10.1016/j.biomaterials.2025.123199] [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: 11/03/2024] [Revised: 01/26/2025] [Accepted: 02/16/2025] [Indexed: 02/28/2025]
Abstract
Notable advancements have been made in utilizing immune checkpoint blockade (ICB) for the treatment of various cancers. However, the overall response rates and therapeutic effectiveness remain unsatisfactory. One cause is the inadequate immune environment characterized by poor T cell infiltration in tumors. To address these limitations, enhancing immune infiltration is crucial for optimizing the therapeutic efficacy of ICB. Activating the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway is essential for initiating immune response and has become a potential target for developing combination therapies with ICB. In this study, we designed and fabricated manganese-containing nanoparticles loaded with the CHK1 inhibitor PF477736, which were subsequently encapsulated with macrophage membrane (PF/MMSN@MPM). This innovative design achieved excellent tumor targeting and demonstrated potent antitumor effects. The combination therapy dually amplified the cGAS-STING pathway, causing a cascade of enhanced therapeutic effects against tumors. Furthermore, single-cell mass cytometry (CyTOF) analysis revealed that PF/MMSN@MPM enhanced the activation and infiltration of immune cells. Moreover, the combination of PF/MMSN@MPM with anti-PD-1 (αPD-1) exhibited a stronger therapeutic effect compared to αPD-1 alone. PF/MMSN@MPM precisely and synergistically activated the cGAS-STING pathway, significantly improving therapeutic efficacy of ICB, and offering promising potential for tumor therapy.
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Affiliation(s)
- Rui Huang
- Department of Ophthalmology, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China; Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai, 200025, China; Institute of Translational Medicine, National Facility for Translational Medicine, Shanghai Jiao Tong University, Shanghai, 200240, China
| | - Yijia Wu
- Department of Ophthalmology, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China; Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai, 200025, China; Institute of Translational Medicine, National Facility for Translational Medicine, Shanghai Jiao Tong University, Shanghai, 200240, China
| | - Feiyang Shen
- Department of Ophthalmology, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China; Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai, 200025, China; Institute of Translational Medicine, National Facility for Translational Medicine, Shanghai Jiao Tong University, Shanghai, 200240, China
| | - Shuai Chen
- Institute of Translational Medicine, National Facility for Translational Medicine, Shanghai Jiao Tong University, Shanghai, 200240, China
| | - Xiaoyu Yang
- Department of Ophthalmology, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China; Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai, 200025, China; Institute of Translational Medicine, National Facility for Translational Medicine, Shanghai Jiao Tong University, Shanghai, 200240, China
| | - Yao Lin
- Institute of Translational Medicine, National Facility for Translational Medicine, Shanghai Jiao Tong University, Shanghai, 200240, China
| | - Yan Fang
- Department of Ophthalmology, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China; Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai, 200025, China; Institute of Translational Medicine, National Facility for Translational Medicine, Shanghai Jiao Tong University, Shanghai, 200240, China.
| | - Jianfeng Shen
- Department of Ophthalmology, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China; Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai, 200025, China; Institute of Translational Medicine, National Facility for Translational Medicine, Shanghai Jiao Tong University, Shanghai, 200240, China.
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Moore J, Gkantalis J, Guix I, Chou W, Yuen K, Lazar AA, Spitzer M, Combes AJ, Barcellos-Hoff MH. A conserved subset of cold tumors responsive to immune checkpoint blockade. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2025:2024.03.06.583752. [PMID: 38496519 PMCID: PMC10942434 DOI: 10.1101/2024.03.06.583752] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 03/19/2024]
Abstract
Background The efficacy of immune checkpoint blockade (ICB) depends on restoring immune recognition of cancer cells that have evaded immune surveillance. At the time of diagnosis, patients with lymphocyte-infiltrated cancers are the most responsive to ICB, yet a considerable fraction of patients have immune-poor tumors. Methods We analyzed transcriptomic data from IMvigor210, TCGA, and TISMO datasets to evaluate the predictive value of βAlt, a score representing the negative correlation of signatures consisting of transforming growth factor beta (TGFβ) targets and genes involved in error-prone DNA repair. The immune context of βAlt was assessed by evaluating tumor-educated immune signatures. An ICB-resistant, high βAlt preclinical tumor model was treated with a TGFβ inhibitor, radiation, and/or ICB and assessed for immune composition and tumor control. Results Here, we show that high βAlt is associated with an immune-poor context yet is predictive of ICB response in both humans and mice. A high βAlt cancer in which TGFβ signaling is compromised generates a TGFβ rich, immunosuppressive tumor microenvironment. Accordingly, preclinical modeling showed that TGFβ inhibition followed by radiotherapy could convert an immune-poor, ICB-resistant tumor to an immune-rich, ICB-responsive tumor. Mechanistically, TGFβ blockade in irradiated tumors activated natural killer cells that were required to recruit lymphocytes to respond to ICB. In support of this, natural killer cell activation signatures were also increased in immune-poor mouse and human tumors that responded to ICB. Conclusions These studies suggest that loss of TGFβ competency identifies a subset of cold tumors that are candidates for ICB. Our mechanistic studies show that inhibiting TGFβ activity converts high βAlt, cold tumors into ICB-responsive tumors via NK cells. Thus, a biomarker consisting of combined TGFβ, DNA repair, and immune context signatures provides a means to prospectively identify patients whose cancers may be converted from 'cold' to 'hot,' which could be exploited for therapeutic treatment.
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Affiliation(s)
- Jade Moore
- Department of Radiation Oncology, University of California, San Francisco, San Francisco, CA, USA
- A member of the imCORE Network
| | - Jim Gkantalis
- Department of Radiation Oncology, University of California, San Francisco, San Francisco, CA, USA
| | - Ines Guix
- Department of Radiation Oncology, University of California, San Francisco, San Francisco, CA, USA
| | - William Chou
- Department of Radiation Oncology, University of California, San Francisco, San Francisco, CA, USA
| | - Kobe Yuen
- Oncology Biomarker Development, Genentech Inc., South San Francisco, CA, USA
| | - Ann A. Lazar
- Division of Oral Epidemiology and Division of Biostatistics, University of California, San Francisco, CA, USA
| | - Mathew Spitzer
- Parker Institute for Cancer Immunotherapy, Department of Otolaryngology-Head and Neck Surgery, Department of Microbiology and Immunology, University of California, San Francisco, CA USA
- A member of the imCORE Network
| | - Alexis J. Combes
- Department of Pathology, CoLabs, University of California, San Francisco, San Francisco, CA, USA
| | - Mary Helen Barcellos-Hoff
- Department of Radiation Oncology, University of California, San Francisco, San Francisco, CA, USA
- Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, USA
- A member of the imCORE Network
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Zhang J, Hu Y, Wen X, Yang Z, Wang Z, Feng Z, Bai H, Xue Q, Miao Y, Tian T, Zheng P, Zhang J, Li J, Qiu L, Xu JJ, Ye D. Tandem-controlled lysosomal assembly of nanofibres induces pyroptosis for cancer immunotherapy. NATURE NANOTECHNOLOGY 2025:10.1038/s41565-025-01857-9. [PMID: 39966684 DOI: 10.1038/s41565-025-01857-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/18/2024] [Accepted: 01/08/2025] [Indexed: 02/20/2025]
Abstract
Pyroptosis has emerged as a promising approach for cancer immunotherapy. However, current pyroptosis inducers lack specificity for cancer cells and have a weak antitumour immune response. Here we report a tumour-specific nanoparticle (NP-NH-D5) that activates pyroptosis by disrupting lysosomes for cancer immunotherapy. NP-NH-D5 undergoes negative-to-positive charge reversal and nanoparticle-to-nanofibre transformation within tumour cell lysosomes through tandem response to extracellular matrix metallopeptidase-2 and intracellular reducing agents. The as-formed non-peptide nanofibres efficiently break the lysosomes and trigger gasdermin-D-mediated pyroptosis, leading to strong immunogenic cell death and alleviation of the immunosuppressive tumour microenvironment. In vivo, NP-NH-D5 inhibits orthotopic 4T1 breast tumours, prevents metastasis and recurrence, and prolongs survival without systemic side effects. Furthermore, it greatly enhances the effectiveness of PD-L1 antibody immunotherapy in the 4T1 late-stage lung metastasis and aggressive orthotopic Pan02 pancreatic tumour models. Our research may open pathways for developing stimuli-responsive pyroptosis inducers for precise cancer immunotherapy.
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Affiliation(s)
- Junya Zhang
- State Key Laboratory of Analytical Chemistry for Life Science, Chemistry and Biomedicine Innovation Center (ChemBIC), School of Chemistry and Chemical Engineering, Nanjing University, Nanjing, China
| | - Yuxuan Hu
- State Key Laboratory of Analytical Chemistry for Life Science, Chemistry and Biomedicine Innovation Center (ChemBIC), School of Chemistry and Chemical Engineering, Nanjing University, Nanjing, China
| | - Xidan Wen
- State Key Laboratory of Analytical Chemistry for Life Science, Chemistry and Biomedicine Innovation Center (ChemBIC), School of Chemistry and Chemical Engineering, Nanjing University, Nanjing, China
| | - Zeyue Yang
- State Key Laboratory of Coordination Chemistry, Chemistry and Biomedicine Innovation Center (ChemBIC), School of Chemistry and Chemical Engineering, Nanjing University, Nanjing, China
| | - Ziyi Wang
- State Key Laboratory of Coordination Chemistry, Chemistry and Biomedicine Innovation Center (ChemBIC), School of Chemistry and Chemical Engineering, Nanjing University, Nanjing, China
| | - Zhiyuan Feng
- State Key Laboratory of Analytical Chemistry for Life Science, Chemistry and Biomedicine Innovation Center (ChemBIC), School of Chemistry and Chemical Engineering, Nanjing University, Nanjing, China
| | - He Bai
- State Key Laboratory of Analytical Chemistry for Life Science, Chemistry and Biomedicine Innovation Center (ChemBIC), School of Chemistry and Chemical Engineering, Nanjing University, Nanjing, China
| | - Qi Xue
- State Key Laboratory of Coordination Chemistry, Chemistry and Biomedicine Innovation Center (ChemBIC), School of Chemistry and Chemical Engineering, Nanjing University, Nanjing, China
| | - Yinxing Miao
- State Key Laboratory of Analytical Chemistry for Life Science, Chemistry and Biomedicine Innovation Center (ChemBIC), School of Chemistry and Chemical Engineering, Nanjing University, Nanjing, China
| | - Tian Tian
- State Key Laboratory of Coordination Chemistry, Chemistry and Biomedicine Innovation Center (ChemBIC), School of Chemistry and Chemical Engineering, Nanjing University, Nanjing, China
| | - Peng Zheng
- State Key Laboratory of Coordination Chemistry, Chemistry and Biomedicine Innovation Center (ChemBIC), School of Chemistry and Chemical Engineering, Nanjing University, Nanjing, China
| | - Jingjing Zhang
- State Key Laboratory of Analytical Chemistry for Life Science, Chemistry and Biomedicine Innovation Center (ChemBIC), School of Chemistry and Chemical Engineering, Nanjing University, Nanjing, China
| | - Jie Li
- State Key Laboratory of Coordination Chemistry, Chemistry and Biomedicine Innovation Center (ChemBIC), School of Chemistry and Chemical Engineering, Nanjing University, Nanjing, China
| | - Ling Qiu
- NHC Key Laboratory of Nuclear Medicine, Jiangsu Key Laboratory of Molecular Nuclear Medicine, Jiangsu Institute of Nuclear Medicine, Wuxi, China
| | - Jing-Juan Xu
- State Key Laboratory of Analytical Chemistry for Life Science, Chemistry and Biomedicine Innovation Center (ChemBIC), School of Chemistry and Chemical Engineering, Nanjing University, Nanjing, China
| | - Deju Ye
- State Key Laboratory of Analytical Chemistry for Life Science, Chemistry and Biomedicine Innovation Center (ChemBIC), School of Chemistry and Chemical Engineering, Nanjing University, Nanjing, China.
