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Zhang S, Miao L, Tian X, Yang B, Luo B. Opportunities and challenges of immuno-oncology: A bibliometric analysis from 2014 to 2023. Hum Vaccin Immunother 2025; 21:2440203. [PMID: 39885669 PMCID: PMC11792843 DOI: 10.1080/21645515.2024.2440203] [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: 09/11/2024] [Revised: 11/22/2024] [Accepted: 12/06/2024] [Indexed: 02/01/2025] Open
Abstract
The emergence of immuno-oncology (IO) has led to revolutionary changes in the field of cancer treatment. Despite notable advancements in this field, a thorough exploration of its full depth and extent has yet to be performed. This study provides a comprehensive overview of publications pertaining to IO. Publications on IO from 2014 to 2023 were retrieved by searching the Web of Science Core Collection database (WoSCC). VOSviewer software and Citespace software were used for the visualized analysis. A total of 1,874 articles have been published in the IO domain. The number of publications and citations has been increasing annually. This study also examines the primary research directions within the field of IO. In conclusion, this study offers a comprehensive overview of the opportunities and challenges associated with IO, illuminating the current status of research and indicating potential future trajectories in this rapidly progressing field. This study provides a comprehensive survey of the current research status and hot spots within the field of IO. It will assist researchers in comprehending the current research emphasis and development trends in this field and offers guidance for future research directions.
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Affiliation(s)
- Siqi Zhang
- School of Clinical Traditional Chinese Medicine, Hubei University of Chinese Medicine, Wuhan, China
- Department of Oncology, Affiliated Hospital of Hubei University of Chinese Medicine, Wuhan, China
- Department of Oncology, Hubei Province Academy of Traditional Chinese Medicine, Wuhan, China
| | - Lina Miao
- Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Xiaoxia Tian
- School of Clinical Traditional Chinese Medicine, Hubei University of Chinese Medicine, Wuhan, China
| | - Bingxu Yang
- School of Clinical Traditional Chinese Medicine, Hubei University of Chinese Medicine, Wuhan, China
| | - Baoping Luo
- School of Clinical Traditional Chinese Medicine, Hubei University of Chinese Medicine, Wuhan, China
- Department of Oncology, Affiliated Hospital of Hubei University of Chinese Medicine, Wuhan, China
- Department of Oncology, Hubei Province Academy of Traditional Chinese Medicine, Wuhan, China
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Song Q, Yu Z, Lu W, Zhuo Z, Chang L, Mei H, Cui Y, Zhang D. PD-1/PD-L1 inhibitors related adverse events: A bibliometric analysis from 2014 to 2024. Hum Vaccin Immunother 2025; 21:2424611. [PMID: 39757956 DOI: 10.1080/21645515.2024.2424611] [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: 07/31/2024] [Revised: 10/14/2024] [Accepted: 10/29/2024] [Indexed: 01/07/2025] Open
Abstract
Programmed cell death-1 (PD-1) inhibitors and programmed cell death ligand 1 (PD-L1) inhibitors are considered effective alternatives for the primary treatment of recurrent metastatic cancers. However, they can induce various adverse events affecting multiple organ systems, potentially diminishing patients' quality of life, and even leading to treatment interruptions. Adverse events related to PD-1/PD-L1 inhibitors differ from those associated with CTLA-4 inhibitors and are more commonly observed in the treatment of solid tumors. This study aimed to address the knowledge gap regarding adverse events related to PD-1/PD-L1 inhibitors. A visual bibliometric network was constructed using VOSviewer, CiteSpace, R software, and the Web of Science Core Collection (WoSCC) to quantitatively analyze this research field. Future research directions were also explored. The USA ranked first in publication count and total citations. Over time, publication types transitioned from case reports to clinical trials. Research on for nivolumab was the most prevalent. The spectrum of cancers treated by PD-1/PD-L1 inhibitors expanded beyond melanoma and lung cancer to include renal cell carcinoma, esophageal cancer, and others. Common adverse events included pneumonitis, myasthenia gravis, and vitiligo. There was a significant increase in multi-phase clinical trials and studies related to biomarkers. This study offers valuable insights for potential collaborators and institutions, highlighting trends in the study of adverse events related to PD-1/PD-L1 inhibitors. The management of these adverse events has become more refined and standardized. Biomarker research and multi-phase clinical trials are likely to be key areas of focus in future studies.
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Affiliation(s)
- Qingya Song
- Department of Oncology, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Zongliang Yu
- Graduate School, Beijing University of Chinese Medicine, Beijing, China
| | - Wenping Lu
- Department of Oncology, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Zhili Zhuo
- Department of Oncology, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Lei Chang
- Graduate School, Beijing University of Chinese Medicine, Beijing, China
| | - Heting Mei
- Graduate School, Beijing University of Chinese Medicine, Beijing, China
| | - Yongjia Cui
- Department of Oncology, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Dongni Zhang
- Department of Oncology, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
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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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Li G, Che X, Wang S, Liu D, Xie D, Jiang B, Zheng Z, Zheng X, Wu G. The role of cisplatin in modulating the tumor immune microenvironment and its combination therapy strategies: a new approach to enhance anti-tumor efficacy. Ann Med 2025; 57:2447403. [PMID: 39757995 PMCID: PMC11705547 DOI: 10.1080/07853890.2024.2447403] [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: 01/16/2024] [Revised: 05/27/2024] [Accepted: 11/23/2024] [Indexed: 01/07/2025] Open
Abstract
Cisplatin is a platinum-based drug that is frequently used to treat multiple tumors. The anti-tumor effect of cisplatin is closely related to the tumor immune microenvironment (TIME), which includes several immune cell types, such as the tumor-associated macrophages (TAMs), cytotoxic T-lymphocytes (CTLs), dendritic cells (DCs), myeloid-derived suppressor cells (MDSCs), regulatory T cells (Tregs), and natural killer (NK) cells. The interaction between these immune cells can promote tumor survival and chemoresistance, and decrease the efficacy of cisplatin monotherapy. Therefore, various combination treatment strategies have been devised to enhance patient responsiveness to cisplatin therapy. Cisplatin can augment anti-tumor immune responses in combination with immune checkpoint blockers (such as PD-1/PD-L1 or CTLA4 inhibitors), lipid metabolism disruptors (like FASN inhibitors and SCD inhibitors) and nanoparticles (NPs), resulting in better outcomes. Exploring the interaction between cisplatin and the TIME will help identify potential therapeutic targets for improving the treatment outcomes in cancer patients.
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Affiliation(s)
- Guandu Li
- Department of Urology, the First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, China
| | - Xiangyu Che
- Department of Urology, the First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, China
| | - Shijin Wang
- Department of Urology, the First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, China
| | - Dequan Liu
- Department of Urology, the First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, China
| | - Deqian Xie
- Department of Urology, the First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, China
| | - Bowen Jiang
- Department of Urology, the First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, China
| | - Zunwen Zheng
- Department of Urology, the First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, China
| | - Xu Zheng
- Department of Cell Biology, College of Basic Medical Science, Dalian Medical University, Dalian, Liaoning, China
| | - Guangzhen Wu
- Department of Urology, the First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, China
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Wang L, Chen SY, Li JL, Dai J, Qin DY, He RQ, Chen G. Anti-inflammatory effects of immunotherapy in clinical treatment and its potential mechanism in alleviating sleeping disorders: A systematic bibliometric study. Hum Vaccin Immunother 2025; 21:2475601. [PMID: 40097368 PMCID: PMC11917172 DOI: 10.1080/21645515.2025.2475601] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2024] [Revised: 02/15/2025] [Accepted: 03/02/2025] [Indexed: 03/19/2025] Open
Abstract
Sleeping disorders negatively affect cancer patient management, quality of life, and recovery. Immunotherapy, a rising cancer treatment, shows potential to improve sleep quality by reducing inflammation. This study analyzed 255 publications (2000-2024) from the Web of Science Core Collection using bibliometric methods. The US and China dominate research output, with The Mayo Clinic as a key contributor. Core topics are "immunotherapy," "quality of life," and "antibodies." Emerging keywords like "cancer," "encephalitis," and "depression" highlight a shift toward clinical psychology in treating tumors and rare diseases. It is noteworthy that with the rapid expansion of immunotherapy in cancer treatment, clinical trials have shown that it can improve sleep quality in cancer patients by reducing inflammation. As its application in cancer treatment expands, immunotherapy's potential for treating sleep disorders is promising. Future development is expected to improve sleep quality and address clinical issues, offering broad prospects for patient outcomes.
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Affiliation(s)
- Lei Wang
- Department of Pathology, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region, P.R. China
| | - Si-Yan Chen
- Day Chemotherapy Center, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region, P.R. China
| | - Jun-Li Li
- Day Chemotherapy Center, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region, P.R. China
| | - Jian Dai
- Department of Clinical Psychology, Jiangbin Hospital of Guangxi Zhuang Autonomous Region, Nanning, Guangxi Zhuang Autonomous Region, P. R. China
| | - Di-Yuan Qin
- Department of Computer Science and Technology, School of Computer and Electronic Information, Guangxi University, Nanning, Guangxi Zhuang Autonomous Region, P. R. China
| | - Rong-Quan He
- Department of Medical Oncology, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region, P. R. China
| | - Gang Chen
- Department of Pathology, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region, P.R. China
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Zuo CJ, Tian J. Advancing the understanding of the role of apoptosis in lung cancer immunotherapy: Global research trends, key themes, and emerging frontiers. Hum Vaccin Immunother 2025; 21:2488074. [PMID: 40186454 PMCID: PMC11980473 DOI: 10.1080/21645515.2025.2488074] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2025] [Revised: 03/12/2025] [Accepted: 03/30/2025] [Indexed: 04/07/2025] Open
Abstract
Apoptosis is vital for improving the efficacy of lung cancer (LC) immunotherapy by targeting cancer cell elimination. Despite its importance, there is a lack of comprehensive bibliometric studies analyzing global research on apoptosis in LC immunotherapy. This analysis aims to address this gap by highlighting key trends, contributors, and future directions. A total of 969 publications from 1996 to 2024 were extracted from the Web of Science Core Collection. Analysis was conducted using VOSviewer, CiteSpace, and the R package 'bibliometrix.' The study included contributions from 6,894 researchers across 1,469 institutions in 61 countries, with research published in 356 journals. The volume of publications has steadily increased, led by China and the United States, with Sichuan University as the top contributor. The journal Cancers published the most articles, while Cancer Research had the highest co-citations. Yu-Quan Wei was the leading author, and Jemal, A. was the most frequently co-cited. Key research themes include "cell death mechanisms," "immune regulation," "combination therapies," "gene and nanomedicine applications," and "traditional Chinese medicine (TCM)." Future research is likely to focus on "coordinated regulation of multiple cell death pathways," "modulation of the tumor immune microenvironment," "optimization of combination therapies," "novel strategies in gene regulation," and the "integration of TCM" for personalized treatment. This is the first bibliometric analysis on the role of apoptosis in LC immunotherapy, providing an landscape of global research patterns and emerging therapeutic strategies. The findings offer insights to guide future research and optimize treatment approaches.
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Affiliation(s)
- Chun-Jian Zuo
- Department of Cardiothoracic Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Jie Tian
- Department of Thoracic Surgery, West China Hospital, Sichuan University, Chengdu, China
- Lung Cancer Center, West China Hospital, Sichuan University, Chengdu, China
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Zhou S, Jiang D, Liu Y, Wang Q, Hu M, Dai K, Chen L, Zhang T, Cai C, Wang J. The role of Sine Oculis Homeobox Homolog 2 in colon Cancer: Insights into prognosis, immune regulation, and therapeutic implications. Biochem Biophys Res Commun 2025; 772:152038. [PMID: 40414014 DOI: 10.1016/j.bbrc.2025.152038] [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: 02/22/2025] [Revised: 04/19/2025] [Accepted: 05/15/2025] [Indexed: 05/27/2025]
Abstract
Colon cancer (CC) remains a significant global health burden, and the search for novel prognostic biomarkers and therapeutic targets is crucial. This study comprehensively analyzed the role of SIX2 (Sine Oculis Homeobox Homolog 2) in CC. Utilizing data from TCGA, GTEx, and CCLE databases, differential expression of SIX2 was observed in multiple cancers, with significant upregulation in many tumors compared to normal tissues. In CC, SIX2's differential expression was notable. Cox regression analysis revealed its prognostic significance, with overexpression associated with poor survival outcomes. SIX2 was strongly associated with gene alterations and correlated with key signaling pathways like WNT and TGF-β. In the tumor microenvironment, SIX2 was related to immune cell infiltration and immune-related molecules. Notably, in CC, it was associated with immunosuppressive cells and checkpoint molecules. Additionally, ABT737 was found to sensitize tumor immunotherapy in the context of SIX2. Animal experiments demonstrated that ABT737 effectively restricted the growth of CC in mice, and its combination with antiPD-1 immunotherapy was more effective. It could reduce the infiltration of CD163+ tumor-associated macrophages but without significantly increasing the infiltration of CD8+ T cells. Our findings suggest that SIX2 is a potential key player in CC, offering insights into future research and the development of targeted therapies.
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Affiliation(s)
- Shicheng Zhou
- Department of Colorectal Surgery, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, Zhejiang, 321000, China
| | - Dan Jiang
- Department of Surgery, Wucheng District People's Hospital, Jinhua, Zhejiang, 321000, China
| | - Yu Liu
- Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
| | - Qin Wang
- Department of Endocrinology, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, Zhejiang, 321000, China
| | - Manyi Hu
- Department of Colorectal Surgery, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, Zhejiang, 321000, China
| | - Kangfu Dai
- Department of Colorectal Surgery, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, Zhejiang, 321000, China
| | - Lin Chen
- Central Laboratory, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, 321000, Zhejiang Province, China
| | - Tianming Zhang
- Department of Colorectal Surgery, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, Zhejiang, 321000, China
| | - Cheng Cai
- Department of Colorectal Surgery, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, Zhejiang, 321000, China.
| | - Jianping Wang
- Department of Colorectal Surgery, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, Zhejiang, 321000, China.
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Tang Y, Yi X, Ai J. mRNA vaccines for prostate cancer: A novel promising immunotherapy. Biochim Biophys Acta Rev Cancer 2025; 1880:189333. [PMID: 40288658 DOI: 10.1016/j.bbcan.2025.189333] [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: 01/21/2025] [Revised: 04/21/2025] [Accepted: 04/21/2025] [Indexed: 04/29/2025]
Abstract
The treatment of advanced prostate cancer (PCa) primarily based on androgen deprivation therapy (ADT); however, patients inevitably progress to the castration-resistant prostate cancer (CRPC) stage. Despite the recent advancements in CRPC treatment with novel endocrine drugs that further inhibit androgen receptor signaling, resistance ultimately develops, underscoring the urgent need for new effective therapeutic strategies. Therapeutic cancer vaccines, a form of immunotherapy, exert anti-cancer effects by activating the host's immune system. Over the past few decades, various conventional therapeutic PCa vaccines based on cells, microbes, proteins, peptides, or DNA have been developed and tested in patients with advanced PCa. These attempts have largely failed to improve survival, with the sole exception of sipuleucel-T, which extended the median overall survival of asymptomatic or minimally symptomatic metastatic CRPC (mCRPC) patients by four months. The rapid development and high efficacy of mRNA vaccines during the COVID-19 pandemic have garnered worldwide attention. Compared to conventional vaccines, mRNA vaccines offer several unique advantages, including high production efficiency, low cost, high safety, strong immune response induction, and high adaptability and precision. These attributes make mRNA vaccines a promising frontier in the treatment of advanced PCa.
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Affiliation(s)
- Yaxiong Tang
- Department of Urology, Institute of Urology, West China Hospital, Sichuan University, 88 South Keyuan Road, Chengdu 610041, China
| | - Xianyanling Yi
- Department of Urology, Institute of Urology, West China Hospital, Sichuan University, 88 South Keyuan Road, Chengdu 610041, China
| | - Jianzhong Ai
- Department of Urology, Institute of Urology, West China Hospital, Sichuan University, 88 South Keyuan Road, Chengdu 610041, China.
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Riviere C, Aljieli M, Mévélec MN, Lantier L, Boursin F, Lajoie L, Ducournau C, Germon S, Moiré N, Dimier-Poisson I, Aubrey N, di Tommaso A. Neospora caninum as delivery vehicle for anti-PD-L1 scFv-Fc: A novel approach for cancer immunotherapy. MOLECULAR THERAPY. ONCOLOGY 2025; 33:200968. [PMID: 40236994 PMCID: PMC11999461 DOI: 10.1016/j.omton.2025.200968] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 07/29/2024] [Revised: 12/29/2024] [Accepted: 03/16/2025] [Indexed: 04/17/2025]
Abstract
Neospora caninum, a potential anticancer agent able to reactivate the immune response within the tumor microenvironment (TME), has recently shown enhanced immunomodulatory properties in different tumor models when armed with the cytokine, Il-15. In the current area of combination immunotherapy strategies designed to overcome treatment resistance, we engineered for the first time the protozoan Neospora caninum to vectorize and secrete a single-chain variable fragment fused to fragment crystallizable region (scFv-Fc) targeting human programmed cell death ligand 1 (PD-L1). Following validation of its secretion through the micronemes (protozoa secretory organelles), we demonstrated that the scFv-Fc could bind PD-L1 on mouse and human tumor cells, block the programmed cell death protein 1 (PD-1)/PD-L1 pathway leading to potentiate the T cell lymphocyte activity. Additionally, the scFv-Fc induced antibody-dependent cellular phagocytosis (ADCP) and antibody-dependent cellular cytotoxicity (ADCC). Those data demonstrate the feasibility of vectoring and secreting a functional antibody fragment by N. caninum, opening promising avenues for future research.
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Affiliation(s)
- Clément Riviere
- BioMAP, UMR ISP 1282 INRAe – Université de Tours, 37200 Tours, France
| | - Muna Aljieli
- BioMAP, UMR ISP 1282 INRAe – Université de Tours, 37200 Tours, France
- Faculty of Pharmacy, University of Gezira, Wad Madani, Sudan
| | | | - Louis Lantier
- BioMAP, UMR ISP 1282 INRAe – Université de Tours, 37200 Tours, France
| | - Fanny Boursin
- BioMAP, UMR ISP 1282 INRAe – Université de Tours, 37200 Tours, France
| | - Laurie Lajoie
- BioMAP, UMR ISP 1282 INRAe – Université de Tours, 37200 Tours, France
| | - Céline Ducournau
- BioMAP, UMR ISP 1282 INRAe – Université de Tours, 37200 Tours, France
| | - Stéphanie Germon
- BioMAP, UMR ISP 1282 INRAe – Université de Tours, 37200 Tours, France
| | - Nathalie Moiré
- BioMAP, UMR ISP 1282 INRAe – Université de Tours, 37200 Tours, France
| | | | - Nicolas Aubrey
- BioMAP, UMR ISP 1282 INRAe – Université de Tours, 37200 Tours, France
| | - Anne di Tommaso
- BioMAP, UMR ISP 1282 INRAe – Université de Tours, 37200 Tours, France
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Sugumar K, Alabd A, Alabd A, Hue JJ, Lyons J, Fields S, Wainberg Z, Zheng L, Coogle B, Kasi A, Grewal N, Kindler HL, Starr J, Sama AR, Winter JM. Exceptional responders to immunotherapy in pancreatic cancer: A multi-institutional case series of a rare occurrence. Oncotarget 2025; 16:427-442. [PMID: 40492845 DOI: 10.18632/oncotarget.28739] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/12/2025] Open
Abstract
INTRODUCTION Immunotherapy has emerged as a standard treatment option for multiple solid tumors. However, most patients with pancreatic cancer (PC) do not derive a significant benefit. Identification and analyses of exceptional responders could eventually offer hints as to why PC is resistant to immunotherapy. METHODS Oncologists from cancer centers in the United States were contacted to identify patients with PC who responded to immunotherapy. Exceptional responders were defined as those having either partial (PR) or complete response (CR) based on Response Evaluation Criteria in Solid Tumors, or biochemical response (CA 19-9 levels) after starting immunotherapy. Patients receiving concurrent chemotherapy were excluded. RESULTS 14 patients met inclusion criteria. Immunotherapy drugs included checkpoint inhibitors and macrophage inhibitors. Eight patients (42%) were MSI (microsatellite instability)-high. Radiologically, 82% had PR. Four patients (28%) had marked reduction in CA 19-9. The median progression-free survival was 12 months from the start of immunotherapy. Median survival was not reached. The 1- and 2-year survival probabilities were 80%, 70% respectively. CONCLUSION Majority of clinical trials evaluating immunotherapy in PC have yielded disappointing response rates compared to other solid tumors. Our case series adds to published data from early-phase trials supporting the promise of immunotherapy in some patients with PC.
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Affiliation(s)
- Kavin Sugumar
- Department of Surgery, University Hospitals Seidman Cancer Center, Cleveland, OH 44106, USA
| | - Andrew Alabd
- Department of Medicine, Cooper University Healthcare, Camden, NJ 08103, USA
| | - Andre Alabd
- Department of Urology, University of Indiana, Indianapolis, IN 46227, USA
| | - Jonathan J Hue
- Department of Surgery, University Hospitals Seidman Cancer Center, Cleveland, OH 44106, USA
| | - Josh Lyons
- Department of Surgery, University Hospitals Seidman Cancer Center, Cleveland, OH 44106, USA
| | - Sherri Fields
- Department of Medicine, UCLA/Santa Monica Cancer Center, CA 90404, USA
| | - Zev Wainberg
- Department of Medicine, UCLA/Santa Monica Cancer Center, CA 90404, USA
| | - Lei Zheng
- Department of Medicine, Johns Hopkins University, Baltimore, MD 21218, USA
| | - Brianna Coogle
- Department of Medicine, University of Kansas Medical Center, Kansas City, KS 66103, USA
| | - Anup Kasi
- Department of Medicine, University of Kansas Medical Center, Kansas City, KS 66103, USA
| | - Nicholas Grewal
- Department of Medicine, University of Chicago, Chicago, IL 60637, USA
| | - Hedy L Kindler
- Department of Medicine, University of Chicago, Chicago, IL 60637, USA
| | - Jason Starr
- Department of Medicine, Mayo Clinic, Jacksonville, FL 32224, USA
| | - Ashwin R Sama
- Department of Medicine, Jefferson Medical Oncology Associates, Philadelphia, PA 19107, USA
| | - Jordan M Winter
- Department of Surgery, University Hospitals Seidman Cancer Center, Cleveland, OH 44106, USA
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Cammarata A, Marino J, Atia MN, Durán H, Glisoni RJ. Novel doxycycline gold nanoparticles via green synthesis using PEO-PPO block copolymers for enhanced radiosensitization of melanoma. Biomater Sci 2025; 13:3223-3241. [PMID: 40261332 DOI: 10.1039/d5bm00253b] [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: 04/24/2025]
Abstract
This study focuses on a green and sustainable nanoplatform for the delivery of therapeutic agents, based on gold nanoparticles (AuNPs) synthesized using PEO-PPO block copolymers (F127, F68, P85, and their F127:P85 combination) as dual-function reducing and stabilizing agents. This eco-friendly approach eliminates the need for toxic chemical reductants, adheres to green chemistry principles, and yields highly stable, biocompatible nanosystems. The resulting polymer-stabilized AuNPs were associated with doxycycline (DOXY), a mitochondrial biogenesis inhibitor with radiosensitizing properties, and characterized using UV-Vis spectroscopy, dynamic light scattering (DLS), transmission electron microscopy (TEM), and X-ray fluorescence (XRF). The nanoparticles exhibited high colloidal stability, with tunable hydrodynamic diameters modulated by the copolymer composition. In vitro studies on A-375 and IIB-MEL-J melanoma cell lines revealed that DOXY-associated AuNPs, combined with gamma radiation (2 Gy, 137Cs), significantly enhanced radiosensitivity, reducing both cell viability and clonogenic survival. The physicochemical features of the nanosystems, particularly particle size and surface composition, influenced cellular uptake and therapeutic response. Notably, AuNPs stabilized with F127:P85 copolymer combination (∼19 nm) outperformed those with F127 (∼30 nm), despite displaying slightly higher polydispersity. Compared to Turkevich AuNPs, our copolymer-coated nanosystems demonstrated superior colloidal stability and cellular internalization. These findings highlight the potential of green-synthesized AuNPs as multifunctional, biocompatible platforms for therapeutic delivery, supporting the development of effective and environmentally responsible multimodal cancer therapies. Moreover, the simplicity, scalability, and cost-effectiveness of the synthesis process support its potential for future translational applications.
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Affiliation(s)
- Agostina Cammarata
- Universidad de Buenos Aires (UBA), Facultad de Farmacia y Bioquímica, Departamento de Microbiología, Inmunología, Biotecnología y Genética, Cátedra de Biotecnología, Junín 956, C1113AAD Buenos Aires, Argentina
- CONICET - Universidad de Buenos Aires, Facultad de Farmacia y Bioquímica, Instituto de Nanobiotecnología (NANOBIOTEC), Buenos Aires, Argentina.
| | - Julieta Marino
- Universidad de Buenos Aires (UBA), Facultad de Farmacia y Bioquímica, Instituto de Química y Fisicoquímica Biológicas "Prof. Alejandro C. Paladini" (IQUIFIB), Buenos Aires, Argentina
| | - Mariel N Atia
- Comisión Nacional de Energía Atómica (CNEA), Gerencia de Investigación y Aplicaciones, Subgerencia de Tecnología y Aplicaciones de Aceleradores, San Martín, Buenos Aires, Argentina
- Instituto de Nanociencia y Nanotecnología (INN-CNEA-CONICET), San Martín, Buenos Aires, Argentina
| | - Hebe Durán
- Comisión Nacional de Energía Atómica (CNEA), Gerencia de Investigación y Aplicaciones, Subgerencia de Tecnología y Aplicaciones de Aceleradores, San Martín, Buenos Aires, Argentina
- Instituto de Nanociencia y Nanotecnología (INN-CNEA-CONICET), San Martín, Buenos Aires, Argentina
- Universidad Nacional de San Martín, Escuela de Ciencia y Tecnología, San Martín, Buenos Aires, Argentina
| | - Romina J Glisoni
- Universidad de Buenos Aires (UBA), Facultad de Farmacia y Bioquímica, Departamento de Microbiología, Inmunología, Biotecnología y Genética, Cátedra de Biotecnología, Junín 956, C1113AAD Buenos Aires, Argentina
- CONICET - Universidad de Buenos Aires, Facultad de Farmacia y Bioquímica, Instituto de Nanobiotecnología (NANOBIOTEC), Buenos Aires, Argentina.
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Yang J, Li X, Li T, Mei J, Chen Y. Recent advances in biomimetic nanodelivery systems for cancer Immunotherapy. Mater Today Bio 2025; 32:101726. [PMID: 40270890 PMCID: PMC12017925 DOI: 10.1016/j.mtbio.2025.101726] [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: 02/26/2025] [Accepted: 04/01/2025] [Indexed: 04/25/2025] Open
Abstract
Tumor immunotherapy is a developing and promising therapeutic method. However, the mechanism of tumor immune microenvironment and individual differences of patients make the clinical application of immunotherapy still very limited. The resulting targeting of the tumor environment and immune system is a suitable strategy for tumor therapy. Biomimetic nanodelivery systems (BNDS) coated with nanoparticles has brought new hope for tumor immunotherapy. Due to its high targeting, maximum drug delivery efficiency and immune escape, BNDS has become one of the options for tumor immunotherapy in the future. BNDS combines the advantages of natural cell membranes and nanoparticles and has good targeting properties. This review summarizes the relationship between tumor and immune microenvironment, classification of immunotherapy, engineering modification of cell membrane, and a comprehensive overview of different types of membrane BNDS in immunotherapy. Furthermore, the prospects and challenges of biomimetic nanoparticles coated with membranes in tumor immunotherapy are further discussed.