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Park MN, Choi J, Maharub Hossain Fahim M, Asevedo EA, Nurkolis F, Ribeiro RIMA, Kang HN, Kang S, Syahputra RA, Kim B. Phytochemical synergies in BK002: advanced molecular docking insights for targeted prostate cancer therapy. Front Pharmacol 2025; 16:1504618. [PMID: 40034825 PMCID: PMC11872924 DOI: 10.3389/fphar.2025.1504618] [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: 10/01/2024] [Accepted: 01/20/2025] [Indexed: 03/05/2025] Open
Abstract
Achyranthes japonica (Miq.) Nakai (AJN) and Melandrium firmum (Siebold and Zucc.) Rohrb. (MFR) are medicinal plants recognized for their bioactive phytochemicals, including ecdysteroids, anthraquinones, and flavonoids. This study investigates the anticancer properties of key constituents of these plants, focusing on the BK002 formulation, a novel combination of AJN and MFR. Specifically, the research employs advanced molecular docking and in silico analyses to assess the interactions of bioactive compounds ecdysterone, inokosterone, and 20-hydroxyecdysone (20-HE) with key prostate cancer-related network proteins, including 5α-reductase, CYP17, DNMT1, Dicer, PD-1, and PD-L1. Molecular docking techniques were applied to evaluate the binding affinities contributions of the bioactive compounds in BK002 against prostate cancer-hub network targets. The primary focus was on enzymes like 5α-reductase and CYP17, which are central to androgen biosynthesis, as well as on cancer-related proteins such as DNA methyltransferase 1 (DNMT1), Dicer, programmed death-1 (PD-1), and programmed death ligand-1 (PD-L1). Based on data from prostate cancer patients, key target networks were identified, followed by in silico analysis of the primary bioactive components of BK002.In silico assessments were conducted to evaluate the safety profiles of these compounds, providing insights into their therapeutic potential. The docking studies revealed that ecdysterone, inokosterone, and 20-hydroxyecdysonec demonstrated strong binding affinities to the critical prostate cancer-related enzymes 5α-reductase and CYP17, contributing to a potential reduction in androgenic activity. These compounds also exhibited significant inhibitory interactions with DNMT1, Dicer, PD-1, and PD-L1, suggesting a capacity to interfere with key oncogenic and immune evasion pathways. Ecdysterone, inokosterone, and 20-hydroxyecdysone have demonstrated the ability to target key oncogenic pathways, and their favorable binding affinity profiles further underscore their potential as novel therapeutic agents for prostate cancer. These findings provide a strong rationale for further preclinical and clinical investigations, supporting the integration of BK002 into therapeutic regimens aimed at modulating tumor progression and immune responses.
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Affiliation(s)
- Moon Nyeo Park
- Department of Pathology, College of Korean Medicine, Kyung Hee University, Seoul, Republic of Korea
| | - Jinwon Choi
- Department of Pathology, College of Korean Medicine, Kyung Hee University, Seoul, Republic of Korea
| | | | - Estéfani Alves Asevedo
- Department of Pathology, College of Korean Medicine, Kyung Hee University, Seoul, Republic of Korea
- Experimental Pathology Laboratory, Midwest Campus, Federal University of São João del-Rei, Divinópolis, Brazil
| | - Fahrul Nurkolis
- Department of Biological Sciences, State Islamic University of Sunan Kalijaga (UIN Sunan Kalijaga), Yogyakarta, Indonesia
| | | | - Han Na Kang
- KM Convergence Research Division, Korea Institute of Oriental Medicine, Daejeon, Republic of Korea
| | - Sojin Kang
- Department of Pathology, College of Korean Medicine, Kyung Hee University, Seoul, Republic of Korea
| | - Rony Abdi Syahputra
- Department of Biological Sciences, State Islamic University of Sunan Kalijaga (UIN Sunan Kalijaga), Yogyakarta, Indonesia
| | - Bonglee Kim
- Department of Pathology, College of Korean Medicine, Kyung Hee University, Seoul, Republic of Korea
- Korean Medicine-Based Drug Repositioning Cancer Research Center, College of Korean Medicine, Kyung Hee University, Seoul, Republic of Korea
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Geng Q, Xu J, Du C, Zhang D, Jin Y, Song J, Qu W, Zhang C, Su G, Jiao P. Small molecules targeting immune checkpoint proteins for cancer immunotherapy: a patent and literature review (2020-2024). Expert Opin Ther Pat 2025:1-32. [PMID: 39907457 DOI: 10.1080/13543776.2025.2462849] [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: 08/06/2024] [Revised: 12/20/2024] [Accepted: 01/29/2025] [Indexed: 02/06/2025]
Abstract
INTRODUCTION Targeting immune checkpoint proteins (ICPs) via small molecules open a new window for cancer immunotherapy. Herein, we summarize recent advances of small molecules with novel chemical structures targeting ICPs, discusses their anti-tumor efficacies, which are important for the development of novel small molecules for cancer immunotherapy. AREAS COVERED In this review, the latest patents and literature were gathered through the comprehensive searches in the databases of European Patent Office (EPO), Cortellis Drug Discovery Intelligence (CDDI), PubMed and Web of Science using ICPs and compounds as key words. EXPERT OPINION To develop novel weapons to fight against cancer, small molecules targeting ICPs including CTLA-4, LAG-3, PD-L1, Siglec-9, TIM-3, TIGIT, and VISTA have been synthesized and evaluated in succession. Chief among them are the small molecules targeting PD-L1, which have been intensively investigated in recent years. Various in vitro assays such as ALPHA, HTRF binding assay, NFAT assay have been successfully developed to screen novel IPCs inhibitors. However, the in vivo assay, for example, using double-humanized PD-1/PD-L1 (hPD-1/hPD-L1) mouse as evaluation model, are seldom reported. Novel pharmacophores with new working mechanisms such as proteolysis targeting chimeras (PROTACs) and peptides are needed to enhance the therapeutic efficacy.
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Affiliation(s)
- Qiaohong Geng
- School of Chemistry and Chemical Engineering, Qilu Normal University, Jinan, Shandong, China
| | - Juanjuan Xu
- Department of Neurology, Changyi People's Hospital, Weifang, Shandong, China
| | - Chunsheng Du
- School of Chemistry and Chemical Engineering, Qilu Normal University, Jinan, Shandong, China
| | - Deheng Zhang
- School of Chemistry and Chemical Engineering, Qilu Normal University, Jinan, Shandong, China
| | - Yanrui Jin
- School of Chemistry and Chemical Engineering, Qilu Normal University, Jinan, Shandong, China
| | - Jiatong Song
- School of Chemistry and Chemical Engineering, Qilu Normal University, Jinan, Shandong, China
| | - Wenjing Qu
- School of Chemistry and Chemical Engineering, Qilu Normal University, Jinan, Shandong, China
| | - Changnan Zhang
- School of Chemistry and Chemical Engineering, Qilu Normal University, Jinan, Shandong, China
| | - Gaoxing Su
- School of Pharmacy, Nantong University, Nantong, Jiangsu, China
| | - Peifu Jiao
- School of Chemistry and Chemical Engineering, Qilu Normal University, Jinan, Shandong, China
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30
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Boehm DT, Landreth KM, Kilic ES, Lee KS, Misra B, Bobbala S, Damron FH, Liu TW. Intratumoral administration of mRNA COVID-19 vaccine delays melanoma growth in mice. Sci Rep 2025; 15:5337. [PMID: 39948424 PMCID: PMC11825918 DOI: 10.1038/s41598-025-89930-0] [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: 08/29/2024] [Accepted: 02/10/2025] [Indexed: 02/16/2025] Open
Abstract
Immunotherapies are effective for cancer treatment but are limited in 'cold' tumor microenvironments due to a lack of infiltrating CD8+ T cells, key players in the anti-cancer immune response. The onset of the COVID-19 pandemic sparked the widespread use of mRNA-formulated vaccines and is well documented that vaccination induces a Th1-skewed immune response. Here, we evaluated the effects of an intratumoral injection of the mRNA COVID-19 vaccine in subcutaneous melanoma tumor mouse models. Tumor growth and survival studies following a single intratumoral injection of the COVID-19 vaccine showed significant tumor suppression and prolonged survival in established B16F10 subcutaneous tumor-bearing mice. mRNA vaccine treatment resulted in a significant increase in CD8+ T cell infiltration into the tumor microenvironment, as observed using intravital imaging and flow cytometry. Further tumor growth suppression was achieved using additional mRNA vaccine treatments. Combination administration of mRNA vaccine with immune checkpoint therapies demonstrated enhanced effects, further delaying tumor growth and improving the survival time of tumor-bearing mice. This study demonstrates that mRNA vaccines may be used as adjuvants for immunotherapies.
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Affiliation(s)
- Dylan T Boehm
- Department of Microbiology, Immunology, and Cell Biology, West Virginia University, 64 Medical Center Drive, Morgantown, WV, 26506, USA
- Vaccine Development Center at West Virginia University Health Sciences Center, Morgantown, WV, USA
| | - Kaitlyn M Landreth
- Department of Microbiology, Immunology, and Cell Biology, West Virginia University, 64 Medical Center Drive, Morgantown, WV, 26506, USA
| | - Emel Sen Kilic
- Department of Microbiology, Immunology, and Cell Biology, West Virginia University, 64 Medical Center Drive, Morgantown, WV, 26506, USA
- Vaccine Development Center at West Virginia University Health Sciences Center, Morgantown, WV, USA
| | - Katherine S Lee
- Department of Microbiology, Immunology, and Cell Biology, West Virginia University, 64 Medical Center Drive, Morgantown, WV, 26506, USA
- Vaccine Development Center at West Virginia University Health Sciences Center, Morgantown, WV, USA
| | - Bishal Misra
- Department of Pharmaceutical Sciences, West Virginia University, Morgantown, WV, 26506, USA
| | - Sharan Bobbala
- Department of Pharmaceutical Sciences, West Virginia University, Morgantown, WV, 26506, USA
| | - F Heath Damron
- Department of Microbiology, Immunology, and Cell Biology, West Virginia University, 64 Medical Center Drive, Morgantown, WV, 26506, USA
- Vaccine Development Center at West Virginia University Health Sciences Center, Morgantown, WV, USA
| | - Tracy W Liu
- Department of Microbiology, Immunology, and Cell Biology, West Virginia University, 64 Medical Center Drive, Morgantown, WV, 26506, USA.
- WVU Cancer Institute, West Virginia University, Morgantown, WV, 26506, USA.