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Affiliation(s)
- Jiawei Yang
- Cixi Biomedical Research Institute, Wenzhou Medical University, Zhejiang, China, No. 508 North Second Ring East Road, Ningbo, 315302, Zhejiang, China
| | - Xueqi Li
- Cixi Biomedical Research Institute, Wenzhou Medical University, Zhejiang, China, No. 508 North Second Ring East Road, Ningbo, 315302, Zhejiang, China
| | - Tongyu Li
- Department of Hematology, The First Affiliated Hospital of Ningbo University, 59 Liuting Street, Haishu District, Ningbo, 315010, China
| | - Jin Mei
- Cixi Biomedical Research Institute, Wenzhou Medical University, Zhejiang, China, No. 508 North Second Ring East Road, Ningbo, 315302, Zhejiang, China
- Institute of Engineering Medicine, The First Affiliated Hospital of Ningbo University, 59 Liuting Street, Haishu District, Ningbo, 315010, China
| | - Ying Chen
- Institute of Engineering Medicine, The First Affiliated Hospital of Ningbo University, 59 Liuting Street, Haishu District, Ningbo, 315010, China
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Zhang H, Xu X, Li S, Huang H, Zhang K, Li W, Wang X, Yang J, Yin X, Qu C, Ni J, Dong X. Advances in nanoplatform-based multimodal combination therapy activating STING pathway for enhanced anti-tumor immunotherapy. Colloids Surf B Biointerfaces 2025; 250:114573. [PMID: 39983453 DOI: 10.1016/j.colsurfb.2025.114573] [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: 09/25/2024] [Revised: 01/24/2025] [Accepted: 02/16/2025] [Indexed: 02/23/2025]
Abstract
Activation of the cyclic GMP-AMP synthase(cGAS)-stimulator of interferon genes (STING) has great potential to promote antitumor immunity. As a major effector of the cell to sense and respond to the aberrant presence of cytoplasmic double-stranded DNA (dsDNA), inducing the expression and secretion of type I interferons (IFN) and STING, cGAS-STING signaling pathway establishes an effective natural immune response, which is one of the fundamental mechanisms of host defense in organisms. In addition to the release of heterologous DNA due to pathogen invasion and replication, mitochondrial damage and massive cell death can also cause abnormal leakage of the body's own dsDNA, which is then recognized by the DNA receptor cGAS and activates the cGAS-STING signaling pathway. However, small molecule STING agonists suffer from rapid excretion, low bioavailability, non-specificity and adverse effects, which limits their therapeutic efficacy and in vivo application. Various types of nano-delivery systems, on the other hand, make use of the different unique structures and surface modifications of nanoparticles to circumvent the defects of small molecule STING agonists such as fast metabolism and low bioavailability. Also, the nanoparticles are precisely directed to the focal site, with their own appropriate particle size combined with the characteristics of passive or active targeting. Herein, combined with the cGAS-STING pathway to activate the immune system and kill tumor tissues directly or indirectly, which help maximize the use of the functions of chemotherapy, photothermal therapy(PTT), chemodynamic therapy(CDT), and radiotherapy(RT). In this review, we will discuss the mechanism of action of the cGAS-STING pathway and introduce nanoparticle-mediated tumor combination therapy based on the STING pathway. Collectively, the effective multimodal nanoplatform, which can activate cGAS-STING pathway for enhanced anti-tumor immunotherapy, has promising avenue clinical applications for cancer treatment.
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Affiliation(s)
- Huizhong Zhang
- School of Chinese Material Medica, Beijing University of Chinese Medicine, Beijing 102488, China
| | - Xiaohan Xu
- School of Chinese Material Medica, Beijing University of Chinese Medicine, Beijing 102488, China
| | - Shiman Li
- School of Chinese Material Medica, Beijing University of Chinese Medicine, Beijing 102488, China
| | - Huating Huang
- School of Chinese Material Medica, Beijing University of Chinese Medicine, Beijing 102488, China
| | - Ke Zhang
- School of Chinese Material Medica, Beijing University of Chinese Medicine, Beijing 102488, China
| | - Wenjing Li
- School of Chinese Material Medica, Beijing University of Chinese Medicine, Beijing 102488, China
| | - Xinzhu Wang
- School of Chinese Material Medica, Beijing University of Chinese Medicine, Beijing 102488, China
| | - Jingwen Yang
- School of Chinese Material Medica, Beijing University of Chinese Medicine, Beijing 102488, China
| | - Xingbin Yin
- School of Chinese Material Medica, Beijing University of Chinese Medicine, Beijing 102488, China
| | - Changhai Qu
- School of Chinese Material Medica, Beijing University of Chinese Medicine, Beijing 102488, China
| | - Jian Ni
- School of Chinese Material Medica, Beijing University of Chinese Medicine, Beijing 102488, China.
| | - Xiaoxv Dong
- School of Chinese Material Medica, Beijing University of Chinese Medicine, Beijing 102488, China.
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14
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Song Y, Chen J, Zhang Y, Wu N, Zhu Y, Chen G, Miao F, Chen Z, Wang Y. Tumor-specific CXCR6 positive precursor CD8 + T cells mediate tumor control in metastatic melanoma. Cell Oncol (Dordr) 2025; 48:693-708. [PMID: 40192941 PMCID: PMC12119687 DOI: 10.1007/s13402-025-01040-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/16/2025] [Indexed: 05/29/2025] Open
Abstract
BACKGROUND Adoptive cell therapy (ACT) mediates durable and complete regression of various cancers. However, its efficacy is limited by the long-term persistence of cytotoxic T lymphocytes, given their irreversible dysfunction within the tumor microenvironment. Herein, we aimed to establish an artificial lung metastasis model to examine T-lymphocyte subsets, in order to identify potential effective cell subsets for ACT. METHODS A metastatic lung melanoma mouse model was established using OVA-expressing melanoma B16 cells. Flow cytometry analysis was conducted to examine the surface markers, transcription factors, and secreted cytokines of tumor-specific CD8+ T cells within metastatic tissues. The infiltrated cells were sorted by flow cytometry for in vitro tumor cell killing assays or in vivo cell infusion therapy combined with chemotherapeutic drugs and immune checkpoint blockade antibodies. RESULTS Exhausted CD8+ T cells (Tex) exhibited high heterogeneity in metastatic tissues. Among Tex cells, the CXCR6- precursor cell showed certain memory characteristics, including phenotype, transcription factors, and maintenance, whereas the CXCR6+ subpopulation partially lost these traits. Moreover, CXCR6+ precursor cells effectively replenished effector-like Tex cells in metastatic tissues and exerted direct cytotoxicity against tumor cells. Notably, transferring these tumor-specific CXCR6+ precursor-exhausted T (Texp) cells into recipients induced a substantial regression of metastasis. In addition, these cells could respond to immune checkpoint blockade, which could better control tumor metastasis. CONCLUSIONS In our study, a subset of antigen-specific CXCR6-expressing Texp cells was observed within the metastatic tissue. The cells served as a crucial source of effector-like Tex cells and exerted direct cytotoxic effects on tumor cells. Adoptive transfer of CXCR6+ Texp cells effectively mitigated lung metastasis in mice. This study helps elucidate the role of Texp cells in metastasis, thereby offering novel insights into enhancing the efficacy and durability of immunotherapy.
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Affiliation(s)
- Yang Song
- Department of Cardio-Thoracic Surgery, Huashan Hospital, Fudan University, Shanghai, China
| | - Ji Chen
- Department of Cardio-Thoracic Surgery, Huashan Hospital, Fudan University, Shanghai, China
| | - Yaqin Zhang
- Department of Cardio-Thoracic Surgery, Huashan Hospital, Fudan University, Shanghai, China
| | - Ning Wu
- Department of Cardio-Thoracic Surgery, Huashan Hospital, Fudan University, Shanghai, China
| | - Yongjun Zhu
- Department of Cardio-Thoracic Surgery, Huashan Hospital, Fudan University, Shanghai, China
| | - Gang Chen
- Department of Cardio-Thoracic Surgery, Huashan Hospital, Fudan University, Shanghai, China
| | - Feng Miao
- Department of Cardio-Thoracic Surgery, Huashan Hospital, Fudan University, Shanghai, China
| | - Zhiming Chen
- Department of Cardio-Thoracic Surgery, Huashan Hospital, Fudan University, Shanghai, China.
| | - Yiqing Wang
- Department of Cardio-Thoracic Surgery, Huashan Hospital, Fudan University, Shanghai, China.
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15
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Liu D, Liu L, Zhang X, Zhao X, Li X, Che X, Wu G. Decoding driver and phenotypic genes in cancer: Unveiling the essence behind the phenomenon. Mol Aspects Med 2025; 103:101358. [PMID: 40037122 DOI: 10.1016/j.mam.2025.101358] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2024] [Revised: 01/25/2025] [Accepted: 02/26/2025] [Indexed: 03/06/2025]
Abstract
Gray hair, widely regarded as a hallmark of aging. While gray hair is associated with aging, reversing this trait through gene targeting does not alter the fundamental biological processes of aging. Similarly, certain oncogenes (such as CXCR4, MMP-related genes, etc.) can serve as markers of tumor behavior, such as malignancy or prognosis, but targeting these genes alone may not lead to tumor regression. We pioneered the name of this class of genes as "phenotypic genes". Historically, cancer genetics research has focused on tumor driver genes, while genes influencing cancer phenotypes have been relatively overlooked. This review explores the critical distinction between driver genes and phenotypic genes in cancer, using the MAPK and PI3K/AKT/mTOR pathways as key examples. We also discuss current research techniques for identifying driver and phenotypic genes, such as whole-genome sequencing (WGS), RNA sequencing (RNA-seq), RNA interference (RNAi), CRISPR-Cas9, and other genomic screening methods, alongside the concept of synthetic lethality in driver genes. The development of these technologies will help develop personalized treatment strategies and precision medicine based on the characteristics of relevant genes. By addressing the gap in discussions on phenotypic genes, this review significantly contributes to clarifying the roles of driver and phenotypic genes, aiming at advancing the field of targeted cancer therapy.
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Affiliation(s)
- Dequan Liu
- Department of Urology, The First Affiliated Hospital of Dalian Medical University, Dalian, 116011, China
| | - Lei Liu
- Department of Urology, The First Affiliated Hospital of Dalian Medical University, Dalian, 116011, China
| | - Xiaoman Zhang
- Department of Urology, The First Affiliated Hospital of Dalian Medical University, Dalian, 116011, China
| | - Xinming Zhao
- Department of Urology, The First Affiliated Hospital of Dalian Medical University, Dalian, 116011, China
| | - Xiaorui Li
- Department of Oncology, Cancer Hospital of Dalian University of Technology, Shenyang, 110042, China.
| | - Xiangyu Che
- Department of Urology, The First Affiliated Hospital of Dalian Medical University, Dalian, 116011, China.
| | - Guangzhen Wu
- Department of Urology, The First Affiliated Hospital of Dalian Medical University, Dalian, 116011, China.
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16
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Wang W, Gao T, Wang Y, Wang R, He M, Wang L, Zhou W, Ding M, Song Y, Ji X, Li X, Song Y, Zhu Y, Zhang Y, Xie Y, Chen Y, Jin Q, Xie M, Zhang L. Macrophage-Tased Dual-Phase T Cell Immunomodulation to Combat Transplant Rejection. Adv Healthc Mater 2025; 14:e2403591. [PMID: 40264278 DOI: 10.1002/adhm.202403591] [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: 09/23/2024] [Revised: 03/31/2025] [Indexed: 04/24/2025]
Abstract
Transplant rejection remains a major challenge, driven primarily by the activation of alloreactive T cells. While enhancement of PD-L1 checkpoint molecules has exhibited potential in inhibiting T cell activity, its efficacy is often hindered by limited specificity and inadequate efficiency. Herein, a novel dual-phase immune modulation strategy is developed in which CTLA4-Ig and PD-L1 provide distinct, non-redundant inhibitory signals during the initial activation phase and the post-activation phase of T cells. PD-L1 is stably expressed on macrophages (sPD-L1 M) through lentiviral transduction, allowing them to leverage their chemotactic and antigen-presenting functions to target and deliver PD-L1 to transplant rejection sites. Notably, sPD-L1 M exhibited adaptive targeting capabilities, increasing their migration to grafts in response to heightened rejection. In an allograft skin model, the combined intravenous administration of sPD-L1 M and subcutaneous administration of CTLA4-Ig demonstrated synergistic efficacy, significantly suppressing alloreactive T cell activation, enhancing the recruitment of regulatory T cells (Tregs), downregulating pro-inflammatory cytokines, and prolonging allograft survival compared to either treatment alone. This study presents a promising strategy to effectively suppress T cell activity and prevent allogeneic immune responses without systemic immunosuppression.
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Affiliation(s)
- Wenyuan Wang
- Department of Ultrasound Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
- Hubei Province Clinical Research Center for Medical Imaging, Wuhan, 430022, China
- Hubei Province Key Laboratory of Molecular Imaging, Wuhan, 430022, China
| | - Tang Gao
- Department of Ultrasound Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
- Hubei Province Clinical Research Center for Medical Imaging, Wuhan, 430022, China
- Hubei Province Key Laboratory of Molecular Imaging, Wuhan, 430022, China
| | - Yihui Wang
- Department of Ultrasound Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
- Hubei Province Clinical Research Center for Medical Imaging, Wuhan, 430022, China
- Hubei Province Key Laboratory of Molecular Imaging, Wuhan, 430022, China
| | - Rui Wang
- Department of Ultrasound Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
- Hubei Province Clinical Research Center for Medical Imaging, Wuhan, 430022, China
- Hubei Province Key Laboratory of Molecular Imaging, Wuhan, 430022, China
| | - Mengrong He
- Department of Ultrasound Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
- Hubei Province Clinical Research Center for Medical Imaging, Wuhan, 430022, China
- Hubei Province Key Laboratory of Molecular Imaging, Wuhan, 430022, China
| | - Lufang Wang
- Department of Ultrasound Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
- Hubei Province Clinical Research Center for Medical Imaging, Wuhan, 430022, China
- Hubei Province Key Laboratory of Molecular Imaging, Wuhan, 430022, China
| | - Wuqi Zhou
- Department of Ultrasound Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
- Hubei Province Clinical Research Center for Medical Imaging, Wuhan, 430022, China
- Hubei Province Key Laboratory of Molecular Imaging, Wuhan, 430022, China
| | - Mengdan Ding
- Department of Ultrasound Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
- Hubei Province Clinical Research Center for Medical Imaging, Wuhan, 430022, China
- Hubei Province Key Laboratory of Molecular Imaging, Wuhan, 430022, China
| | - Yuan Song
- Department of Ultrasound Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
- Hubei Province Clinical Research Center for Medical Imaging, Wuhan, 430022, China
- Hubei Province Key Laboratory of Molecular Imaging, Wuhan, 430022, China
| | - Xiang Ji
- Department of Ultrasound Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
- Hubei Province Clinical Research Center for Medical Imaging, Wuhan, 430022, China
- Hubei Province Key Laboratory of Molecular Imaging, Wuhan, 430022, China
| | - Xueke Li
- Department of Ultrasound Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
- Hubei Province Clinical Research Center for Medical Imaging, Wuhan, 430022, China
- Hubei Province Key Laboratory of Molecular Imaging, Wuhan, 430022, China
| | - Yishu Song
- Department of Ultrasound Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
- Hubei Province Clinical Research Center for Medical Imaging, Wuhan, 430022, China
- Hubei Province Key Laboratory of Molecular Imaging, Wuhan, 430022, China
| | - Ye Zhu
- Department of Ultrasound Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
- Hubei Province Clinical Research Center for Medical Imaging, Wuhan, 430022, China
- Hubei Province Key Laboratory of Molecular Imaging, Wuhan, 430022, China
| | - Yiwei Zhang
- Department of Ultrasound Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
- Hubei Province Clinical Research Center for Medical Imaging, Wuhan, 430022, China
- Hubei Province Key Laboratory of Molecular Imaging, Wuhan, 430022, China
| | - Yuji Xie
- Department of Ultrasound Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
- Hubei Province Clinical Research Center for Medical Imaging, Wuhan, 430022, China
- Hubei Province Key Laboratory of Molecular Imaging, Wuhan, 430022, China
| | - Yan Chen
- Department of Ultrasound Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
- Hubei Province Clinical Research Center for Medical Imaging, Wuhan, 430022, China
- Hubei Province Key Laboratory of Molecular Imaging, Wuhan, 430022, China
| | - Qiaofeng Jin
- Department of Ultrasound Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
- Hubei Province Clinical Research Center for Medical Imaging, Wuhan, 430022, China
- Hubei Province Key Laboratory of Molecular Imaging, Wuhan, 430022, China
| | - Mingxing Xie
- Department of Ultrasound Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
- Hubei Province Clinical Research Center for Medical Imaging, Wuhan, 430022, China
- Hubei Province Key Laboratory of Molecular Imaging, Wuhan, 430022, China
| | - Li Zhang
- Department of Ultrasound Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
- Hubei Province Clinical Research Center for Medical Imaging, Wuhan, 430022, China
- Hubei Province Key Laboratory of Molecular Imaging, Wuhan, 430022, China
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Shi Q, Luo Y, Xiang Q, Kang X, Feng Z. CD28 Superfamily Costimulatory Molecules in Chronic Pain: Focus on Immunomodulation. Mol Neurobiol 2025; 62:7915-7926. [PMID: 39956885 DOI: 10.1007/s12035-025-04746-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2023] [Accepted: 02/03/2025] [Indexed: 02/18/2025]
Abstract
Chronic pain has substantial effects on patients' quality of life and psychological well-being. It does not respond satisfactorily to available medicinal therapeutics because its mechanism remains unclear. Recent studies have shown a strong relationship between chronic pain and immunomodulation. As important members of the immune response, CD28 superfamily costimulatory molecules were demonstrated to have an analgesic effect on chronic pain. Based on research on the role of these molecules in chronic pain, new and highly effective analgesic medicines are anticipated that could be used in combination with some previous analgesic medicines to reduce substance abuse and side effects. This review of the literature will examine the pain-regulating mechanisms of CD28 superfamily costimulatory molecules, focusing on immunomodulation. In addition, this review will discuss the potential and difficulties of developing novel analgesic medicines targeting CD28 superfamily costimulatory molecules.
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Affiliation(s)
- Qinglu Shi
- Department of Pain Medicine, The First Affiliated Hospital, Zhejiang University School of Medicine, No. 79 Qingchun Road, Hangzhou, 310003, Zhejiang, China
| | - Yujia Luo
- Department of Pain Medicine, The First Affiliated Hospital, Zhejiang University School of Medicine, No. 79 Qingchun Road, Hangzhou, 310003, Zhejiang, China
| | - Qiaomin Xiang
- Department of Pain Medicine, The First Affiliated Hospital, Zhejiang University School of Medicine, No. 79 Qingchun Road, Hangzhou, 310003, Zhejiang, China
- Department of Anesthesiology, Ninghai First Hospital, Ningbo, Zhejiang, China
| | - Xianhui Kang
- Department of Anesthesiology, The First Affiliated Hospital, Zhejiang University School of Medicine, No. 79 Qingchun Road, Hangzhou, 310003, Zhejiang, China.
| | - Zhiying Feng
- Department of Pain Medicine, The First Affiliated Hospital, Zhejiang University School of Medicine, No. 79 Qingchun Road, Hangzhou, 310003, Zhejiang, China.
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18
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Chen X, Fu H, Zhu S, Xiang Z, Fu H, Sun Z, Zhang S, Zheng X, Hu X, Chao M, Mao Z, Bi Y, Wang W, Ding Y. The Moonlighting Function of Glutaminase 2 Promotes Immune Evasion of Pancreatic Ductal Adenocarcinoma by Tubulin Tyrosine Ligase-like 1-Mediated Yes1 Associated Transcriptional Regulator Glutamylation. Gastroenterology 2025; 168:1137-1152. [PMID: 39924055 DOI: 10.1053/j.gastro.2025.01.240] [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: 08/16/2024] [Revised: 01/08/2025] [Accepted: 01/27/2025] [Indexed: 02/11/2025]
Abstract
BACKGROUND & AIMS Elevated programmed cell death-ligand 1 (PD-L1) expression in tumor cells facilitates immune evasion. However, the mechanism via which PD-L1 expression is regulated in pancreatic ductal adenocarcinoma (PDAC) cells remains inadequately elucidated. METHODS Immunoprecipitation, pull-down assays, and mass spectrometry were used to identify glutaminase 2 (GLS2) and yes1 associated transcriptional regulator (YAP1) binding proteins and modification sites. Immunoblotting, immunofluorescence, chromatin immunoprecipitation, and luciferase reporter assays were used to analyze YAP1 activation. Protein expression levels were assessed using immunoblotting, immunoprecipitation, immunofluorescence, and immunohistochemistry. RNA expression levels were analyzed using real-time quantitative polymerase chain reaction. RESULTS Hypoxia-induced general control nondepressible 5 (GCN5)-mediated acetylation of GLS2 at K151, which enhanced GLS2 interaction with YAP1. Subsequently, tubulin tyrosine ligase-like 1 mediated YAP1 glutamylation at E100 and promoted its nuclear translocation and the activation-dependent transcriptional up-regulation of PD-L1 expression. The expression of GLS2-K151R or YAP1-E100A mutants in PDAC cells blocked hypoxia-induced PD-L1 expression and enhanced CD4+ and CD8+ T-cell activation and tumor infiltration, thereby suppressing PDAC tumor growth. Simultaneous administration of MB-3, a GCN5 inhibitor, and an anti-programmed cell death 1 (PD-1) antibody abolished tumor immune evasion, boosting the anti-tumor efficacy of immune checkpoint blockade. Furthermore, GLS2-K151 acetylation and YAP1 E100 glutamylation levels correlated positively with PD-L1 expression and poor prognosis in PDAC patients. CONCLUSIONS The present study revealed a novel mechanism by which hypoxia up-regulates PD-L1 expression and highlighted the involvement of GLS2 in noncanonical metabolic pathways involved in tumor immune evasion, with implications for PDAC treatment.
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Affiliation(s)
- Xiao Chen
- Department of Hepatobiliary and Pancreatic Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, People's Republic of China; Key Laboratory of Precision Diagnosis and Treatment for Hepatobiliary and Pancreatic Tumor of Zhejiang Province, Hangzhou, Zhejiang, People's Republic of China; Research Center of Diagnosis and Treatment Technology for Hepatocellular Carcinoma of Zhejiang Province, Hangzhou, Zhejiang, People's Republic of China; Center for Medical Research and Innovation in Digestive System Tumors, Ministry of Education, China; Cancer Center, Zhejiang University, Hangzhou, Zhejiang, People's Republic of China; ZJU-Pujian Research & Development Center of Medical Artificial Intelligence for Hepatobiliary and Pancreatic Disease, Hangzhou, Zhejiang, People's Republic of China
| | - Haotian Fu
- Department of Hepatobiliary and Pancreatic Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, People's Republic of China; Key Laboratory of Precision Diagnosis and Treatment for Hepatobiliary and Pancreatic Tumor of Zhejiang Province, Hangzhou, Zhejiang, People's Republic of China; Research Center of Diagnosis and Treatment Technology for Hepatocellular Carcinoma of Zhejiang Province, Hangzhou, Zhejiang, People's Republic of China; Center for Medical Research and Innovation in Digestive System Tumors, Ministry of Education, China; Cancer Center, Zhejiang University, Hangzhou, Zhejiang, People's Republic of China; ZJU-Pujian Research & Development Center of Medical Artificial Intelligence for Hepatobiliary and Pancreatic Disease, Hangzhou, Zhejiang, People's Republic of China
| | - Shimao Zhu
- Department of Hepatobiliary and Pancreatic Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, People's Republic of China; Key Laboratory of Precision Diagnosis and Treatment for Hepatobiliary and Pancreatic Tumor of Zhejiang Province, Hangzhou, Zhejiang, People's Republic of China; Research Center of Diagnosis and Treatment Technology for Hepatocellular Carcinoma of Zhejiang Province, Hangzhou, Zhejiang, People's Republic of China; Center for Medical Research and Innovation in Digestive System Tumors, Ministry of Education, China; Cancer Center, Zhejiang University, Hangzhou, Zhejiang, People's Republic of China; ZJU-Pujian Research & Development Center of Medical Artificial Intelligence for Hepatobiliary and Pancreatic Disease, Hangzhou, Zhejiang, People's Republic of China
| | - Zheng Xiang
- Department of Gastroenterology and Hepatology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, People's Republic of China
| | - Hong Fu
- Department of Hepatobiliary and Pancreatic Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, People's Republic of China; Key Laboratory of Precision Diagnosis and Treatment for Hepatobiliary and Pancreatic Tumor of Zhejiang Province, Hangzhou, Zhejiang, People's Republic of China; Research Center of Diagnosis and Treatment Technology for Hepatocellular Carcinoma of Zhejiang Province, Hangzhou, Zhejiang, People's Republic of China; Center for Medical Research and Innovation in Digestive System Tumors, Ministry of Education, China; Cancer Center, Zhejiang University, Hangzhou, Zhejiang, People's Republic of China; ZJU-Pujian Research & Development Center of Medical Artificial Intelligence for Hepatobiliary and Pancreatic Disease, Hangzhou, Zhejiang, People's Republic of China
| | - Zhongquan Sun
- Department of Hepatobiliary and Pancreatic Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, People's Republic of China; Key Laboratory of Precision Diagnosis and Treatment for Hepatobiliary and Pancreatic Tumor of Zhejiang Province, Hangzhou, Zhejiang, People's Republic of China; Research Center of Diagnosis and Treatment Technology for Hepatocellular Carcinoma of Zhejiang Province, Hangzhou, Zhejiang, People's Republic of China; Center for Medical Research and Innovation in Digestive System Tumors, Ministry of Education, China; Cancer Center, Zhejiang University, Hangzhou, Zhejiang, People's Republic of China; ZJU-Pujian Research & Development Center of Medical Artificial Intelligence for Hepatobiliary and Pancreatic Disease, Hangzhou, Zhejiang, People's Republic of China
| | - Sitong Zhang
- Department of Hepatobiliary and Pancreatic Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, People's Republic of China; Key Laboratory of Precision Diagnosis and Treatment for Hepatobiliary and Pancreatic Tumor of Zhejiang Province, Hangzhou, Zhejiang, People's Republic of China; Research Center of Diagnosis and Treatment Technology for Hepatocellular Carcinoma of Zhejiang Province, Hangzhou, Zhejiang, People's Republic of China; Center for Medical Research and Innovation in Digestive System Tumors, Ministry of Education, China; Cancer Center, Zhejiang University, Hangzhou, Zhejiang, People's Republic of China; ZJU-Pujian Research & Development Center of Medical Artificial Intelligence for Hepatobiliary and Pancreatic Disease, Hangzhou, Zhejiang, People's Republic of China
| | - Xiaofeng Zheng
- Cancer Center, Zhejiang University, Hangzhou, Zhejiang, People's Republic of China; Department of Pathology & Pathophysiology, and Department of Breast Surgery of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou Zhejiang, People's Republic of China
| | - Xun Hu
- Cancer Institute (Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education), The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Ming Chao
- Interventional Radiology, Department of Radiology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Zhengwei Mao
- Department of Hepatobiliary and Pancreatic Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, People's Republic of China; Key Laboratory of Precision Diagnosis and Treatment for Hepatobiliary and Pancreatic Tumor of Zhejiang Province, Hangzhou, Zhejiang, People's Republic of China; MOE Key Laboratory of Macromolecular Synthesis and Functionalization, Department of Polymer Science and Engineering, Zhejiang University, Hangzhou Zhejiang, People's Republic of China
| | - Yanli Bi
- Department of Hepatobiliary and Pancreatic Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, People's Republic of China; Key Laboratory of Precision Diagnosis and Treatment for Hepatobiliary and Pancreatic Tumor of Zhejiang Province, Hangzhou, Zhejiang, People's Republic of China; Research Center of Diagnosis and Treatment Technology for Hepatocellular Carcinoma of Zhejiang Province, Hangzhou, Zhejiang, People's Republic of China; Center for Medical Research and Innovation in Digestive System Tumors, Ministry of Education, China; Cancer Center, Zhejiang University, Hangzhou, Zhejiang, People's Republic of China; ZJU-Pujian Research & Development Center of Medical Artificial Intelligence for Hepatobiliary and Pancreatic Disease, Hangzhou, Zhejiang, People's Republic of China
| | - Weilin Wang
- Department of Hepatobiliary and Pancreatic Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, People's Republic of China; Key Laboratory of Precision Diagnosis and Treatment for Hepatobiliary and Pancreatic Tumor of Zhejiang Province, Hangzhou, Zhejiang, People's Republic of China; Research Center of Diagnosis and Treatment Technology for Hepatocellular Carcinoma of Zhejiang Province, Hangzhou, Zhejiang, People's Republic of China; Center for Medical Research and Innovation in Digestive System Tumors, Ministry of Education, China; Cancer Center, Zhejiang University, Hangzhou, Zhejiang, People's Republic of China; ZJU-Pujian Research & Development Center of Medical Artificial Intelligence for Hepatobiliary and Pancreatic Disease, Hangzhou, Zhejiang, People's Republic of China.
| | - Yuan Ding
- Department of Hepatobiliary and Pancreatic Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, People's Republic of China; Key Laboratory of Precision Diagnosis and Treatment for Hepatobiliary and Pancreatic Tumor of Zhejiang Province, Hangzhou, Zhejiang, People's Republic of China; Research Center of Diagnosis and Treatment Technology for Hepatocellular Carcinoma of Zhejiang Province, Hangzhou, Zhejiang, People's Republic of China; Center for Medical Research and Innovation in Digestive System Tumors, Ministry of Education, China; Cancer Center, Zhejiang University, Hangzhou, Zhejiang, People's Republic of China; ZJU-Pujian Research & Development Center of Medical Artificial Intelligence for Hepatobiliary and Pancreatic Disease, Hangzhou, Zhejiang, People's Republic of China.