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Li X, Wu N, Wang C, Pei B, Ma X, Xie J, Yang W. NALCN expression is down-regulated and associated with immune infiltration in gastric cancer. Front Immunol 2025; 16:1512107. [PMID: 40013144 PMCID: PMC11860897 DOI: 10.3389/fimmu.2025.1512107] [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: 10/16/2024] [Accepted: 01/29/2025] [Indexed: 02/28/2025] Open
Abstract
Background NALCN has been identified as a tumor suppressor gene, and its role in human cancer progression has garnered significant attention. However, there is a paucity of experimental studies specifically addressing the relationship between NALCN and immune cell infiltration in gastric cancer (GC). Methods The expression levels of NALCN in tumor tissues, peripheral blood and gastric cancer cells lines from patients with GC were assessed using RNA sequencing, immunohistochemistry (IHC) staining and RT-qPCR. Data obtained from the Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) databases were utilized to investigate the correlation between NALCN expression and immune cell infiltration in GC. Subsequently, the relationship between NALCN expression and infiltrating immune cells in GC tissues was examined through immunofluorescence method. Additionally, in vitro experiments were conducted to evaluate the impact of NALCN knockdown on T cells function in GC cell lines. Results RNA sequencing analysis revealed that NALCN expression was significantly downregulated in GC tissues. Specifically, NALCN levels were lower in GC tumor tissues and plasma compared to adjacent non-tumor tissues and healthy controls. Consistent with these findings, the expression trend of NALCN mRNA in the GEO database mirrored the experimental results. Mechanistically, NALCN knockdown markedly enhanced cell proliferation, colony formation and migration while reducing apoptosis rates in AGS and GES-1 cells. Analysis of the TCGA database indicated a positive correlation between NALCN expression and the infiltration of B cells, cytotoxic cells, immature dendritic cells (iDC) cells, CD8+ T cells, and others in GC tissue. Conversely, Th17 and Th2 cells infiltration exhibited a negative correlation with NALCN expression. Immunofluorescence staining confirmed that B cells and CD8 T cells were more abundant in GC tumor tissues with high NALCN expression, whereas Th17 and Th2 cells were less prevalent. Subsequently, we co-cultured GC cells transfected with NALCN knockdown or control vectors along with their supernatants with T cells. The results demonstrated that NALCN knockdown in GC cells or their supernatants inhibited T cell proliferation compared to control conditions. Moreover, NALCN may play a role in glucose and glutamine uptake. Conclusions NALCN facilitates immune cell aggregation in GC and has potential as a biomarker for immune infiltration.
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Affiliation(s)
- Xuewei Li
- Department of Biochemistry and Molecular Biology, Shanxi Key Laboratory of Birth Defect and Cell Regeneration, Shanxi Medical University, Taiyuan, China
- MOE Key Laboratory of Coal Environmental Pathogenicity and Prevention, Shanxi Medical University, Taiyuan, China
| | - Na Wu
- Department of Digestive Oncology, Cancer Center, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Third Hospital of Shanxi Medical University, Taiyuan, China
| | - Chen Wang
- Department of Digestive Oncology, Cancer Center, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Third Hospital of Shanxi Medical University, Taiyuan, China
| | - Beibei Pei
- Department of Digestive Oncology, Cancer Center, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Third Hospital of Shanxi Medical University, Taiyuan, China
| | - Xiaoyan Ma
- Department of Digestive Oncology, Cancer Center, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Third Hospital of Shanxi Medical University, Taiyuan, China
| | - Jun Xie
- Department of Biochemistry and Molecular Biology, Shanxi Key Laboratory of Birth Defect and Cell Regeneration, Shanxi Medical University, Taiyuan, China
- MOE Key Laboratory of Coal Environmental Pathogenicity and Prevention, Shanxi Medical University, Taiyuan, China
| | - Wenhui Yang
- Department of Gastroenterology, Shanxi Province Cancer Hospital/Shanxi Hospital Affiliated to Cancer Hospital, Chinese Academy of Medical Sciences/Cancer Hospital Affiliated to Shanxi Medical University, Taiyuan, China
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Sun C, Liu S, Lau JW, Yang H, Chen Y, Xing B. Enzyme-Activated Orthogonal Proteolysis Chimeras for Tumor Microenvironment-Responsive Immunomodulation. Angew Chem Int Ed Engl 2025:e202423057. [PMID: 39932237 DOI: 10.1002/anie.202423057] [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: 11/26/2024] [Indexed: 02/20/2025]
Abstract
Precise modulation of dynamic and complex tumor microenvironment (TME) to disrupt tumorigenesis and reshape intratumoral immune infiltration has emerged as promising approaches for enhanced cancer therapy. Among recent innovations, proteolysis-targeting chimeras (PROTACs) represent a burgeoning chemical knockdown technology capable of degrading oncogenic protein homeostasis and inducing dynamic alternations within carcinoma settings, offering potential for antitumor manipulation. However, achieving selectivity in PROTACs that respond to disease environmental stimulation and precisely perturb on-target proteins remains challenging. The multi-step synthesis and limited permeability, attributed to high-molecular-weight and heterobifunctional structures, further hinder their in vivo efficacy. Herein, we present a unique TME-responsive enzyme-activated clickable PROTACs, which features a short peptide-tagged pomalidomide derivative to undergo tumor-specific cleavage by cathepsin protease to induce orthogonal crosslinking of the exposed cysteine with 2-cyanobenzothiazole-labeled epigenetic protein-ligand JQ1, facilitating in situ degrader formation within tumor regions only. Systematic protein profiling and proteomic analysis revealed that such TME-specific clickable-PROTACs not only selectively eliminate epigenetic proteins without tedious pre-synthesis to bridge disparate small-molecule bi-warhead fragments, but also demonstrated superior tumor penetration compared to conventional high-molecular-weight PROTACs. Importantly, these clickable-PROTACs efficiently downregulated immune checkpoint programmed death-ligand 1 (PD-L1) both in vitro and in vivo, remodeling TME for enhanced therapeutics, especially in anti-tumoral immunomodulation.
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Affiliation(s)
- Caixia Sun
- School of Chemistry, Chemical Engineering and Biotechnology, Nanyang Technological University, 21 Nanyang Link, Singapore, 637371, Singapore
| | - Songhan Liu
- School of Chemistry, Chemical Engineering and Biotechnology, Nanyang Technological University, 21 Nanyang Link, Singapore, 637371, Singapore
| | - Jun Wei Lau
- Department of Chemistry, National University of Singapore, Singapore, 117543, Singapore
| | - Hanyu Yang
- School of Chemistry, Chemical Engineering and Biotechnology, Nanyang Technological University, 21 Nanyang Link, Singapore, 637371, Singapore
| | - Yun Chen
- School of Chemistry, Chemical Engineering and Biotechnology, Nanyang Technological University, 21 Nanyang Link, Singapore, 637371, Singapore
| | - Bengang Xing
- Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, 11 Yuk Choi Rd, Hung Hom, Kowloon, Hong Kong SAR, China
- School of Chemistry, Chemical Engineering and Biotechnology, Nanyang Technological University, 21 Nanyang Link, Singapore, 637371, Singapore
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Hussain Z, Zhang Y, Qiu L, Gou S, Liu K. Exploring Clec9a in dendritic cell-based tumor immunotherapy for molecular insights and therapeutic potentials. NPJ Vaccines 2025; 10:27. [PMID: 39920156 PMCID: PMC11806010 DOI: 10.1038/s41541-025-01084-2] [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: 07/18/2024] [Accepted: 01/30/2025] [Indexed: 02/09/2025] Open
Abstract
The pivotal role of type 1 conventional dendritic cells (cDC1s) in the field of dendritic cell (DC)-based tumor immunotherapies has been gaining increasing recognition due to their superior antigen cross-presentation abilities and essential role in modulating immune responses. This review specifically highlights the C-type lectin receptor family 9 member A (Clec9a or DNGR-1), which is exclusively expressed on cDC1s and plays a pivotal role in augmenting antigen cross-presentation and cytotoxic T lymphocyte (CTL) responses while simultaneously mitigating off-target effects. These effects include the enhancement of the cDC1s cross-presentation, reducing autoimmune responses and systemic inflammation, as well as preventing the non-specific activation of other immune cells. Consequently, these actions may contribute to reduced toxicity and enhanced treatment efficacy in immunotherapy. The exceptional ability of Clec9a to cross-present dead cell-associated antigens and enhance both humoral and CTL responses makes it an optimal receptor for DC-based strategies aimed at strengthening antitumor immunity. This review provides a comprehensive overview of the molecular characterization, expression, and signaling mechanisms of Clec9a. Furthermore, it discusses the role of Clec9a in the induction and functional activation of Clec9a+ cDC1s, with a particular focus on addressing the challenges related to off-target effects and immune tolerance in the development of tumor vaccines. Additionally, this review explores the potential of Clec9a-targeted approaches to enhance the immunogenicity of tumor vaccines and addresses the utilization of Clec9a as a delivery target for specific agonists (such as STING agonists and αGC) to enhance their therapeutic effects. This novel approach leverages Clec9a's capacity to improve the precision and efficacy of these immunomodulatory molecules in tumor treatment. In summary, this review presents compelling evidence positioning Clec9a as a promising target for DC-based tumor immunotherapy, capable of enhancing the efficacy of vaccines and immune responses while minimizing adverse effects.
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Affiliation(s)
- Zubair Hussain
- Department of Pathophysiology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, Henan, China
- Tianjian Laboratory of Advanced Biomedical Sciences, Academy of Medical Sciences, Zhengzhou University, Zhengzhou, Henan, China
- State Key Laboratory of Metabolic dysregulation & the Prevention and Treatment of Esophageal Cancer, Zhengzhou, Henan, China
- Cancer Chemoprevention International Collaboration Laboratory, Zhengzhou, Henan, China
| | - Yueteng Zhang
- Department of Pathophysiology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, Henan, China
| | - Lu Qiu
- Department of Pathology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Shanshan Gou
- Tianjian Laboratory of Advanced Biomedical Sciences, Academy of Medical Sciences, Zhengzhou University, Zhengzhou, Henan, China.
| | - Kangdong Liu
- Department of Pathophysiology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, Henan, China.
- Tianjian Laboratory of Advanced Biomedical Sciences, Academy of Medical Sciences, Zhengzhou University, Zhengzhou, Henan, China.
- State Key Laboratory of Metabolic dysregulation & the Prevention and Treatment of Esophageal Cancer, Zhengzhou, Henan, China.
- Cancer Chemoprevention International Collaboration Laboratory, Zhengzhou, Henan, China.
- China‒US (Henan) Hormel Cancer Institute, Zhengzhou, Henan, China.