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Lin HY, Jeon AJ, Chen K, Lee CJM, Wu L, Chong SL, Anene-Nzelu CG, Foo RSY, Chow PKH. The epigenetic basis of hepatocellular carcinoma - mechanisms and potential directions for biomarkers and therapeutics. Br J Cancer 2025; 132:869-887. [PMID: 40057667 DOI: 10.1038/s41416-025-02969-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2024] [Revised: 01/23/2025] [Accepted: 02/20/2025] [Indexed: 05/17/2025] Open
Abstract
Hepatocellular carcinoma (HCC) is the sixth leading cancer worldwide and has complex pathogenesis due to its heterogeneity, along with poor prognoses. Diagnosis is often late as current screening methods have limited sensitivity for early HCC. Moreover, current treatment regimens for intermediate-to-advanced HCC have high resistance rates, no robust predictive biomarkers, and limited survival benefits. A deeper understanding of the molecular biology of HCC may enhance tumor characterization and targeting of key carcinogenic signatures. The epigenetic landscape of HCC includes complex hallmarks of 1) global DNA hypomethylation of oncogenes and hypermethylation of tumor suppressors; 2) histone modifications, altering chromatin accessibility to upregulate oncogene expression, and/or suppress tumor suppressor gene expression; 3) genome-wide rearrangement of chromatin loops facilitating distal enhancer-promoter oncogenic interactions; and 4) RNA regulation via translational repression by microRNAs (miRNAs) and RNA modifications. Additionally, it is useful to consider etiology-specific epigenetic aberrancies, especially in viral hepatitis and metabolic dysfunction-associated steatotic liver disease (MASLD), which are the main risk factors of HCC. This article comprehensively explores the epigenetic signatures in HCC, highlighting their potential as biomarkers and therapeutic targets. Additionally, we examine how etiology-specific epigenetic patterns and the integration of epigenetic therapies with immunotherapy could advance personalized HCC treatment strategies.
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Affiliation(s)
- Hong-Yi Lin
- Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
| | - Ah-Jung Jeon
- Department of Research and Development, Mirxes, Singapore, Singapore
| | - Kaina Chen
- Department of Gastroenterology and Hepatology, Singapore General Hospital, Singapore, Singapore
| | - Chang Jie Mick Lee
- Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
- Cardiovascular Research Institute, National University Heart Centre, Singapore, Singapore
| | - Lingyan Wu
- Program in Translational and Clinical Research in Liver Cancer, National Cancer Centre Singapore, Singapore, Singapore
| | - Shay-Lee Chong
- Program in Translational and Clinical Research in Liver Cancer, National Cancer Centre Singapore, Singapore, Singapore
| | | | - Roger Sik-Yin Foo
- Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
- Cardiovascular Research Institute, National University Heart Centre, Singapore, Singapore
- Department of Cardiology, National University Heart Centre, Singapore, Singapore
| | - Pierce Kah-Hoe Chow
- Program in Translational and Clinical Research in Liver Cancer, National Cancer Centre Singapore, Singapore, Singapore.
- Department of Hepato-pancreato-biliary and Transplant Surgery, Division of Surgery and Surgical Oncology, Singapore General Hospital and National Cancer Centre Singapore, Singapore, Singapore.
- Surgery Academic Clinical Programme, Duke-NUS Medical School, Singapore, Singapore.
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20
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Arabi S, Fadaee M, Kazemi T, Rahmani M. Advancements in colorectal cancer immunotherapy: from CAR-T cells to exosome-based therapies. J Drug Target 2025; 33:749-760. [PMID: 39754507 DOI: 10.1080/1061186x.2024.2449482] [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: 09/27/2024] [Revised: 12/03/2024] [Accepted: 12/30/2024] [Indexed: 01/06/2025]
Abstract
Colorectal cancer (CRC) continues to be a major worldwide health issue, with elevated death rates linked to late stages of the illness. Immunotherapy has made significant progress in developing effective techniques to improve the immune system's capacity to identify and eradicate cancerous cells. This study examines the most recent advancements in CAR-T cell treatment and exosome-based immunotherapy for CRC. CAR-T cell therapy, although effective in treating blood cancers, encounters obstacles when used against solid tumours such as CRC. These obstacles include the presence of an immunosuppressive tumour microenvironment and a scarcity of tumour-specific antigens. Nevertheless, novel strategies like dual-receptor CAR-T cells and combination therapy involving cytokines have demonstrated promise in surmounting these obstacles. Exosome-based immunotherapy is a promising approach for targeted delivery of therapeutic drugs to tumour cells, with high specificity and minimal off-target effects. However, there are still obstacles to overcome in the field, such as resistance to treatment, adverse effects associated with the immune system, and the necessity for more individualised methods. The current research is focused on enhancing these therapies, enhancing the results for patients, and ultimately incorporating these innovative immunotherapeutic approaches into the standard treatment protocols for CRC.
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Affiliation(s)
- Sepideh Arabi
- Department of Immunology, Faculty of Medicine, Kurdistan University of Medical Sciences, Sanandaj, Iran
| | - Manouchehr Fadaee
- Student Research Committee, Tabriz University of Medical Science, Tabriz, Iran
- Department of Immunology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Tohid Kazemi
- Department of Immunology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
- Immunology Research Center, Tabriz University of Medical Science, Tabriz, Iran
| | - Mohammadreza Rahmani
- Department of Immunology, Faculty of Medicine, Kurdistan University of Medical Sciences, Sanandaj, Iran
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21
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Fu Y, Yang Q, Xu N, Zhang X. MiRNA affects the advancement of breast cancer by modulating the immune system's response. Biochim Biophys Acta Mol Basis Dis 2025; 1871:167759. [PMID: 40037267 DOI: 10.1016/j.bbadis.2025.167759] [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: 10/29/2024] [Revised: 02/05/2025] [Accepted: 02/26/2025] [Indexed: 03/06/2025]
Abstract
Breast cancer (BC), which is the most common tumor in women, has greatly endangered women's lives and health. Currently, patients with BC receive comprehensive treatments, including surgery, chemotherapy, radiotherapy, endocrine therapy, and targeted therapy. According to the latest research, the development of BC is closely related to the inflammatory immune response, and the immunogenicity of BC has steadily been recognized. As such, immunotherapy is one of the promising and anticipated forms of treatment for BC. The potential values of miRNA in the diagnosis and prognosis of BC have been established, and aberrant expression of associated miRNA can either facilitate or inhibit progression of BC. In the tumor immune microenvironment (TME), miRNAs are considered to be an essential molecular mechanism by which tumor cells interact with immunocytes and immunologic factors. Aberrant expression of miRNAs results in reprogramming of tumor cells actively, which may suppress the generation and activation of immunocytes and immunologic factors, avoid tumor cells apoptosis, and ultimately result in uncontrolled proliferation and deterioration. Therefore, through activating and regulating the immunocytes related to tumors and associated immunologic factors, miRNA can contribute to the advancement of BC. In this review, we assessed the function of miRNA and associated immune system components in regulating the advancement of BC, as well as the potential and viability of using miRNA in immunotherapy for BC.
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Affiliation(s)
- Yeqin Fu
- Zhejiang cancer hospital, Hangzhou, Zhejiang 310022, China; Postgraduate Training Base Alliance of Wenzhou Medical University (Zhejiang Cancer Hospital), Hangzhou, Zhejiang 310022, China
| | - Qiuhui Yang
- The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Traditional Chinese Medicine), 310006, China
| | - Ning Xu
- Zhejiang cancer hospital, Hangzhou, Zhejiang 310022, China; School of Medicine, Shaoxing University, Shaoxing, Zhejiang 312000, China
| | - Xiping Zhang
- Zhejiang cancer hospital, Hangzhou, Zhejiang 310022, China.
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22
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Braverman EL, Mognol GP, Minn AJ, Vignali DAA, Varner JA. One Step Ahead: Preventing Tumor Adaptation to Immune Therapy. Am Soc Clin Oncol Educ Book 2025; 45:e481556. [PMID: 40334183 DOI: 10.1200/edbk-25-481556] [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: 05/09/2025]
Abstract
Immune checkpoint inhibitors are cancer therapeutics that have shown remarkable success in extending lives in many cancers, including melanoma, MSI-high cancers, and other cancers. However, these therapeutics have not shown benefit for many patients with cancer, especially those with advanced cancer diagnoses. In addition, many patients develop resistance to these therapeutics and/or life-altering adverse events that can include cardiotoxicity, pneumonitis, thyroiditis, pancreatitis, and hepatitis. Extensive efforts to improve cancer care by uncovering mechanisms of resistance to immune therapy in solid tumors have led to identification of new sources of resistance and to the development of new approaches to activate or sustain antitumor immunity. Chronic stimulation of T cells by tumors and by checkpoint inhibitors can lead to a progressive state of T-cell exhaustion. Chronic T-cell activation by the tumor microenvironment (TME) or immune therapeutics can upregulate the expression and function of alternate checkpoints, including the T-cell protein LAG-3. Persistent interferon signaling in the TME can drive epigenetic changes in cancer cells that enable tumors to counter immune activation and disrupt tumor cell elimination. In addition, immune-suppressive macrophages can flood tumors in response to signals from dying tumor cells, further preventing effective immune responses. New clinical developments and/or approvals for therapies that target alternate immune checkpoints, such as the T-cell checkpoint LAG-3; myeloid cell proteins, such as the kinase phosphoinositide 3-kinase gamma isoform; and chronic interferon signaling, such as Jak 1 inhibitors, have been approved for cancer care or shown promise in recent clinical trials.
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Affiliation(s)
- Erica L Braverman
- Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA
- Department of Pediatrics, Division of Pediatric Hematology/Oncology, University of Pittsburgh School of Medicine, Pittsburgh, PA
| | - Giuliana P Mognol
- Moores Cancer Center, University of California, San Diego, La Jolla, CA
| | - Andy J Minn
- Institute for Immunology and Immune Health, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA
- Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA
| | - Dario A A Vignali
- Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA
- Tumor Microenvironment Center, UPMC Hillman Cancer Center, Pittsburgh, PA
- Cancer Immunology and Immunotherapy Program, UPMC Hillman Cancer Center, Pittsburgh, PA
| | - Judith A Varner
- Moores Cancer Center, University of California, San Diego, La Jolla, CA
- Department of Pathology, University of California, San Diego, La Jolla, CA
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23
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Jung J, Park SY, Jo HB, Park JY, Kim D, Lee K, Choi S. Pneumocystis jirovecii pneumonia in patients with lung cancer receiving immune checkpoint inhibitors: a retrospective nationwide population-based cohort study from South Korea. Discov Oncol 2025; 16:950. [PMID: 40442406 PMCID: PMC12122411 DOI: 10.1007/s12672-025-02627-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/15/2024] [Accepted: 05/08/2025] [Indexed: 06/02/2025] Open
Abstract
BACKGROUND This study determined the incidence of Pneumocystis jirovecii pneumonia (PCP) in patients with lung cancer based on immune checkpoint inhibitor (ICI) exposure. METHODS National claims data were obtained from 68,174 patients with lung cancer treated with ICIs or comparator non-ICIs (cytotoxic chemotherapy, targeted therapy, or both) between August 2017 and December 2021 in South Korea. The ICI exposure group included patients who were treated with ICIs at least once during the study period. The incidence and standardized incidence ratios were computed according to sex, 10-year age, and calendar-specific cancer population, to estimate the effects of ICIs and non-ICIs on the incidence of PCP. A logistic regression analysis was performed that adjusted for sex, age, comorbidities, and concomitant immunosuppressive drugs use. RESULTS A total of 18,043 (26.4%) patients were in the ICI exposure group, and 50,131 (73.6%) were in the ICI non-exposure group. More than half of the patients in the ICI exposure group were men aged 60-79 years. Twenty-one PCP events occurred every 42,000.39 person-years in the ICI exposure group, and the incidence of PCP was lower than that in the ICI non-exposure group. Compared to the total cancer population, the incidence of PCP in patients with lung cancer was not significantly affected by ICI exposure, sex, or age. A 36% decreased risk of PCP with ICI exposure compared with non-exposure was estimated; however, this result was not statistically significant. CONCLUSIONS The incidence of PCP in patients with lung cancer treated with ICIs did not differ significantly from that in patients not treated with ICIs.
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Affiliation(s)
- Jiyun Jung
- Department of Biostatistics, Dongguk University College of Medicine, Goyang-si, Gyeonggi-do, Republic of Korea
| | - Seong Yeon Park
- Division of Infectious Diseases, Department of Internal Medicine, Dongguk University Ilsan Hospital, Goyang-si, Gyeonggi-do, Republic of Korea
| | - Hee Bum Jo
- Division of Infectious Diseases, Department of Internal Medicine, Incheon Sejong Hospital, Incheon, Republic of Korea
| | - Jae Yoon Park
- Division of Nephrology, Department of Internal Medicine, Dongguk University Ilsan Hospital, Goyang-si, Gyeonggi-do, Republic of Korea
| | - Dalyong Kim
- Division of Hematology and Medical Oncology, Department of Internal Medicine, Dongguk University Ilsan Hospital, Goyang-si, Gyeonggi-do, Republic of Korea
| | - Kyoungmin Lee
- Division of Hemato-Oncology, Department of Internal Medicine, Korea University Guro Hospital, Korea University College of Medicine, Seoul, Republic of Korea
| | - Sungim Choi
- Division of Infectious Diseases, Department of Internal Medicine, Dongguk University Ilsan Hospital, Goyang-si, Gyeonggi-do, Republic of Korea.
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24
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Ren L, Yao R, Hou T, Liu C, Zhao F, Chen X, Zhang Z, Huang Y. Pan-cancer analysis of homologous recombination deficiency and homologous recombination repair-associated gene alterations in solid tumors from a large Asian cohort. BMC Cancer 2025; 25:946. [PMID: 40420266 DOI: 10.1186/s12885-025-14267-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2025] [Accepted: 05/05/2025] [Indexed: 05/28/2025] Open
Abstract
BACKGROUND Homologous recombination deficiency (HRD) is associated with sensitivity to platinum-based chemotherapy and PARP inhibitors in BRCA-associated cancers, including ovarian, breast, prostate, and pancreatic cancers. This study explores HRD and homologous recombination repair (HRR) gene alterations in a pan-cancer cohort to guide precision oncology. METHODS Clinical and genomic data from 9,262 patients with 17 solid tumor types were analyzed using the OncoScreenTM Plus kit. HRD scores, biallelic HRR and tumor suppressor gene alterations, and their clinical correlations were evaluated. RESULTS HRD scores varied across cancer types, all showing a long tail in distribution. The prevalence of pathogenic alterations in pan-cancer HRR was 21.3%, with 13.7% of the cases having an HRD score ≥42. HRD-related events (LOH, LST, and TAI) exhibited similarities and cancer-specific patterns at the chromosomal arm level. Biallelic loss of HRR genes, especially BRCA1, BRCA2, RAD51D, RAD51 C, and PPP2R2 A was linked to higher HRD scores in BRCA-associated cancers, while BARD1, RAD51D, RAD54L, BRCA1, and MRE11 were associated with elevated HRD scores in in other cancer types (non-BRCA cancers). TP53 biallelic alterations, with or without HRR alterations, were linked to increased HRD scores. Higher HRD scores were associated with late-stage, older, metastatic, PD-L1 positive, non-MSI-H/non-POLE samples were correlated with genomic instability indexes, such as structural chromosomal instability (SCIN), weighted genome instability index (WGII), and whole-genome doubling (WGD). CONCLUSIONS This is the largest pan-cancer HRD study in an Asian population, providing insights for future HRD testing and targeted therapy.
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Affiliation(s)
- Lili Ren
- Department of Medical Oncology, Affiliated Hospital of Hebei University, Hebei Key Laboratory of Cancer Radiotherapy and Chemotherapy, Baoding, China
| | - Runsi Yao
- Department of Obstetrics, Shenzhen Second People's Hospital, The First Affiliated Hospital of Shenzhen University, Shenzhen, China
| | - Ting Hou
- Burning Rock Biotech, Building 6, Phase 2, Standard Industrial Unit, No. 7 LuoXuan 4 th Road, International Biotech Island, Guangzhou, 510300, China
| | - Chenglin Liu
- Burning Rock Biotech, Building 6, Phase 2, Standard Industrial Unit, No. 7 LuoXuan 4 th Road, International Biotech Island, Guangzhou, 510300, China
| | - Fei Zhao
- Burning Rock Biotech, Building 6, Phase 2, Standard Industrial Unit, No. 7 LuoXuan 4 th Road, International Biotech Island, Guangzhou, 510300, China
| | - Xiaojun Chen
- Department of Oncology, Shanghai Medical College of Fudan University, 270 Dong-An Rd, Xuhui District, Shanghai, 200032, China.
- Department of Gynecologic Oncology, Fudan University Shanghai Cancer Center, 270 Dong-An Rd, Xuhui District, Shanghai, 200032, China.
| | - Zhou Zhang
- Burning Rock Biotech, Building 6, Phase 2, Standard Industrial Unit, No. 7 LuoXuan 4 th Road, International Biotech Island, Guangzhou, 510300, China.
| | - Yan Huang
- Department of Oncology, Shanghai Medical College of Fudan University, 270 Dong-An Rd, Xuhui District, Shanghai, 200032, China.
- Department of Gynecologic Oncology, Fudan University Shanghai Cancer Center, 270 Dong-An Rd, Xuhui District, Shanghai, 200032, China.
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25
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Wang W, Hu K, Xue J, Chen J, Du X, Zhao T, Chen Y, Tang X, Xu L, Hao X, Li X, Yang Y. In vivo FAP-CAR macrophages enhance chemotherapy and immunotherapy against pancreatic cancer by removing the fibrosis barrier. J Control Release 2025:113888. [PMID: 40425095 DOI: 10.1016/j.jconrel.2025.113888] [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: 05/07/2025] [Accepted: 05/24/2025] [Indexed: 05/29/2025]
Abstract
Patients with pancreatic ductal adenocarcinoma (PDAC) derive limited benefits from chemotherapy or immunotherapy, with a five-year survival rate still below 10 %. The key therapeutic challenge is the dense fibrosis barrier driven by activated cancer-associated fibroblasts (CAFs) and their secreted collagen, which impedes drug penetration and characterizes PDAC as an immune-desert tumor. To address this challenge, we developed in vivo chimeric antigen receptor macrophages (FAP-CAR-M) targeting fibroblast activation protein-α (FAP), the marker of activated CAFs, to enhance chemo and immunotherapy against PDAC by removing the fibrosis barrier using mannose-modified mRNA-LNP (MLNP). Our results demonstrate that mRNA-MLNP can efficiently reprogram M2 macrophages into FAP-CAR-M. With the FAP-CAR-M treatment, the activated CAF markers (FAP), collagen volume fraction (CVF), and the type I collagen (col1a1) secretion were decreased by 3-fold, 5-fold, and 4-fold in orthotopic PDAC, respectively. By removing the fibrosis barrier, FAP-CAR-M enhanced the penetration of gemcitabine (GEM) and immune cells, improved PDAC sensitivity to chemo and immunotherapy, and significantly prolonged survival. Therefore, in vivo FAP-CAR-M may represent a potential therapeutic approach to enhance chemo and immunotherapy against PDAC by removing the fibrosis barrier.
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Affiliation(s)
- Wenguang Wang
- School of Translational Research, China Pharmaceutical University, Nanjing 211198, China; Vaccine Center, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing 211198, China; Center for New Drug Safety Evaluation and Research, China Pharmaceutical University, Nanjing 211198, China.
| | - Kaiyuan Hu
- School of Translational Research, China Pharmaceutical University, Nanjing 211198, China; Vaccine Center, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing 211198, China; Center for New Drug Safety Evaluation and Research, China Pharmaceutical University, Nanjing 211198, China
| | - Junjie Xue
- School of Translational Research, China Pharmaceutical University, Nanjing 211198, China; Vaccine Center, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing 211198, China; Center for New Drug Safety Evaluation and Research, China Pharmaceutical University, Nanjing 211198, China
| | - Jingyi Chen
- School of Translational Research, China Pharmaceutical University, Nanjing 211198, China; Vaccine Center, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing 211198, China; Center for New Drug Safety Evaluation and Research, China Pharmaceutical University, Nanjing 211198, China
| | - Xiuli Du
- School of Translational Research, China Pharmaceutical University, Nanjing 211198, China; Vaccine Center, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing 211198, China; Center for New Drug Safety Evaluation and Research, China Pharmaceutical University, Nanjing 211198, China
| | - Tian Zhao
- School of Translational Research, China Pharmaceutical University, Nanjing 211198, China; Vaccine Center, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing 211198, China; Center for New Drug Safety Evaluation and Research, China Pharmaceutical University, Nanjing 211198, China
| | - Yiwei Chen
- School of Translational Research, China Pharmaceutical University, Nanjing 211198, China; Vaccine Center, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing 211198, China; Center for New Drug Safety Evaluation and Research, China Pharmaceutical University, Nanjing 211198, China
| | - Xinying Tang
- School of Translational Research, China Pharmaceutical University, Nanjing 211198, China; Vaccine Center, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing 211198, China; Center for New Drug Safety Evaluation and Research, China Pharmaceutical University, Nanjing 211198, China
| | - Lu Xu
- Department of Hematology, The First Affiliated Hospital of Hainan Medical University, No. 31 Longhua Road, Longhua District, Haikou 570102, Hainan Province, China
| | - Xinbao Hao
- Department of Hematology, The First Affiliated Hospital of Hainan Medical University, No. 31 Longhua Road, Longhua District, Haikou 570102, Hainan Province, China
| | - Xianjing Li
- School of Translational Research, China Pharmaceutical University, Nanjing 211198, China; Vaccine Center, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing 211198, China; Center for New Drug Safety Evaluation and Research, China Pharmaceutical University, Nanjing 211198, China
| | - Yong Yang
- School of Translational Research, China Pharmaceutical University, Nanjing 211198, China; Vaccine Center, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing 211198, China; Center for New Drug Safety Evaluation and Research, China Pharmaceutical University, Nanjing 211198, China.
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Wekking D, Silva CAC, Viscò R, Denaro N, Lambertini M, Maccioni A, Loddo E, Willard-Gallo K, Scartozzi M, Derosa L, Solinas C. The interplay between gut microbiota, antibiotics, and immune checkpoint inhibitors in patients with cancer: A narrative review with biological and clinical aspects. Crit Rev Oncol Hematol 2025; 212:104767. [PMID: 40414545 DOI: 10.1016/j.critrevonc.2025.104767] [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: 04/05/2025] [Revised: 05/11/2025] [Accepted: 05/13/2025] [Indexed: 05/27/2025] Open
Abstract
Immune checkpoint inhibitors (ICIs) targeting the programmed cell death-1 (PD-1), programmed cell death ligand-1 (PD-L1), and cytotoxic T-lymphocyte antigen 4 (CTLA-4) pathways have revolutionized cancer therapy. However, primary and secondary resistance to ICI pose significant challenges. Recent studies underscore the critical role of gut microbiota (GM) in modulating ICI efficacy by shaping host immune responses and regulating the tumor microenvironment (TME). The composition of the GM has been linked to ICI treatment outcomes, with certain microbial taxa, such as Faecalibacterium spp., Bifidobacterium spp., Eubacterium spp., Roseburia spp., and Akkermansia muciniphila, associated with favorable responses. Mechanistically, the GM affects immune responses via multiple pathways, including induction of T cell differentiation, promotion of anti- or proinflammatory cytokine environments, and enhancement of T cell priming and effector functions. Moreover, microbial-derived metabolites play a role in shaping tumor immune responses and influencing ICI efficacy. Antibiotic treatment can disrupt GM diversity and composition (gut dysbiosis), potentially diminishing ICI effectiveness. A deeper understanding of the interplay between GM, antibiotic treatment, and ICI efficacy is crucial for developing personalized therapeutic strategies to improve patient outcomes. Herein, we review current evidence on the association between specific microbial taxa and tumor immunosurveillance, the impact of antibiotics on the GM composition and immune modulation, and its implications for ICI therapy efficacy.
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Affiliation(s)
- Demi Wekking
- Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands.
| | - Carolina Alves Costa Silva
- Gustave Roussy Cancer Campus (GRCC), Clinicobiome, Villejuif, France; Institut National de la Santé Et de la Recherche Médicale (INSERM) U1015, Equipe Labellisée-Ligue Nationale contre le Cancer, Villejuif, France
| | - Roberto Viscò
- Ospedale Sant'Antonio Abate, Patologica Clinica, ASP Trapani, Italy
| | - Nerina Denaro
- Medical Oncology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico Milano, Italy
| | - Matteo Lambertini
- Department of Internal Medicine and Medical Specialties (DIMI), School of Medicine, University of Genova, Genova, Italy; Department of Medical Oncology, U.O.C. Clinica di Oncologia Medica, IRCCS Ospedale Policlinico San Martino, Genova, Italy
| | - Antonio Maccioni
- Medical Oncology AOU Cagliari Policlinico Duilio Casula, Monserrato (CA) Italy
| | - Erica Loddo
- Gastroenterology University Hospital, Cagliari, Italy
| | | | - Mario Scartozzi
- Medical Oncology AOU Cagliari Policlinico Duilio Casula, Monserrato (CA) Italy; University Hospital of Cagliari, Italy
| | - Lisa Derosa
- Gustave Roussy Cancer Campus (GRCC), Clinicobiome, Villejuif, France; Institut National de la Santé Et de la Recherche Médicale (INSERM) U1015, Equipe Labellisée-Ligue Nationale contre le Cancer, Villejuif, France; Faculté de Médecine, Université Paris-Saclay, Kremlin-Bicêtre, France
| | - Cinzia Solinas
- Medical Oncology AOU Cagliari Policlinico Duilio Casula, Monserrato (CA) Italy
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Zhang H, Gong L, Yu L, Xian C, Ma Z, Wang X, Xia R. Emerging roles of non-coding RNA derived from extracellular vesicles in regulating PD-1/PD-L1 pathway: insights into cancer immunotherapy and clinical applications. Cancer Cell Int 2025; 25:188. [PMID: 40410719 PMCID: PMC12103061 DOI: 10.1186/s12935-025-03809-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2024] [Accepted: 05/05/2025] [Indexed: 05/25/2025] Open
Abstract
Numerous studies have demonstrated that extracellular vesicles (EVs) carry a variety of noncoding RNAs (ncRNAs), which can be taken up by neighboring cells or transported to distant sites via bodily fluids, thereby facilitating intercellular communication and regulating multiple cellular functions. Within the tumor microenvironment, EV-ncRNA, on the one hand, regulate the expression of PD-L1, thereby influencing tumor immune evasion, promoting tumor cell proliferation, and enhancing tumor growth, invasion, and metastasis in vivo. On the other hand, these specific EV-ncRNAs can also modulate the functions of immune cells (such as CD8 + T cells, macrophages, and NK cells) through various molecular mechanisms, inducing an immunosuppressive microenvironment and promoting resistance to anti-PD-1 therapy. Therefore, delving into the molecular mechanisms underlying EV-ncRNA regulation of immune checkpoints presents compelling therapeutic prospects for strategies that selectively target EV-ncRNAs. In this review, we elaborate on the cutting-edge research progress related to EV-ncRNAs in the context of cancer and dissect their pivotal roles in the PD-1/PD-L1 immune checkpoint pathway. We also highlight the promising clinical applications of EV-ncRNAs in anti-PD-1/PD-L1 immunotherapy, bridging basic research with practical clinical applications.