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Gao R, Liang W, Chen J, Yang M, Yu X, Wang X. Comparisons of adverse events associated with immune checkpoint inhibitors in the treatment of non-small cell lung cancer: a real-world disproportionality analysis based on the FDA adverse event reporting system. BMC Cancer 2025; 25:216. [PMID: 39920614 PMCID: PMC11806835 DOI: 10.1186/s12885-025-13614-1] [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: 06/27/2024] [Accepted: 01/30/2025] [Indexed: 02/09/2025] Open
Abstract
BACKGROUND Immune checkpoint inhibitor (ICI) therapy is increasingly used to treat non-small cell lung cancer (NSCLC). However, little attention has been given to the comparative analysis of adverse events (AEs) associated with different ICIs. METHODS Disproportionality analysis and Bayesian confidence propagation neural network (BCPNN) were utilized to identify pharmacovigilance signals from the FDA Adverse Event Reporting System (FAERS). We compared the sex distribution of patients, risk of suffering more severe adverse reactions, and risk of hospitalization associated with different ICIs, using pairwise matrices that displayed odds ratio (OR) and their 95% confidence interval (CI). And we also compared the outcomes of reactions by using ordinal logistic regression. RESULTS We analyzed 13,580 reports of AEs associated with five ICIs, namely, durvalumab, pembrolizumab, ipilimumab, atezolizumab, and nivolumab from January 2013 to October 2022. Significant differences were observed in sex distribution of patients, risk of suffering more severe adverse reactions, risk of hospitalization, and the outcomes of reactions. In terms of respiratory AEs, pembrolizumab exhibited a higher risk compared to durvalumab (OR = 2.48, 95% CI: 1.72-3.59), atezolizumab (OR = 1.84, 95% CI: 1.07-3.16), and nivolumab (OR = 4.21, 95% CI: 1.72-10.28), while ipilimumab exhibited a higher risk compared to durvalumab (OR = 2.76, 95% CI: 1.14-6.65) and nivolumab (OR = 4.67, 95% CI: 1.14-15.51). In terms of endocrine and metabolic AEs, durvalumab (OR = 7.80, 95% CI: 1.33-45.90) and nivolumab (OR = 5.20, 95% CI: 1.17-23.03) exhibited a higher risk compared to ipilimumab. CONCLUSION Each ICI has distinctive features of pharmacovigilance signals. It is essential to acknowledge the AEs associated with the relevant system when clinicians administer ICIs.
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Affiliation(s)
- Ruichen Gao
- Department of Pulmonary and Critical Care Medicine, Affiliated Changzhou Second Hospital of Nanjing Medical University, 468 Yanling Middle Road, Changzhou, Jiangsu, 213000, China
| | - Wenjun Liang
- Department of Pulmonary and Critical Care Medicine, Affiliated Changzhou Second Hospital of Nanjing Medical University, 468 Yanling Middle Road, Changzhou, Jiangsu, 213000, China
| | - Jintao Chen
- Department of Pulmonary and Critical Care Medicine, Affiliated Changzhou Second Hospital of Nanjing Medical University, 468 Yanling Middle Road, Changzhou, Jiangsu, 213000, China
| | - Mingxia Yang
- Department of Pulmonary and Critical Care Medicine, Affiliated Changzhou Second Hospital of Nanjing Medical University, 468 Yanling Middle Road, Changzhou, Jiangsu, 213000, China
| | - Xiaowei Yu
- Department of Pulmonary and Critical Care Medicine, Affiliated Changzhou Second Hospital of Nanjing Medical University, 468 Yanling Middle Road, Changzhou, Jiangsu, 213000, China
| | - Xiaohua Wang
- Department of Pulmonary and Critical Care Medicine, Affiliated Changzhou Second Hospital of Nanjing Medical University, 468 Yanling Middle Road, Changzhou, Jiangsu, 213000, China.
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Jain A, Stebbing J. The Relationship Between Response Rate and Survival Benefits in Randomized Immunotherapy Studies. Cancers (Basel) 2025; 17:495. [PMID: 39941863 PMCID: PMC11815975 DOI: 10.3390/cancers17030495] [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: 12/25/2024] [Revised: 01/27/2025] [Accepted: 01/28/2025] [Indexed: 02/16/2025] Open
Abstract
Understanding the relationship between the Objective Response Rate (ORR) and survival outcomes, notably Progression-Free Survival (PFS) and Overall Survival (OS), is relevant for assessing the efficacy of regimens in oncology. We evaluate the relationship between ORR, PFS and OS in immuno-oncology (IO) trials. Data from 68 clinical trials submitted to the FDA were evaluated, examining immunotherapy regimens, notably immune checkpoint inhibitors such as anti-programmed death (ligand)-1 [anti-PD-(L)1], cytotoxic T-lymphocyte-associated protein-4 (CTLA-4) inhibitors and combination therapies [e.g., IO + IO, anti-PD-L1 + chemotherapy, anti-PD-L1 + CTLA-4, anti-PD-L1 + TKI (tyrosine kinase inhibitors)]. Studies were included based on their reporting of ORR, PFS, and OS. Of the 68 clinical trials reviewed, 55 were included in the analysis. The correlation between ORR and PFS was moderate across most immunotherapy regimens, indicating that ORR can serve as a useful predictor of short-term disease control. However, the correlation between ORR and OS was weaker, especially in trials including combination therapies, indicating that ORR alone may not reliably predict long-term survival outcomes. ORR predicts PFS better in first-line treatment but declines in later lines and remains a weak OS predictor overall. Differing degrees of correlation between ORR and survival metrics, particularly across treatment lines and combinations, are observed. While ORR can serve as a surrogate marker for PFS in IO trials, its utility in predicting OS is restricted and the interpretation of the relationship between ORR and PFS or OS is a key limitation. Rather, a decline in PFS with increasing ORR may reflect trial differences rather than a direct relationship. Future analyses should adopt better methodologies to capture these dynamics and focus on improving surrogate endpoints for immunotherapy to improve clinical trial design and patient outcomes.
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Affiliation(s)
- Aditi Jain
- Edinburgh Medical School, Biomedical Sciences, The University of Edinburgh, Edinburgh EH8 9YL, UK
| | - Justin Stebbing
- School of Life Sciences, Anglia Ruskin University, Cambridge CB1 1PT, UK
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Mori K, Numakura K, Matsushita Y, Kojima T, Osawa T, Sazuka T, Hatakeyama S, Goto K, Yamana K, Kandori S, Kimura T, Nishiyama N, Bando Y, Fujita K, Ueda K, Tanaka H, Tomida R, Kurahashi T, Kitamura H, Miyake H, Habuchi T. Primary resistance to nivolumab plus ipilimumab therapy affects second-line treatment outcomes in patients with metastatic renal cell carcinoma. Cancer Sci 2025; 116:444-452. [PMID: 39550694 PMCID: PMC11786309 DOI: 10.1111/cas.16326] [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: 05/22/2024] [Revised: 07/19/2024] [Accepted: 08/08/2024] [Indexed: 11/18/2024] Open
Abstract
Nivolumab plus ipilimumab (NIVO+IPI) has a long-term response rate of 30% for patients with metastatic renal cell carcinoma (mRCC). However, 20% of patients develop primary resistant disease (PRD) to NIVO+IPI and show poor survival outcomes. In this study, we aimed to evaluate the effect of PRD as a second-line treatment in patients with mRCC. The data used in this multi-institutional, retrospective cohort were collected between August 2015 and January 2023. In total, 189 patients with mRCC were treated with NIVO+IPI and then with a vascular endothelial growth factor receptor-tyrosine kinase inhibitor. Associations between PRD and progression-free survival of second-line treatment (PFS), progression-free survival 2 (PFS2), and overall survival (OS) were analyzed. The median age at NIVO+IPI initiation was 67 years in the male-dominant population (n = 140, 74.1%), and most patients had clear cell histology (n = 140, 74.1%). PRD was recorded in 42 (22.2%) of 189 patients during NIVO+IPI therapy. Patients who experienced PRD showed poor PFS (hazard ratio [HR], 1.788; 95% confidence interval [CI], 1.176-2.718; p = 0.007), PFS2 (HR, 4.127; 95% CI, 2.649-6.431; p < 0.001), and OS (HR, 3.330; 95% CI, 2.040-5.437; p < 0.001). Before starting second-line therapy, patients with PRD tended to have a poor performance status compared with non-PRD patients and a higher IMDC risk. Second-line drug therapy was not associated with treatment outcomes in patients with PRD. PRD in patients with mRCC receiving NIVO+IPI as first-line treatment was associated with poor clinical course, even with second-line therapy.
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Affiliation(s)
- Kanami Mori
- Department of UrologyAkita University Graduate School of MedicineAkitaJapan
| | - Kazuyuki Numakura
- Department of UrologyAkita University Graduate School of MedicineAkitaJapan
| | - Yuto Matsushita
- Department of UrologyHamamatsu University School of MedicineHamamatsuJapan
| | | | - Takahiro Osawa
- Department of Renal and Genitourinary SurgeryHokkaido UniversitySapporoJapan
| | - Tomokazu Sazuka
- Department of Urology, Graduate School of Medicine and School of MedicineChiba UniversityChibaJapan
| | - Shingo Hatakeyama
- Department of UrologyHirosaki University Graduate School of MedicineHirosakiJapan
| | - Keisuke Goto
- Department of Urology, Graduate School of Biomedical ScienceHiroshima UniversityHiroshimaJapan
| | - Kazutoshi Yamana
- Department of Urology and Molecular OncologyNiigata University Graduate School of Medical and Dental SciencesNiigataJapan
| | - Shuya Kandori
- Department of UrologyInstitute of Medicine, University of TsukubaTsukubaJapan
| | - Takahiro Kimura
- Department of UrologyJikei University School of MedicineTokyoJapan
| | - Naotaka Nishiyama
- Department of Urology, Faculty of MedicineUniversity of ToyamaToyamaJapan
| | - Yukari Bando
- Department of UrologyKobe University Graduate School of MedicineKobeJapan
| | - Kazutoshi Fujita
- Department of UrologyKindai University Faculty of MedicineOsaka‐sayamaJapan
| | - Kosuke Ueda
- Department of UrologyKurume University School of MedicineKurumeJapan
| | - Hajime Tanaka
- Department of UrologyTokyo Medical and Dental UniversityTokyoJapan
| | - Ryotaro Tomida
- Department of UrologyTokushima University Graduate School of Biomedical SciencesTokushimaJapan
| | | | - Hiroshi Kitamura
- Department of Urology, Faculty of MedicineUniversity of ToyamaToyamaJapan
| | - Hideaki Miyake
- Department of UrologyKobe University Graduate School of MedicineKobeJapan
| | - Tomonori Habuchi
- Department of UrologyAkita University Graduate School of MedicineAkitaJapan
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Ma L, Li Y, Sakamoto Y, Xie L, Suzuki S, Yoshida Y, Sui L, Guo G, Wen J, Ren W, Kakimi K, Osada K, Takahashi A, Shimokawa T. Optimal radiation dose to induce an abscopal effect by combining carbon-ion radiotherapy and anti-CTLA4 antibody. Neoplasia 2025; 60:101099. [PMID: 39674115 PMCID: PMC11699741 DOI: 10.1016/j.neo.2024.101099] [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: 02/01/2024] [Revised: 11/19/2024] [Accepted: 11/27/2024] [Indexed: 12/16/2024]
Abstract
BACKGROUND AND PURPOSE Although carbon-ion radiotherapy (CIRT) has led to good outcomes, controlling metastasis is still crucial for improving overall survival. This study aimed to evaluate the effectiveness of by two combinations, one of CIRT and anti-CTLA4 antibody, the other of CIRT and anti-PD-1 antibody, applied at different radiation doses for distal tumour and metastasis suppression. MATERIALS AND METHODS Murine cancer cells (colon carcinoma Colon-26 cells for experiments and osteosarcoma LM8 cells for verification) were grafted into both sides of the hind legs of syngeneic mice. Right-side tumours were irradiated with 3 Gy or 10 Gy CIRT while the left-side tumours were not irradiated, followed by the administration of the anti-CTLA4 antibody or anti-PD-1 antibody. The diameter of the tumours in both legs was measured 3 times per week after irradiation. The number of pulmonary metastases was evaluated within 3 weeks after irradiation. RESULTS Compared with the control group, the high-dose group showed promising anti-cancer benefits in terms of both irradiated tumours and lung metastasis, but neither 10 Gy CIRT combined with the anti-CTLA4 antibody nor 10 Gy CIRT combined with the anti-PD-1 antibody suppressed the growth of distant unirradiated tumours. In the low-dose group, the effect on primary tumour control was slightly weaker than that in the high-dose treatment group, but significant suppressive effects on both distant unirradiated tumours and metastases were observed following 3 Gy CIRT combined with anti-CTLA4 antibody treatment. Specifically, the volume of distant unirradiated tumours decreased by 40 % compared with that of the control group, and no lung metastasis was observed. CONCLUSION Our findings suggest that there is an optimal dose range for the abscopal effect generated with the CIRT combined with anti-CTLA4 antibody, and it highlights a new opportunity for increased induction efficiency of the abscopal effect of combination therapy.
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Affiliation(s)
- Liqiu Ma
- Institute for Quantum Medical Science, National Institutes for Quantum Science and Technology (QST), Chiba 263-8555, Japan; Gunma University Heavy Ion Medical Center, Gunma 371-8511, Japan; Department of Nuclear Physics, China Institute of Atomic Energy, Beijing 102413, China.
| | - Yang Li
- Gunma University Heavy Ion Medical Center, Gunma 371-8511, Japan
| | - Yoshimitsu Sakamoto
- Institute for Quantum Medical Science, National Institutes for Quantum Science and Technology (QST), Chiba 263-8555, Japan
| | - Lin Xie
- Institute for Quantum Medical Science, National Institutes for Quantum Science and Technology (QST), Chiba 263-8555, Japan
| | - Saaya Suzuki
- Institute for Quantum Medical Science, National Institutes for Quantum Science and Technology (QST), Chiba 263-8555, Japan
| | - Yukari Yoshida
- Gunma University Heavy Ion Medical Center, Gunma 371-8511, Japan
| | - Li Sui
- Department of Nuclear Physics, China Institute of Atomic Energy, Beijing 102413, China
| | - Gang Guo
- Department of Nuclear Physics, China Institute of Atomic Energy, Beijing 102413, China
| | - Jialing Wen
- Department of Nuclear Physics, China Institute of Atomic Energy, Beijing 102413, China
| | - Wangcai Ren
- Department of Nuclear Physics, China Institute of Atomic Energy, Beijing 102413, China
| | - Kazuhiro Kakimi
- Department of Immunology, Kindai University Faculty of Medicine, Osaka 589-0014, Japan
| | - Kensuke Osada
- Institute for Quantum Medical Science, National Institutes for Quantum Science and Technology (QST), Chiba 263-8555, Japan
| | | | - Takashi Shimokawa
- Institute for Quantum Medical Science, National Institutes for Quantum Science and Technology (QST), Chiba 263-8555, Japan.
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Hsu CY, Pallathadka H, Jasim SA, Rizaev J, Olegovich Bokov D, Hjazi A, Mahajan S, Mustafa YF, Husseen B, Jawad MA. Innovations in cancer immunotherapy: A comprehensive overview of recent breakthroughs and future directions. Crit Rev Oncol Hematol 2025; 206:104588. [PMID: 39667718 DOI: 10.1016/j.critrevonc.2024.104588] [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: 11/07/2024] [Revised: 12/03/2024] [Accepted: 12/04/2024] [Indexed: 12/14/2024] Open
Abstract
A major advance in cancer treatment has been the development and refinement of cancer immunotherapy. The discovery of immunotherapies for a wide range of cancers has revolutionized cancer treatment paradigms. Despite relapse or refractory disease, immunotherapy approaches can prolong the life expectancy of metastatic cancer patients. Multiple therapeutic approaches and agents are currently being developed to manipulate various aspects of the immune system. Oncolytic viruses, cancer vaccines, adoptive cell therapies, monoclonal antibodies, cytokine therapies, and inhibitors of immune checkpoints have all proven successful in clinical trials. There are several types of immunotherapeutic approaches available for treating cancer, and others are being tested in preclinical and clinical settings. Immunotherapy has proven successful, and many agents and strategies have been developed to improve its effectiveness. The purpose of this article is to present a comprehensive overview of current immunotherapy approaches used to treat cancer. Cancer immunotherapy advancements, emerging patterns, constraints, and potential future breakthroughs are also discussed.
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Affiliation(s)
- Chou-Yi Hsu
- Thunderbird School of Global Management, Arizona State University Tempe Campus, Phoenix, AZ 85004, USA
| | | | - Saade Abdalkareem Jasim
- Medical Laboratory Techniques department, College of Health and medical technology, University of Al-maarif, Anbar, Iraq.
| | - Jasur Rizaev
- Department of Public health and Healthcare management, Rector, Samarkand State Medical University, Samarkand, Uzbekistan
| | - Dmitry Olegovich Bokov
- Institute of Pharmacy named after A.P. Nelyubin, Sechenov First Moscow State Medical University, Russia; Laboratory of Food Chemistry, Federal Research Center of Nutrition, Biotechnology and Food Safety, Moscow, Russia
| | - Ahmed Hjazi
- Department of Medical Laboratory, College of Applied Medical Sciences, Prince Sattam bin Abdulaziz University, Al-Kharj 11942, Saudi Arabia
| | - Shriya Mahajan
- Centre of Research Impact and Outcome, Chitkara University, Rajpura, Punjab 140417, India
| | - Yasser Fakri Mustafa
- Department of Pharmaceutical Chemistry, College of Pharmacy, University of Mosul, Mosul 41001, Iraq
| | - Beneen Husseen
- Medical laboratory technique college, the Islamic University, Najaf, Iraq; Medical laboratory technique college, the Islamic University of Al Diwaniyah, Al Diwaniyah, Iraq; Medical laboratory technique college, the Islamic University of Babylon, Babylon, Iraq
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Nihira NT, Wu W, Hosoi M, Togashi Y, Sunada S, Miyoshi Y, Miki Y, Ohta T. Nuclear PD-L1 triggers tumour-associated inflammation upon DNA damage. EMBO Rep 2025; 26:635-655. [PMID: 39747659 PMCID: PMC11811057 DOI: 10.1038/s44319-024-00354-9] [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: 06/25/2024] [Revised: 12/02/2024] [Accepted: 12/08/2024] [Indexed: 01/04/2025] Open
Abstract
Immune checkpoint inhibitors against PD-1/PD-L1 are highly effective in immunologically hot tumours such as triple-negative breast cancer, wherein constitutive DNA damage promotes inflammation, while inducing PD-L1 expression to avoid attack by cytotoxic T cells. However, whether and how PD-L1 regulates the DNA damage response and inflammation remains unclear. Here, we show that nuclear PD-L1 activates the ATR-Chk1 pathway and induces proinflammatory chemocytokines upon genotoxic stress. PD-L1 interacts with ATR and is essential for Chk1 activation and chromatin binding. cGAS-STING and NF-κB activation in the late phase of the DNA damage response is inhibited by PD-L1 deletion or by inhibitors of ATR and Chk1. Consequently, the induction of proinflammatory chemocytokines at this stage is inhibited by deletion of PD-L1, but restored by the ATR activator Garcinone C. Inhibition of nuclear localisation by PD-L1 mutations or the HDAC2 inhibitor Santacruzamate A inhibits chemocytokine induction. Conversely, the p300 inhibitor C646, which accelerates PD-L1 nuclear localisation, promotes chemocytokine induction. These findings suggest that nuclear PD-L1 strengthens the properties of hot tumours and contributes to shaping the tumour microenvironment.
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Affiliation(s)
- Naoe T Nihira
- Department of Translational Oncology, St. Marianna University Graduate School of Medicine, Kawasaki, 216-8511, Japan
| | - Wenwen Wu
- Department of Translational Oncology, St. Marianna University Graduate School of Medicine, Kawasaki, 216-8511, Japan
| | - Mitsue Hosoi
- Department of Translational Oncology, St. Marianna University Graduate School of Medicine, Kawasaki, 216-8511, Japan
| | - Yukiko Togashi
- Department of Translational Oncology, St. Marianna University Graduate School of Medicine, Kawasaki, 216-8511, Japan
| | - Shigeaki Sunada
- Juntendo Advanced Research Institute for Health Science, Juntendo University, Tokyo, 113-8421, Japan
| | - Yasuo Miyoshi
- Department of Surgery, Division of Breast and Endocrine Surgery, School of Medicine, Hyogo Medical University, Nishinomiya City, Hyogo, Japan
| | - Yoshio Miki
- Research and Development Center for Precision Medicine, University of Tsukuba, Ibaraki, 305-8550, Japan
| | - Tomohiko Ohta
- Department of Translational Oncology, St. Marianna University Graduate School of Medicine, Kawasaki, 216-8511, Japan.
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Chen G, Li W, Ge R, Guo T, Zhang Y, Zhou C, Lin M. NUSAP1 Promotes Immunity and Apoptosis by the SHCBP1/JAK2/STAT3 Phosphorylation Pathway to Induce Dendritic Cell Generation in Hepatocellular Carcinoma. J Immunother 2025; 48:46-57. [PMID: 38980111 PMCID: PMC11753460 DOI: 10.1097/cji.0000000000000531] [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: 02/14/2024] [Accepted: 05/29/2024] [Indexed: 07/10/2024]
Abstract
Hepatocellular carcinoma (HCC) is the most common type of liver cancer and is associated with high morbidity and mortality rates. The aims of this study were to investigate the immune-promoting action of nucleolar and spindle-associated protein 1 (NUSAP1) and identify an immunotherapy target for HCC. The Cancer Genome Atlas (TCGA) was used to analyze interaction molecules and immune correlation. The interaction between NUSAP1 and SHC binding and spindle associated 1 (SHCBP1) was examined. The role of the SHCBP1/Janus kinase 2/signal transducer and activator of transcription 3 (SHCBP1/JAK2/STAT3) pathway in this process was explored. After co-culture with HCC cell lines, the differentiation of peripheral blood mononuclear cells (PBMCs) into dendritic cells (DC) was evaluated by measuring the expression of surface factors CD1a and CD86. Pathological tissues from 50 patients with HCC were collected to validate the results of cell experiments. The expression levels of CD1a and CD86 in tissues were also determined. The results show that NUSAP1 interacted with SHCBP1 and was positively correlated with DC. In HCC cell lines, an interaction was observed between NUSAP1 and SHCBP1. It was verified that NUSAP1 inhibited the JAK2/STAT3 phosphorylation pathway by blocking SHCBP1. After co-culture, the levels of CD1a and CD86 in PBMC were elevated. In the clinical specimens, CD1a and CD86 expression levels were significantly higher in the high-NUSAP1 group versus the low-NUSAP1 group. In Summary, NUSAP1 enhanced immunity by inhibiting the SHCBP1/JAK2/STAT3 phosphorylation pathway and promoted DC generation and HCC apoptosis. NUSAP1 may be a target of immunotherapy for HCC.