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Affiliation(s)
- Haixia Zhang
- Health Science Center, Yangtze University, Nanhuan Road 1, Jingzhou, 434023, Hubei, China
| | - Lianfeng Gong
- Health Science Center, Yangtze University, Nanhuan Road 1, Jingzhou, 434023, Hubei, China
| | - Li Yu
- Health Science Center, Yangtze University, Nanhuan Road 1, Jingzhou, 434023, Hubei, China
- Department of Urology, General Hospital of The Yangtze River Shipping, Wuhan, 430010, China
| | - Chenge Xian
- Naidong District People's Hospital, Shannan, 856004, Tibet Autonomous Region, China
| | - Zhaowu Ma
- Health Science Center, Yangtze University, Nanhuan Road 1, Jingzhou, 434023, Hubei, China.
| | - Xianwang Wang
- Health Science Center, Yangtze University, Nanhuan Road 1, Jingzhou, 434023, Hubei, China.
- Shannan Maternal and Child Health Hospital, Shannan, 856099, Tibet Autonomous Region, China.
| | - Ruohan Xia
- Health Science Center, Yangtze University, Nanhuan Road 1, Jingzhou, 434023, Hubei, China.
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Jiang Y, Zhang J, Yu J, Luo W, Du Q, Liu W, Xu Q, Li X, Liu H, Huang D, Qin T. HDAC6 facilitates LUAD progression by inducing EMT and enhancing macrophage polarization towards the M2 phenotype. NPJ Precis Oncol 2025; 9:150. [PMID: 40404897 PMCID: PMC12098887 DOI: 10.1038/s41698-025-00949-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2024] [Accepted: 05/14/2025] [Indexed: 05/24/2025] Open
Abstract
Histone deacetylase 6 (HDAC6) plays a critical role in lung adenocarcinoma (LUAD) prognosis and the tumor immune microenvironment (TIME). This study, utilizing public datasets and experimental validation, revealed that HDAC6 is upregulated in LUAD, correlating with poor survival outcomes and an immunosuppressive TIME characterized by increased Tregs, CAFs, M2 macrophages, and MDSCs. HDAC6-high patients showed reduced immunotherapy response. HDAC6 knockout inhibited tumor growth, suppressed PI3K/AKT/mTOR signaling and EMT, and enhanced apoptosis and M1 macrophage recruitment. HDAC6 inhibition synergized with anti-PD-1 therapy, suggesting a potential combinatorial strategy for LUAD treatment. HDAC6 serves as a key prognostic marker and therapeutic target in LUAD.
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Affiliation(s)
- Yantao Jiang
- Department of Thoracic Oncology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin, China
| | - Ju Zhang
- Department of Nuclear Medicine, Rizhao People's Hospital, Rizhao, China
| | - Junjie Yu
- Department of Thoracic Oncology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin, China
| | - Wei Luo
- Department of Thoracic Oncology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin, China
| | - Qingwu Du
- Department of Thoracic Oncology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin, China
| | - Wenting Liu
- Department of Respiratory Medicine, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Qi Xu
- Department of Thoracic Oncology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin, China
| | - Xueyang Li
- Department of Thoracic Oncology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin, China
| | - Huiyan Liu
- Department of Thoracic Oncology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin, China
| | - Dingzhi Huang
- Department of Thoracic Oncology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin, China.
| | - Tingting Qin
- Department of Thoracic Oncology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin, China.
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Miyamae C, Isozaki Y, Tsumoto K, Tomita M. Dual generation of stereo- and linear-specific monoclonal antibodies through B-cell receptors by DNA and cell immunization for therapeutic applications. Biochim Biophys Acta Gen Subj 2025:130822. [PMID: 40412732 DOI: 10.1016/j.bbagen.2025.130822] [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: 07/16/2024] [Revised: 04/08/2025] [Accepted: 05/17/2025] [Indexed: 05/27/2025]
Abstract
The optimized stereospecific targeting (SST) technique features selective generation of conformation-specific monoclonal antibodies against membranous proteins with high specificity after DNA and cell immunization. This technology consists of two critical steps, which are specific selection of sensitized B lymphocytes by antigen-expressing myeloma cells through B-cell receptors (BCRs) and selective fusion of B cell-myeloma cell complexes by electrical pulses to produce hybridoma cells secreting stereospecific monoclonal antibodies. Here we were able to verify the critical step for the selection of B lymphocytes by intact antigen-expressing myeloma cells by a double-label immunofluorescence analysis. Interestingly, the cell complex was a single attachment. Furthermore, we newly found the new progress that the optimized SST technique offered dual production of anti-intact and anti-linear specific monoclonal antibodies against a human ephrin type-A receptor 2 (hEphA2), . The optimized SST technique may be useful for producing not only stereospecific monoclonal antibodies, but also primary-specific monoclonal antibodies based on the selection of sensitized B lymphocytes by the target intact antigen through BCRs. It would elicit more advanced medical applications by generating dual monoclonal antibodies against the intact antigen.
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Affiliation(s)
- Chiho Miyamae
- Division of Chemistry for Materials, Graduate School of Engineering, Mie University, 1577 Kurimamachiya-cho, Tsu, Mie 514-8507, Japan
| | - Yushi Isozaki
- Division of Chemistry for Materials, Graduate School of Engineering, Mie University, 1577 Kurimamachiya-cho, Tsu, Mie 514-8507, Japan; Graduate School of Science, University of Hyogo, 3-2-1 Kouto, Kamigori, Ako Hyogo 678-1297, Japan.
| | - Kanta Tsumoto
- Division of Chemistry for Materials, Graduate School of Engineering, Mie University, 1577 Kurimamachiya-cho, Tsu, Mie 514-8507, Japan
| | - Masahiro Tomita
- Division of Chemistry for Materials, Graduate School of Engineering, Mie University, 1577 Kurimamachiya-cho, Tsu, Mie 514-8507, Japan
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Li X, Han Z, Ai J. Synergistic targeting strategies for prostate cancer. Nat Rev Urol 2025:10.1038/s41585-025-01042-6. [PMID: 40394240 DOI: 10.1038/s41585-025-01042-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/11/2025] [Indexed: 05/22/2025]
Abstract
Prostate cancer is the second most commonly diagnosed cancer and the fifth leading cause of death among men worldwide. Androgen deprivation therapy is a common prostate cancer treatment, but its efficacy is often hindered by the development of resistance, which results in reducing survival benefits. Immunotherapy showed great promise in treating solid tumours; however, clinically significant improvements have not been demonstrated for patients with prostate cancer, highlighting specific drawbacks of this therapeutic modality. Hence, exploring novel strategies to synergistically enhance the efficacy of prostate cancer immunotherapy is imperative. Clinical investigations have focused on the combined use of targeted or gene therapy and immunotherapy for prostate cancer. Notably, tumour-specific antigens and inflammatory mediators are released from tumour cells after targeted or gene therapy, and the recruitment and infiltration of immune cells, including CD8+ T cells and natural killer cells activated by immunotherapy, are further augmented, markedly improving the efficacy and prognosis of prostate cancer. Thus, immunotherapy, targeted therapy and gene therapy could have reciprocal synergistic effects in prostate cancer in combination, resulting in a proposed synergistic model encompassing these three therapeutic modalities, presenting novel potential treatment strategies for prostate cancer.
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Affiliation(s)
- Xuanji Li
- Department of Urology, Institute of Urology, West China Hospital, Sichuan University, Chengdu, China
| | - Zeyu Han
- Department of Urology, Institute of Urology, West China Hospital, Sichuan University, Chengdu, China
| | - Jianzhong Ai
- Department of Urology, Institute of Urology, West China Hospital, Sichuan University, Chengdu, China.
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Keshavarz Sadegh R, Saleki K, Rezaei N. Immune checkpoint inhibitor (ICI) therapy in central nervous system cancers: State-of-the-art and future outlook. Int Immunopharmacol 2025; 159:114837. [PMID: 40394797 DOI: 10.1016/j.intimp.2025.114837] [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: 01/11/2025] [Revised: 04/28/2025] [Accepted: 05/07/2025] [Indexed: 05/22/2025]
Abstract
Invasive central nervous system (CNS) cancers are an area where the development of breakthrough therapies is urgently needed. For instance, conditions such as glioblastoma multiforme (GBM) are associated with poor clinical prognosis, with the majority of trials offering no improvement to marginally enhanced survival. Unleashing the potential of targeting the immune system in CNS cancers has gained attention in recent years. Inhibition of immune checkpoints such as CTLA-4, PD-1/PD-L1, TIM-3, and LAG-3 has been attempted in recent trials. While potentially offering a notable edge over other immunotherapies, multi-organ adverse events have been found with the administration of immune checkpoint inhibitors (ICIs). The present review captures the state-of-the-art evidence on ICI treatments in different CNS cancers. Also, we discuss the value of combinational therapies involving ICIs as well as next-generation therapeutics such as bispecific antibodies targeting PD-1/LAG-3/TIM-3 and CRISPR-Cas9-edited PD-1-knock-out checkpoint-resistant CAR T-cells.
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Affiliation(s)
- Roghaye Keshavarz Sadegh
- Student Research Committee, Qazvin University of Medical Sciences, Qazvin, Iran; USERN Office, Qazvin University of Medical Sciences, Qazvin, Iran
| | - Kiarash Saleki
- Student Research Committee, Babol University of Medical Sciences, Babol, Iran; Research Center for Immunodeficiencies, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran; Network of Immunity in Infection, Malignancy and Autoimmunity (NIIMA), Universal Scientific Education and Research Network (USERN), Tehran, Iran; USERN MUBabol Office, Universal Scientific Education and Research Network (USERN), Babol, Iran
| | - Nima Rezaei
- Research Center for Immunodeficiencies, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran; Network of Immunity in Infection, Malignancy and Autoimmunity (NIIMA), Universal Scientific Education and Research Network (USERN), Tehran, Iran; Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.
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Zhang K, Chen S, Zhou Z, Yu S, Zhan Y, Zhang X. Current trends and landscape of drug resistance in renal cell carcinoma: a bibliometric analysis. Discov Oncol 2025; 16:820. [PMID: 40389616 PMCID: PMC12089581 DOI: 10.1007/s12672-025-02594-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/13/2025] [Accepted: 05/06/2025] [Indexed: 05/21/2025] Open
Abstract
INTRODUCTION Renal cell carcinoma (RCC) is a common type of kidney cancer, and the prognosis for patients with advanced-stage disease remains poor. One major obstacle is the development of drug resistance, which severely limits the effectiveness of therapeutic interventions. This bibliometric study aims to provide a comprehensive overview of current research trends on drug resistance in RCC. METHODS This study examines publications on drug resistance in RCC from 2000 to 2023, sourced from the Web of Science Core Collection (WoSCC). Detailed analyses were conducted to identify research hotspots, academic collaborations, and emerging trends. CiteSpace, SCImago Graphica, and VOSviewer were utilized to conduct these analyses comprehensively. RESULTS This study analyzed a total of 2,804 publications from the WoSCC database. The number of annual publications showed a consistent upward trend, with an average annual growth rate of 8.12%. The United States had the highest number of publications, followed by China and Japan. The most productive institutions were the University of Texas System, Harvard University, and the National Institutes of Health (NIH). Alfred H. Schinkel emerged as the most prolific author, also having the highest H-index. The three most frequent research categories were oncology, pharmacology and pharmacy, and biochemistry and molecular biology. The evolution of research topics was assessed in 5-year intervals, revealing that recent themes such as ferroptosis and immunotherapy have gained increasing attention. Keyword analysis indicated a shift in research focus toward cell lipid metabolism, androgen receptor and specific molecular signatures. CONCLUSION This study offers the first comprehensive bibliometric analysis specifically focused on drug resistance in RCC. It identifies current research trends, highlights emerging hotspots, and provides insights into key contributors and ongoing challenges in the field. Our study provides a theoretical reference and guidance to guide future research efforts to address drug resistance in RCC more effectively.
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Affiliation(s)
- Kenan Zhang
- Department of Urology, the First Hospital Affiliated to Zhengzhou University, No.1 Jianshe Dong Road, District of ErQi, Zhengzhou, 450002, Henan, People's Republic of China
| | - Shixu Chen
- Department of Urology, the First Hospital Affiliated to Zhengzhou University, No.1 Jianshe Dong Road, District of ErQi, Zhengzhou, 450002, Henan, People's Republic of China
| | - Zhenzhen Zhou
- Department of Urology, the First Hospital Affiliated to Zhengzhou University, No.1 Jianshe Dong Road, District of ErQi, Zhengzhou, 450002, Henan, People's Republic of China
| | - Shuanbao Yu
- Department of Urology, the First Hospital Affiliated to Zhengzhou University, No.1 Jianshe Dong Road, District of ErQi, Zhengzhou, 450002, Henan, People's Republic of China
| | - Yonghao Zhan
- Department of Urology, the First Hospital Affiliated to Zhengzhou University, No.1 Jianshe Dong Road, District of ErQi, Zhengzhou, 450002, Henan, People's Republic of China.
| | - Xuepei Zhang
- Department of Urology, the First Hospital Affiliated to Zhengzhou University, No.1 Jianshe Dong Road, District of ErQi, Zhengzhou, 450002, Henan, People's Republic of China.