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Affiliation(s)
- Guojie Chen
- Medical School of Nantong University, Nantong, Jiangsu, China
- Clinical Laboratory, Affiliated Taizhou People’s Hospital of Nanjing Medical University, Taizhou, Jiangsu, China
| | - WenYa Li
- Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China
| | - Ruomu Ge
- Clinical Laboratory, Affiliated Taizhou People’s Hospital of Nanjing Medical University, Taizhou, Jiangsu, China
| | - Ting Guo
- Clinical Laboratory, Affiliated Taizhou People’s Hospital of Nanjing Medical University, Taizhou, Jiangsu, China
| | - Yuhan Zhang
- The First School of Clinical Medicine, Southern Medical University, Guangzhou, Guangdong, China
| | - Chenglin Zhou
- Laboratory Department, Affiliated Taizhou People’s Hospital of Nanjing Medical University, Taizhou, Jiangsu, China
| | - Mei Lin
- Clinical Laboratory, Affiliated Taizhou People’s Hospital of Nanjing Medical University, Taizhou, Jiangsu, China
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Khilar S, Dembinska-Kenner A, Hall H, Syrmos N, Ligarotti GKI, Plaha P, Apostolopoulos V, Chibbaro S, Barbagallo GMV, Ganau M. Towards a New Dawn for Neuro-Oncology: Nanomedicine at the Service of Drug Delivery for Primary and Secondary Brain Tumours. Brain Sci 2025; 15:136. [PMID: 40002469 PMCID: PMC11852924 DOI: 10.3390/brainsci15020136] [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: 01/21/2025] [Accepted: 01/28/2025] [Indexed: 02/27/2025] Open
Abstract
(1) Background/Objectives: Primary and secondary brain tumours often hold devastating prognoses and low survival rates despite the application of maximal neurosurgical resection, and state-of-the-art radiotherapy and chemotherapy. One limiting factor in their management is that several antineoplastic agents are unable to cross the blood-brain barrier (BBB) to reach the tumour microenvironment. Nanomedicine could hold the potential to become an effective means of drug delivery to overcome previous hurdles towards effective neuro-oncological treatments. (2) Methods: A scoping review following the PRISMA-ScR guidelines and checklist was conducted using key terms input into PubMed to find articles that reflect emerging trends in the utilisation of nanomedicine in drug delivery for primary and secondary brain tumours. (3) Results: The review highlights various strategies by which different nanoparticles can be exploited to bypass the BBB; we provide a synthesis of the literature on the ongoing contributions to therapeutic protocols based on chemotherapy, immunotherapy, focused ultrasound, radiotherapy/radiosurgery, and radio-immunotherapy. (4) Conclusions: The emerging trends summarised in this scoping review indicate encouraging advantageous properties of nanoparticles as potential effective drug delivery mechanisms; however, there are still nanotoxicity issues that largely remain to be addressed before the translation of these innovations from laboratory to clinical practice.
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Affiliation(s)
- Smita Khilar
- Department of Neurosurgery, Oxford University Hospitals NHS Foundation Trust, Oxford OX3 0AG, UK; (S.K.); (H.H.)
| | - Antonina Dembinska-Kenner
- Department of Neurosurgery, Oxford University Hospitals NHS Foundation Trust, Oxford OX3 0AG, UK; (S.K.); (H.H.)
| | - Helen Hall
- Department of Neurosurgery, Oxford University Hospitals NHS Foundation Trust, Oxford OX3 0AG, UK; (S.K.); (H.H.)
| | - Nikolaos Syrmos
- School of Medicine, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece
| | | | - Puneet Plaha
- Department of Neurosurgery, Oxford University Hospitals NHS Foundation Trust, Oxford OX3 0AG, UK; (S.K.); (H.H.)
| | - Vasileios Apostolopoulos
- Department of Neurosurgery, Oxford University Hospitals NHS Foundation Trust, Oxford OX3 0AG, UK; (S.K.); (H.H.)
| | - Salvatore Chibbaro
- Neurosurgery Unit, Department of Medical and Surgical Sciences and Neurosciences, Siena University, 53100 Siena, Italy
| | | | - Mario Ganau
- Department of Neurosurgery, Oxford University Hospitals NHS Foundation Trust, Oxford OX3 0AG, UK; (S.K.); (H.H.)
- Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford OX3 9DU, UK
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Li Y, Dong Y, Shen D, Guo Y, Cao Y, Zhang K, Li X, Zhu R, Yi J, Yao X, Dang X, Li R, Zhang Z, Qin Z, Yang W. Personalized Nanovaccine Based on STING-Activating Nanocarrier for Robust Cancer Immunotherapy. ACS NANO 2025; 19:3226-3239. [PMID: 39817337 DOI: 10.1021/acsnano.4c11014] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/18/2025]
Abstract
Tumor-specific T cells play a vital role in potent antitumor immunity. However, their efficacy is severely affected by the spatiotemporal orchestration of antigen-presentation as well as the innate immune response in dendritic cells (DCs). Herein, we develop a minimalist nanovaccine that exploits a dual immunofunctional polymeric nanoplatform (DIPNP) to encapsulate ovalbumin (OVA) via electrostatic interaction when the nanocarrier serves as both STING agonist and immune adjuvant in DCs. In vitro results reveal that the nanocarrier induces STING activation via facilitating interferon regulatory factor 3 phosphorylation by block poly 18-crown-6-yl methacrylate (P18C6MA) mediated K+ perturbation cascade with endoplasmic reticulum stress, and stimulates DC maturation via the Toll-like receptor 4 activation by primary amine. In vivo studies indicate that the smart nanovaccine dramatically inhibits tumor growth with a long-term immune memory response in both the B16-OVA and EG7-OVA tumor models. After combination with programmed death ligand-1 antibody (aPD-L1), mice survival rate is notably prolonged. In addition, DIPNP forms a personalized nanovaccine after resected autologous primary tumor cell membranes decoration with a high antitumor activity in a homologous distant tumor model. The rational design provides inspiration for personalized nanovaccine construction via immunofunctional nanocarriers.
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Affiliation(s)
- Yongjuan Li
- Medical Research Center, The First Affiliated Hospital of Zhengzhou University, The Center of Infection and Immunity, Academy of Medical Sciences, Zhengzhou University, Zhengzhou, Henan 450001, China
| | - Ya Dong
- Medical Research Center, The First Affiliated Hospital of Zhengzhou University, The Center of Infection and Immunity, Academy of Medical Sciences, Zhengzhou University, Zhengzhou, Henan 450001, China
| | - Danyang Shen
- Medical Research Center, The First Affiliated Hospital of Zhengzhou University, The Center of Infection and Immunity, Academy of Medical Sciences, Zhengzhou University, Zhengzhou, Henan 450001, China
| | - Yichen Guo
- School of Pharmaceutical Sciences, Henan Key Laboratory of Nanomedicine for Targeting Diagnosis and Treatment, Zhengzhou University, Zhengzhou, Henan 450001, China
| | - Yongjian Cao
- School of Pharmaceutical Sciences, Henan Key Laboratory of Nanomedicine for Targeting Diagnosis and Treatment, Zhengzhou University, Zhengzhou, Henan 450001, China
| | - Kaixin Zhang
- School of Pharmaceutical Sciences, Henan Key Laboratory of Nanomedicine for Targeting Diagnosis and Treatment, Zhengzhou University, Zhengzhou, Henan 450001, China
| | - Xinyan Li
- Medical Research Center, The First Affiliated Hospital of Zhengzhou University, The Center of Infection and Immunity, Academy of Medical Sciences, Zhengzhou University, Zhengzhou, Henan 450001, China
| | - Rongrong Zhu
- School of Pharmaceutical Sciences, Henan Key Laboratory of Nanomedicine for Targeting Diagnosis and Treatment, Zhengzhou University, Zhengzhou, Henan 450001, China
| | - Jinmeng Yi
- Medical Research Center, The First Affiliated Hospital of Zhengzhou University, The Center of Infection and Immunity, Academy of Medical Sciences, Zhengzhou University, Zhengzhou, Henan 450001, China
| | - Xiaohan Yao
- Medical Research Center, The First Affiliated Hospital of Zhengzhou University, The Center of Infection and Immunity, Academy of Medical Sciences, Zhengzhou University, Zhengzhou, Henan 450001, China
| | - Xiaowei Dang
- Medical Research Center, The First Affiliated Hospital of Zhengzhou University, The Center of Infection and Immunity, Academy of Medical Sciences, Zhengzhou University, Zhengzhou, Henan 450001, China
| | - Rui Li
- Medical Research Center, The First Affiliated Hospital of Zhengzhou University, The Center of Infection and Immunity, Academy of Medical Sciences, Zhengzhou University, Zhengzhou, Henan 450001, China
| | - Zhenzhong Zhang
- School of Pharmaceutical Sciences, Henan Key Laboratory of Nanomedicine for Targeting Diagnosis and Treatment, Zhengzhou University, Zhengzhou, Henan 450001, China
| | - Zhihai Qin
- Medical Research Center, The First Affiliated Hospital of Zhengzhou University, The Center of Infection and Immunity, Academy of Medical Sciences, Zhengzhou University, Zhengzhou, Henan 450001, China
| | - Weijing Yang
- Medical Research Center, The First Affiliated Hospital of Zhengzhou University, The Center of Infection and Immunity, Academy of Medical Sciences, Zhengzhou University, Zhengzhou, Henan 450001, China
- School of Pharmaceutical Sciences, Henan Key Laboratory of Nanomedicine for Targeting Diagnosis and Treatment, Zhengzhou University, Zhengzhou, Henan 450001, China
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Chang Y, Long M, Shan H, Liu L, Zhong S, Luo JL. Combining gut microbiota modulation and immunotherapy: A promising approach for treating microsatellite stable colorectal cancer. Crit Rev Oncol Hematol 2025; 208:104629. [PMID: 39864533 DOI: 10.1016/j.critrevonc.2025.104629] [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: 12/04/2024] [Revised: 01/20/2025] [Accepted: 01/21/2025] [Indexed: 01/28/2025] Open
Abstract
Colorectal cancer (CRC) is one of the most prevalent and lethal cancers worldwide, ranking third in incidence and second in mortality. While immunotherapy has shown promise in patients with deficient mismatch repair (dMMR) or high microsatellite instability (MSI-H), its effectiveness in proficient mismatch repair (pMMR) or microsatellite stable (MSS) CRC remains limited. Recent advances highlight the gut microbiota as a potential modulator of anti-tumor immunity. The gut microbiome can significantly influence the efficacy of immune checkpoint inhibitors (ICIs), especially in pMMR/MSS CRC, by modulating immune responses and systemic inflammation. This review explores the role of the gut microbiota in pMMR/MSS CRC, the mechanisms by which it may enhance immunotherapy, and current strategies for microbiota modulation. We discuss the potential benefits of combining microbiota-targeting interventions with immunotherapy to improve treatment outcomes for pMMR/MSS CRC patients.
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Affiliation(s)
- Yujie Chang
- The Cancer Research Institute and the Second Affiliated Hospital, Hengyang Medical School, University of South China (USC), Hunan 421001, China; MOE Key Lab of Rare Pediatric Diseases, Hengyang Medical School, USC, Hunan 421001, China
| | - Min Long
- The Cancer Research Institute and the Second Affiliated Hospital, Hengyang Medical School, University of South China (USC), Hunan 421001, China; MOE Key Lab of Rare Pediatric Diseases, Hengyang Medical School, USC, Hunan 421001, China
| | - Hanguo Shan
- The Cancer Research Institute and the Second Affiliated Hospital, Hengyang Medical School, University of South China (USC), Hunan 421001, China; Hunan Provincial Key Laboratory of Basic and Clinical Pharmacological Research of Gastrointestinal Cancer, USC, Hunan 421001, China
| | - Logen Liu
- Hunan Provincial Key Laboratory of Basic and Clinical Pharmacological Research of Gastrointestinal Cancer, USC, Hunan 421001, China
| | - Shangwei Zhong
- The Cancer Research Institute and the Second Affiliated Hospital, Hengyang Medical School, University of South China (USC), Hunan 421001, China; MOE Key Lab of Rare Pediatric Diseases, Hengyang Medical School, USC, Hunan 421001, China
| | - Jun-Li Luo
- The Cancer Research Institute and the Second Affiliated Hospital, Hengyang Medical School, University of South China (USC), Hunan 421001, China; Hunan Provincial Key Laboratory of Basic and Clinical Pharmacological Research of Gastrointestinal Cancer, USC, Hunan 421001, China; MOE Key Lab of Rare Pediatric Diseases, Hengyang Medical School, USC, Hunan 421001, China; National Health Commission Key Laboratory of Birth Defect Research and Prevention, Hunan Provincial Maternal and Child Health Care Hospital, USC, Hunan 410008, China.
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Long D, Ding Y, Wang P, Wei L, Ma K. Multi-Omics Analysis Reveals Immune Infiltration and Clinical Significance of Phosphorylation Modification Enzymes in Lung Adenocarcinoma. Int J Mol Sci 2025; 26:1066. [PMID: 39940833 PMCID: PMC11817228 DOI: 10.3390/ijms26031066] [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: 12/25/2024] [Revised: 01/21/2025] [Accepted: 01/21/2025] [Indexed: 02/16/2025] Open
Abstract
Protein phosphorylation is a dynamic and reversible modification involved in almost all cellular processes. Numerous investigations have shown that protein phosphorylation modification enzymes (PPMEs) that regulate protein phosphorylation play an important role in the occurrence and treatment of tumors. However, there is still a lack of effective insights into the value of PPMEs in the classification and treatment of patients with lung adenocarcinoma (LUAD). Here, four topological algorithms identified 15 hub PPMEs from a protein-protein interaction (PPI) network. This PPI network was constructed using 124 PPMEs significantly correlated with 35 cancer hallmark-related pathways. Our study illustrates that these hub PPMEs can affect the survival of patients with LUAD in the form of somatic mutation or expression perturbation. Consistency clustering based on hub PPMEs recognized two phosphorylation modification subtypes (namely cluster1 and cluster2) from LUAD. Compared with patients in cluster1, the survival prognosis of patients in cluster2 is worse. This disparity is probably attributed to the higher tumor mutation burden, the higher male proportion, and the more significant expression disturbance in patients in cluster2. Moreover, phosphorylation modification subtypes also have different characteristics in terms of immune activity, immune infiltration level, immunotherapy response, and drug sensitivity. We constructed a PSig scoring system by using a principal component analysis algorithm to estimate the level of phosphorylation modification in individual LUAD patients. Patients in the high and low PSig score groups demonstrated different characteristics in terms of survival rate, tumor mutation burden, somatic gene mutation rate, immune cell abundance, and sensitivity to immunotherapy and drug treatment. This work reveals that phosphorylation plays a non-negligible role in the tumor microenvironment and immunotherapy of LUAD. Evaluating the phosphorylation status of individual LUAD patients by the PSig score can contribute to enhancing our cognition of the tumor microenvironment and guiding the formulation of more effective personalized treatment strategies.
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Affiliation(s)
- Deyu Long
- The Key Laboratory of Xinjiang Endemic and Ethnic Diseases, Ministry of Education, Shihezi University Medical College, Shihezi 832000, China
- Center of Bioinformatics, College of Life Sciences, Northwest A&F University, Yangling 712100, China
| | - Yanheng Ding
- Center of Bioinformatics, College of Life Sciences, Northwest A&F University, Yangling 712100, China
| | - Peng Wang
- Center of Bioinformatics, College of Life Sciences, Northwest A&F University, Yangling 712100, China
| | - Lili Wei
- The Key Laboratory of Xinjiang Endemic and Ethnic Diseases, Ministry of Education, Shihezi University Medical College, Shihezi 832000, China
| | - Ketao Ma
- The Key Laboratory of Xinjiang Endemic and Ethnic Diseases, Ministry of Education, Shihezi University Medical College, Shihezi 832000, China
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Mousavikia SN, Darvish L, Firouzjaei AA, Toossi MTB, Azimian H. PI3K/AKT/mTOR Targeting in Colorectal Cancer Radiotherapy: A Systematic Review. J Gastrointest Cancer 2025; 56:52. [PMID: 39849185 DOI: 10.1007/s12029-024-01160-1] [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: 12/11/2024] [Indexed: 01/25/2025]
Abstract
BACKGROUND Radioresistance is a major challenge in the treatment of patients with colorectal cancer (CRC) and impairs the efficacy of radiotherapy. The PI3K/AKT/mTOR signaling pathway plays a critical role in CRC and contributes to the development of radioresistance. Accordingly, targeting this signaling pathway may be a promising strategy to improve oncotherapy. METHODS We performed a systematic search of Scopus, PubMed, Web of Science, Embase, and Medline databases. We included articles that investigated the effects of PI3K/AKT/mTOR pathway inhibitors on improving the efficacy of radiotherapy. RESULT Of the 32 articles included in our review, 27 were preclinical studies and 5 were clinical trials. We examined the effects of various signaling pathway inhibitors in combination with radiotherapy. While the efficacy of these therapies when used alone is limited, their combination is associated with reduced survival, induction of apoptosis, and cell cycle arrest, which may increase radiosensitivity. Despite the limited number of studies, this combination therapy has shown favorable treatment outcomes in patients with CRC. CONCLUSION PI3K/AKT/mTOR is a critical signaling pathway for cancer cell survival. By inhibiting this pathway, we can increase the efficacy of radiotherapy. These results provide valuable insights for the further development of research and clinical practice in the treatment of colorectal cancer.
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Affiliation(s)
- S N Mousavikia
- Medical Physics Research Center, Basic Sciences Research Institute, Mashhad University of Medical Sciences, Mashhad, Iran
- Department of Medical Physics, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - L Darvish
- Department of Radiology, Faculty of Paramedicine, Hormozgan University of Medical Sciences, Bandar Abbas, Iran
- Mother and Child Welfare Research Center, Hormozgan University of Medical Sciences, Bandar Abbas, Iran
| | - A A Firouzjaei
- Bioinformatics Research Center, Basic Sciences Research Institute, Mashhad University of Medical Sciences, Mashhad, Iran
| | - M T Bahreyni Toossi
- Medical Physics Research Center, Basic Sciences Research Institute, Mashhad University of Medical Sciences, Mashhad, Iran
| | - H Azimian
- Medical Physics Research Center, Basic Sciences Research Institute, Mashhad University of Medical Sciences, Mashhad, Iran.
- Department of Medical Physics, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.
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Sang M, Ge J, Ge J, Tang G, Wang Q, Wu J, Mao L, Ding X, Zhou X. Immune regulatory genes impact the hot/cold tumor microenvironment, affecting cancer treatment and patient outcomes. Front Immunol 2025; 15:1382842. [PMID: 39911580 PMCID: PMC11794490 DOI: 10.3389/fimmu.2024.1382842] [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: 02/06/2024] [Accepted: 12/31/2024] [Indexed: 02/07/2025] Open
Abstract
Background and aims Immunologically hot tumors, characterized by an inflamed tumor microenvironment (TME), contrast significantly with immunologically cold tumors. The identification of these tumor immune subtypes holds clinical significance, as hot tumors may exhibit improved prognoses and heightened responsiveness to checkpoint blockade therapy. Nevertheless, as yet there is no consensus regarding the clinically relevant definition of hot/cold tumors, and the influence of immune genes on the formation of hot/cold tumors remains poorly understood. Methods Data for 33 different types of cancer were obtained from The Cancer Genome Atlas database, and their immune composition was assessed using the CIBERSORT algorithm. Tumors were categorized as either hot or cold based on their distinct immune composition, ongoing immune response, and overall survival. A customized immunogram was created to identify important immunological characteristics. Kyoto Encyclopedia of Genes and Genomes and Hallmark pathway enrichment were evaluated through gene set variation analysis. Additionally, hub genes that regulate the tumor microenvironment were identified, and their expression patterns were analyzed using single-cell RNA sequencing. Furthermore, drug sensitivity and molecular docking analyses were performed to identify potential drug candidates capable of transforming cold tumors into hot tumors. For validation, a clinical cohort of patients diagnosed with pancreatic adenocarcinoma was examined using multiplex immunohistochemistry. Results We were able to differentiate between hot and cold tumors in various types of cancer (bladder urothelial carcinoma, pancreatic adenocarcinoma, and cervical squamous cell carcinoma) by analyzing the presence of CD8+ T cells, activated natural killer cells, and M2-type macrophages, as well as the cytolytic activity and T cell proliferation. Hub genes that regulate the TME, including PDCD1, CD276, and NT5E, were discovered. The increased expression of NT5E and its prognostic significance were confirmed through multiplex immunohistochemistry in pancreatic adenocarcinoma. Finally, dasatinib and tozasertib were identified as drug candidates capable of converting cold pancreatic adenocarcinoma tumors into hot tumors. Conclusion In this study, we developed a framework for discerning clinically significant immune subtypes across various cancer types, further identifying several potential targets for converting cold tumors into hot tumors to enhance anticancer treatment efficacy.
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Affiliation(s)
- Mengmeng Sang
- Department of Immunology, School of Medicine, Nantong University, Nantong, China
| | - Jia Ge
- Department of Immunology, School of Medicine, Nantong University, Nantong, China
| | - Juan Ge
- Department of Immunology, School of Medicine, Nantong University, Nantong, China
- Department of Respiratory Medicine, Affiliated Nantong Hospital of Shanghai University, Nantong, China
| | - Gu Tang
- Department of Immunology, School of Medicine, Nantong University, Nantong, China
| | - Qiwen Wang
- Department of Gastroenterology, Affiliated Hospital of Nantong University, Nantong, China
| | - Jiarun Wu
- Department of Immunology, School of Medicine, Nantong University, Nantong, China
| | - Liming Mao
- Department of Immunology, School of Medicine, Nantong University, Nantong, China
- Basic Medical Research Center, School of Medicine, Nantong University, Nantong, China
| | - Xiaoling Ding
- Department of Gastroenterology, Affiliated Hospital of Nantong University, Nantong, China
| | - Xiaorong Zhou
- Department of Immunology, School of Medicine, Nantong University, Nantong, China
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Xu J, Li Z, Tong Q, Zhang S, Fang J, Wu A, Wei G, Zhang C, Yu S, Zheng B, Lin H, Liao X, Xiao Z, Lu W. CD133 +PD-L1 + cancer cells confer resistance to adoptively transferred engineered macrophage-based therapy in melanoma. Nat Commun 2025; 16:895. [PMID: 39837811 PMCID: PMC11751330 DOI: 10.1038/s41467-025-55876-0] [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: 02/12/2024] [Accepted: 01/02/2025] [Indexed: 01/23/2025] Open
Abstract
Adoptive transfer of genetically or nanoparticle-engineered macrophages represents a promising cell therapy modality for treatment of solid tumor. However, the therapeutic efficacy is suboptimal without achieving a complete tumor regression, and the underlying mechanism remains elusive. Here, we discover a subpopulation of cancer cells with upregulated CD133 and programmed death-ligand 1 in mouse melanoma, resistant to the phagocytosis by the transferred macrophages. Compared to the CD133-PD-L1- cancer cells, the CD133+PD-L1+ cancer cells express higher transforming growth factor-β signaling molecules to foster a resistant tumor niche, that restricts the trafficking of the transferred macrophages by stiffened extracellular matrix, and inhibits their cell-killing capability by immunosuppressive factors. The CD133+PD-L1+ cancer cells exhibit tumorigenic potential. The CD133+PD-L1+ cells are further identified in the clinically metastatic melanoma. Hyperthermia reverses the resistance of CD133+PD-L1+ cancer cells through upregulating the 'eat me' signal calreticulin, significantly improving the efficacy of adoptive macrophage therapy. Our findings demonstrate the mechanism of resistance to adoptive macrophage therapy, and provide a de novo strategy to counteract the resistance.
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Affiliation(s)
- Jiaojiao Xu
- School of Pharmacy, Key Laboratory of Smart Drug Delivery Ministry of Education, State Key Laboratory of Molecular Engineering of Polymers, Fudan University, Shanghai, 201203, China
- Minhang Hospital, Fudan University, Shanghai, 201199, China
| | - Zhe Li
- School of Pharmacy, Key Laboratory of Smart Drug Delivery Ministry of Education, State Key Laboratory of Molecular Engineering of Polymers, Fudan University, Shanghai, 201203, China
- Minhang Hospital, Fudan University, Shanghai, 201199, China
| | - Qinli Tong
- School of Pharmacy, Key Laboratory of Smart Drug Delivery Ministry of Education, State Key Laboratory of Molecular Engineering of Polymers, Fudan University, Shanghai, 201203, China
- Minhang Hospital, Fudan University, Shanghai, 201199, China
| | - Sihang Zhang
- School of Pharmacy, Key Laboratory of Smart Drug Delivery Ministry of Education, State Key Laboratory of Molecular Engineering of Polymers, Fudan University, Shanghai, 201203, China
- Minhang Hospital, Fudan University, Shanghai, 201199, China
| | - Jianchen Fang
- Department of Pathology, Shanghai Key Laboratory for Nucleic Acid Chemistry and Nanomedicine, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200127, China
| | - Aihua Wu
- School of Pharmacy, Key Laboratory of Smart Drug Delivery Ministry of Education, State Key Laboratory of Molecular Engineering of Polymers, Fudan University, Shanghai, 201203, China
- Minhang Hospital, Fudan University, Shanghai, 201199, China
| | - Guoguang Wei
- School of Pharmacy, Key Laboratory of Smart Drug Delivery Ministry of Education, State Key Laboratory of Molecular Engineering of Polymers, Fudan University, Shanghai, 201203, China
- Minhang Hospital, Fudan University, Shanghai, 201199, China
| | - Chen Zhang
- School of Pharmacy, Key Laboratory of Smart Drug Delivery Ministry of Education, State Key Laboratory of Molecular Engineering of Polymers, Fudan University, Shanghai, 201203, China
- Minhang Hospital, Fudan University, Shanghai, 201199, China
| | - Sheng Yu
- School of Pharmacy, Key Laboratory of Smart Drug Delivery Ministry of Education, State Key Laboratory of Molecular Engineering of Polymers, Fudan University, Shanghai, 201203, China
- Minhang Hospital, Fudan University, Shanghai, 201199, China
| | - Binbin Zheng
- School of Pharmacy, Key Laboratory of Smart Drug Delivery Ministry of Education, State Key Laboratory of Molecular Engineering of Polymers, Fudan University, Shanghai, 201203, China
- Minhang Hospital, Fudan University, Shanghai, 201199, China
| | - Hongzheng Lin
- School of Pharmacy, Key Laboratory of Smart Drug Delivery Ministry of Education, State Key Laboratory of Molecular Engineering of Polymers, Fudan University, Shanghai, 201203, China
- Minhang Hospital, Fudan University, Shanghai, 201199, China
| | - Xueling Liao
- School of Pharmacy, Key Laboratory of Smart Drug Delivery Ministry of Education, State Key Laboratory of Molecular Engineering of Polymers, Fudan University, Shanghai, 201203, China
| | - Zeyu Xiao
- Department of Pathology, Shanghai Key Laboratory for Nucleic Acid Chemistry and Nanomedicine, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200127, China.
- Department of Pharmacology and Chemical Biology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.
| | - Wei Lu
- School of Pharmacy, Key Laboratory of Smart Drug Delivery Ministry of Education, State Key Laboratory of Molecular Engineering of Polymers, Fudan University, Shanghai, 201203, China.
- Minhang Hospital, Fudan University, Shanghai, 201199, China.
- Quzhou Fudan Institute, Quzhou, Zhejiang, 324002, China.
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Hajipour Keyvani A, Mohammadnejad P, Pazoki-Toroudi H, Perez Gilabert I, Chu T, Manshian BB, Soenen SJ, Sohrabi B. Advancements in Cancer Treatment: Harnessing the Synergistic Potential of Graphene-Based Nanomaterials in Combination Therapy. ACS APPLIED MATERIALS & INTERFACES 2025; 17:2756-2790. [PMID: 39745785 DOI: 10.1021/acsami.4c15536] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/18/2025]
Abstract
Combination therapy, which involves using multiple therapeutic modalities simultaneously or sequentially, has become a cornerstone of modern cancer treatment. Graphene-based nanomaterials (GBNs) have emerged as versatile platforms for drug delivery, gene therapy, and photothermal therapy. These materials enable a synergistic approach, improving the efficacy of treatments while reducing side effects. This review explores the roles of graphene, graphene oxide (GO), and graphene quantum dots (GQDs) in combination therapies and highlights their potential to enhance immunotherapy and targeted cancer therapies. The large surface area and high drug-loading capacity of graphene facilitate the codelivery of multiple therapeutic agents, promoting targeted and sustained release. GQDs, with their unique optical properties, offer real-time imaging capabilities, adding another layer of precision to treatment. However, challenges such as biocompatibility, long-term toxicity, and scalability need to be addressed to ensure clinical safety. Preclinical studies show promising results for GBNs, suggesting their potential to revolutionize cancer treatment through innovative combination therapies.
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Affiliation(s)
- Armin Hajipour Keyvani
- Surface Chemistry Research Laboratory, Faculty of Chemistry, Iran University of Science and Technology, Tehran 16846-13114, Iran
| | - Parizad Mohammadnejad
- Surface Chemistry Research Laboratory, Faculty of Chemistry, Iran University of Science and Technology, Tehran 16846-13114, Iran
| | - Hamidreza Pazoki-Toroudi
- Physiology Research Center, Faculty of Medicine, Iran University of Medical Sciences, Tehran 14496-14535, Iran
| | - Irati Perez Gilabert
- NanoHealth and Optical Imaging Group, Department of Imaging and Pathology, KU Leuven, Rellis Research Group, Gaston Geenslaan 3 - Box 901, 3001 Leuven, Belgium
| | - Tianjiao Chu
- NanoHealth and Optical Imaging Group, Department of Imaging and Pathology, KU Leuven, Rellis Research Group, Gaston Geenslaan 3 - Box 901, 3001 Leuven, Belgium
| | - Bella B Manshian
- Translational Cell and Tissue Research Unit, Department of Imaging and Pathology, KU Leuven, RK-Herestraat 49 - Box 505,3000 Leuven, Belgium
| | - Stefaan J Soenen
- NanoHealth and Optical Imaging Group, Department of Imaging and Pathology, KU Leuven, Rellis Research Group, Gaston Geenslaan 3 - Box 901, 3001 Leuven, Belgium
- Leuven Cancer Institute, Faculty of Medicine, KU Leuven, Rellis Research Group, Gaston Geenslaan 3 - Box 901, 3001 Leuven, Belgium
| | - Beheshteh Sohrabi
- Surface Chemistry Research Laboratory, Faculty of Chemistry, Iran University of Science and Technology, Tehran 16846-13114, Iran
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Xu H, Tao H. T cell receptor signaling pathway subgroups and construction of a novel prognostic model in osteosarcoma. Heliyon 2025; 11:e41191. [PMID: 39811323 PMCID: PMC11732464 DOI: 10.1016/j.heliyon.2024.e41191] [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: 06/02/2024] [Revised: 07/23/2024] [Accepted: 12/12/2024] [Indexed: 01/16/2025] Open
Abstract
Background T cell receptor (TCR) signaling pathway is closely related to tumor progress and immunotherapy. This study aimed to explore the clinical significance, prognosis, immune infiltration and chemotherapy sensitivity of TCR in osteosarcoma (OS). Material and methods OS data were obtained from TARGET and GEO database. TCR signaling pathway-related genes (TCRGs) were extracted from Molecular Signatures Database. Unsupervised non-negative matrix factorization clustering analysis was used to identify OS molecular subtypes. Differential expressed TCRGs between molecular subtypes were screened with univariate Cox regression, LASSO regression and multivariate Cox regression. Subsequently, an OS-associated prognostic model was constructed and validated. Nomogram was established and verified. Immune landscape analysis including immune infiltration analysis, ESTIMATE algorithm and immune checkpoints expression levels of molecular subtypes and different risk groups were analyzed. Finally, chemotherapy sensitivity and potential therapeutic agents between different risk groups was identified. Results Two TCRGs related subclusters were identified. Two hundred and seventy-two Differential expressed TCRGs were screened between two subclusters. A robust prognostic model were constructed. High and low risk groups were stratified. Low risk group showed higher ESTIMATE, immune and stromal scores, while high risk group exhibited higher tumor purity and the lower expression levels of immune checkpoints. A nomogram comprising metastasis and risk score was successfully built. The sensitivity to chemotherapy agents were different across high and low risk groups. Conclusions Our study proposed TCR related molecular subtypes and provided a prognostic model for OS. Our findings may bring a new insight into the immunotherapy for OS patients.
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Affiliation(s)
- Huan Xu
- Department of Joint Surgery, Lishui Hospital, Zhejiang University School of Medicine, Lishui, China
| | - Huimin Tao
- Department of Orthopedics Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
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Wang Q, Yu M, Zhang S. The characteristics of the tumor immune microenvironment in colorectal cancer with different MSI status and current therapeutic strategies. Front Immunol 2025; 15:1440830. [PMID: 39877377 PMCID: PMC11772360 DOI: 10.3389/fimmu.2024.1440830] [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: 05/30/2024] [Accepted: 12/16/2024] [Indexed: 01/31/2025] Open
Abstract
Colorectal cancer (CRC) remains a significant cause of cancer-related mortality worldwide. Despite advancements in surgery, chemotherapy, and radiotherapy, the effectiveness of these conventional treatments is limited, particularly in advanced cases. Therefore, transition to novel treatment is urgently needed. Immunotherapy, especially immune checkpoint inhibitors (ICIs), has shown promise in improving outcomes for CRC patients. Notably, patients with deficient mismatch repair (dMMR) or microsatellite instability-high (MSI-H) tumors often benefit from ICIs, while the majority of CRC cases, which exhibit proficient mismatch repair (pMMR) or microsatellite-stable (MSS) status, generally show resistance to this approach. It is assumed that the MSI phenotype cause some changes in the tumor microenvironment (TME), thus triggering antitumor immunity and leading to response to immunotherapy. Understanding these differences in the TME relative to MSI status is essential for developing more effective therapeutic strategies. This review provides an overview of the TME components in CRC and explores current approaches aimed at enhancing ICI efficacy in MSS CRC.
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Affiliation(s)
- Qingzhe Wang
- Department of Targeting Therapy and Immunology, Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Min Yu
- Division of Thoracic Tumor Multimodality Treatment, Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Shuang Zhang
- Department of Targeting Therapy and Immunology, Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China
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