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Wang PJ, Wang J, Yao XM, Cheng WL, Sun L, Yan J, Yu YL, Li SY, Li DP, Jia JH. Evaluation of efficacy and safety of targeted therapy and immune checkpoint inhibitors in metastatic colorectal cancer. World J Gastrointest Oncol 2025; 17:105027. [DOI: 10.4251/wjgo.v17.i5.105027] [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: 01/08/2025] [Revised: 03/07/2025] [Accepted: 03/25/2025] [Indexed: 05/15/2025] Open
Abstract
BACKGROUND Colorectal cancer (CRC) is among the most prevalent and deadly cancers globally, particularly in China. Treatment challenges remain in advanced and metastatic cases, especially in third- and fourth-line settings. The combination of targeted therapies with immune checkpoint inhibitors (ICIs) has shown potential in addressing the limitations of single-agent treatments.
AIM To evaluate the efficacy and safety of targeted therapy (TT) alone and in combination with ICIs for metastatic CRC (mCRC).
METHODS A multicenter retrospective observational study was conducted to evaluate the efficacy and safety of TT alone and in combination with ICIs for mCRC. A total of 99 patients treated with regorafenib or fruquintinib, with or without ICIs, were enrolled. Propensity score matching (PSM) and inverse probability weighting (IPW) were employed to balance baseline characteristics. The primary endpoint was progression-free survival (PFS), while overall survival (OS) and safety were secondary.
RESULTS Patients who received combined therapy showed significantly longer median PFS rates compared to those who underwent TT in all analyses (original: 6.0 vs 3.4 months, P < 0.01; PSM: 6.15 vs 4.25 months, P < 0.05; IPW: 5.6 vs 3.3 months, P < 0.01). Although the median OS showed a trend toward improvement in the combination group, the difference was insignificant. Cox regression analysis revealed that combining TT with ICIs significantly reduced the risk of disease progression (hazard ratio = 0.38, P < 0.001). Adverse events (AEs) were generally manageable with both regimens, while serious AEs (grade 3-4) were primarily hypertension, fatigue, and reduced platelet counts. All AEs were controlled effectively by symptomatic treatment or discontinuation of the drug, and no treatment-related deaths were observed.
CONCLUSION The combination of TT with ICIs offers a significant advantage in terms of PFS for patients with advanced mCRC, accompanied by a favorable safety profile. These findings underscore the benefits of combination therapy in this setting, warranting further investigation in larger prospective clinical trials.
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Affiliation(s)
- Peng-Jian Wang
- Clinical Medical School, North China University of Science and Technology, Tangshan 063000, Hebei Province, China
| | - Jing Wang
- Department of Radiochemotherapy, North China University of Science and Technology Affiliated Hospital, Tangshan 063000, Hebei Province, China
| | - Xue-Min Yao
- Department of Radiochemotherapy, North China University of Science and Technology Affiliated Hospital, Tangshan 063000, Hebei Province, China
| | - Wei-Li Cheng
- Department of Digestive Oncology, Tianjin Tumor Hospital Qinhuangdao Hospital, Qinhuangdao 066000, Hebei Province, China
| | - Lu Sun
- Department of Radiochemotherapy, Tangshan People’s Hospital, Tangshan 063000, Hebei Province, China
| | - Jie Yan
- Clinical Medical School, North China University of Science and Technology, Tangshan 063000, Hebei Province, China
| | - Yong-Ling Yu
- Department of Radiochemotherapy, North China University of Science and Technology Affiliated Hospital, Tangshan 063000, Hebei Province, China
| | - Su-Yao Li
- Department of Radiochemotherapy, North China University of Science and Technology Affiliated Hospital, Tangshan 063000, Hebei Province, China
| | - Da-Peng Li
- Department of Digestive Oncology, Tianjin Tumor Hospital Qinhuangdao Hospital, Qinhuangdao 066000, Hebei Province, China
| | - Jing-Hao Jia
- Department of Radiochemotherapy, North China University of Science and Technology Affiliated Hospital, Tangshan 063000, Hebei Province, China
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Li S, Zhou X, Feng H, Huang K, Chen M, Lin M, Lin H, Deng Z, Chen Y, Liao W, Zhang Z, Chen J, Guan B, Su T, Feng Z, Shu G, Yu A, Pan Y, Fu L. Deciphering the Immunomodulatory Function of GSN + Inflammatory Cancer-Associated Fibroblasts in Renal Cell Carcinoma Immunotherapy: Insights From Pan-Cancer Single-Cell Landscape and Spatial Transcriptomics Analysis. Cell Prolif 2025:e70062. [PMID: 40375605 DOI: 10.1111/cpr.70062] [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: 03/04/2025] [Revised: 04/13/2025] [Accepted: 05/02/2025] [Indexed: 05/18/2025] Open
Abstract
The heterogeneity of cancer-associated fibroblasts (CAFs) could affect the response to immune checkpoint inhibitor (ICI) therapy. However, limited studies have investigated the role of inflammatory CAFs (iCAFs) in ICI therapy using pan-cancer single-cell RNA sequencing (scRNA-seq) and spatial transcriptomics sequencing (ST-seq) analysis. We performed pan-cancer scRNA-seq and ST-seq analyses to identify the subtype of GSN+ iCAFs, exploring its spatial distribution characteristics in the context of ICI therapy. The pan-cancer scRNA-seq and bulk RNA-seq data are incorporated to develop the Caf.Sig model, which predicts ICI response based on CAF gene signatures and machine learning approaches. Comprehensive scRNA-seq analysis, along with in vivo and in vitro experiments, investigates the mechanisms by which GSN+ iCAFs influence ICI efficacy. The Caf.Sig model demonstrates well performances in predicting ICI therapy response in pan-cancer patients. A higher proportion of GSN+ iCAFs is observed in ICI non-responders compared to responders in the pan-cancer landscape and clear cell renal cell carcinoma (ccRCC). Using real-world immunotherapy data, the Caf.Sig model accurately predicts ICI response in pan-cancer, potentially linked to interactions between GSN+ iCAFs and CD8+ Tex cells. ST-seq analysis confirms that interactions and cellular distances between GSN+ iCAFs and CD8+ exhausted T (Tex) cells impact ICI efficacy. In a co-culture system of primary CAFs, primary tumour cells and CD8+ T cells, downregulation of GSN on CAFs drives CD8+ T cells towards a dysfunctional state in ccRCC. In a subcutaneously tumour-grafted mouse model, combining GSN overexpression with ICI treatment achieves optimal efficacy in ccRCC. Our study provides the Caf.Sig model as an outperforming approach for patient selection of ICI therapy, and advances our understanding of CAF biology and suggests potential therapeutic strategies for upregulating GSN in CAFs in cancer immunotherapy.
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Affiliation(s)
- Shan Li
- Department of Urology, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China
- Uro-Oncology Institute of Central South University, Changsha, Hunan, China
- Department of Urology, Children's Hospital of Chongqing Medical University, Chongqing, China
| | - Xinwei Zhou
- Department of Urology, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, China
| | - Haoqian Feng
- Department of Urology, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, China
| | - Kangbo Huang
- Department of Urology, Sun Yat-Sen University Cancer Center, Guangzhou, China
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-Sen University Cancer Center, Guangzhou, China
| | - Minyu Chen
- Department of Urology, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, China
| | - Mingjie Lin
- Department of Urology, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, China
| | - Hansen Lin
- Department of Urology, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, China
| | - Zebing Deng
- Department of Urology, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China
- Uro-Oncology Institute of Central South University, Changsha, Hunan, China
| | - Yuhang Chen
- Department of Geniturinary Oncology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin, China
| | - Wuyuan Liao
- Department of Urology, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, China
| | - Zhengkun Zhang
- Department of Urology, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, China
| | - Jinwei Chen
- Department of Urology, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, China
| | - Bohong Guan
- Department of Urology, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, China
| | - Tian Su
- Department of Pediatric Intensive Care Unit (PICU), Guangdong Provincial People's Hospital Heyuan Hospital, Heyuan, Guangdong, China
| | - Zihao Feng
- Department of Urology, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, China
| | - Guannan Shu
- Department of Urology, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou Institute of Pediatrics, Guangdong Provincial Clinical Research Center for Child Health, Guangzhou, China
| | - Anze Yu
- Department of Urology, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, China
| | - Yihui Pan
- Department of Urology, The Third Affiliated Hospital of Soochow University, Changzhou, China
| | - Liangmin Fu
- Department of Urology, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China
- Uro-Oncology Institute of Central South University, Changsha, Hunan, China
- Department of Urology, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, China
- Key Laboratory of Diabetes Immunology (Central South University), Ministry of Education, National Clinical Research Center for Metabolic Disease, Changsha, Hunan, China
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Xie X, Chen L, Kong X, Huo Y, Huang W, Huang J, Zhang L, Jiang H, Gao J. Comparative efficacy and safety of PD-1 versus PD-L1 inhibitors in breast cancer treatment: A systematic review and meta analysis. Int J Cancer 2025; 156:1936-1949. [PMID: 40110878 DOI: 10.1002/ijc.35313] [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: 06/13/2024] [Revised: 11/25/2024] [Accepted: 12/10/2024] [Indexed: 03/22/2025]
Abstract
The comparative efficacy and safety of programmed death-ligand 1 (PD-L1) inhibitors versus programmed death protein 1 (PD-1) inhibitors in breast cancer treatment remain inconclusive, as no head-to-head randomized controlled trials (RCTs) conducted. This study aims to evaluate the efficacy and safety of PD-1/PD-L1 inhibitors as monotherapy or in combination with chemotherapy for breast cancer. A systematic review and meta-analysis were performed using major databases and oncology conference proceedings. The primary outcomes were overall survival (OS) for advanced breast cancer and pathological complete response (PCR) rate for early breast cancer. Secondary outcomes included progression-free survival (PFS) for advanced breast cancer and incidence of adverse events (AEs). Seventeen studies met the inclusion criteria, consisting of seven RCTs on early-stage and 10 on advanced breast cancer. For advanced breast cancer, PD-1/PD-L1 inhibitors modestly improved OS compared to chemotherapy, with no significant differences between PD-1 and PD-L1 inhibitors. PD-L1 inhibitors showed greater improvement in PFS compared to PD-1 inhibitors. The likelihood of AEs of any grade was higher with PD-L1 inhibitor treatment than with PD-1 inhibitor treatment. In early breast cancer, combining PD-1/PD-L1 inhibitors with chemotherapy inducing higher PCR rates than chemotherapy alone, with PD-1 inhibitors achieving better outcomes than PD-L1 inhibitors. PD-1 inhibitors were linked to slightly higher rates of grade >2 AEs compared to PD-L1 inhibitors. The findings indicate that PD-1 inhibitors may offer advantages for advanced breast cancer due to similar OS and a lower rate of AEs. For early breast cancer, PD-1 inhibitors are recommended given their superior PCR rates.
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Affiliation(s)
- Xintong Xie
- Department of Breast Surgical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital & Shenzhen Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Shenzhen, China
| | - Lingzhu Chen
- The School of Public Health and Preventive Medicine, Monash University, Melbourne, Victoria, Australia
- Center of Biomedical Research, Suzhou Industrial Park Monash Research Institute of Science and Technology, Suzhou, China
| | - Xiangyi Kong
- Department of Breast Surgical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital & Shenzhen Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Shenzhen, China
- Department of Breast Surgical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Yujia Huo
- The School of Public Health and Preventive Medicine, Monash University, Melbourne, Victoria, Australia
- Center of Biomedical Research, Suzhou Industrial Park Monash Research Institute of Science and Technology, Suzhou, China
| | - Weiyuan Huang
- The School of Public Health and Preventive Medicine, Monash University, Melbourne, Victoria, Australia
- Center of Biomedical Research, Suzhou Industrial Park Monash Research Institute of Science and Technology, Suzhou, China
| | - Junjie Huang
- The Jockey Club School of Public Health and Primary Care, Faculty of Medicine, Chinese University of Hong Kong, Hongkong, China
| | - Lin Zhang
- The School of Public Health and Preventive Medicine, Monash University, Melbourne, Victoria, Australia
- Center of Biomedical Research, Suzhou Industrial Park Monash Research Institute of Science and Technology, Suzhou, China
| | - Hongnan Jiang
- Department of Breast Surgical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital & Shenzhen Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Shenzhen, China
| | - Jidong Gao
- Department of Breast Surgical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital & Shenzhen Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Shenzhen, China
- Department of Breast Surgical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
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Jiang M, Li J, Wei J, Yang X, Wang W. Advances in neoantigen-based immunotherapy for head and neck squamous cell carcinoma: a comprehensive review. Front Oncol 2025; 15:1593048. [PMID: 40444094 PMCID: PMC12119297 DOI: 10.3389/fonc.2025.1593048] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2025] [Accepted: 04/17/2025] [Indexed: 06/02/2025] Open
Abstract
Head and Neck Squamous Cell Carcinoma (HNSCC), ranking among the six most prevalent malignancies worldwide, is characterized by significant heterogeneity. Conventional monotherapeutic approaches, including surgical intervention, radiotherapy, and chemotherapy, often fail to achieve complete tumor cell elimination, consequently leading to disease recurrence and metastatic progression. In this context, personalized immunotherapeutic strategies, particularly cancer vaccines and immune checkpoint inhibitors, have emerged as promising therapeutic modalities for patients with recurrent/metastatic (R/M) HNSCC. Neoantigens, which exhibit selective expression in tumor tissues while remaining absent in normal tissues, have garnered considerable attention as novel targets for HNSCC personalized immunotherapy. However, the marked heterogeneity of HNSCC, coupled with patient-specific HLA variations, necessitates precise technical identification and evaluation of neoantigens at the individual level-a significant contemporary challenge. This comprehensive review systematically explores the landscape of neoantigen-based immunotherapy in HNSCC, including neoantigen sources, screening strategies, identification methods, and their clinical applications. Additionally, it evaluates the therapeutic potential of combining neoantigen-based approaches with other immunotherapeutic modalities, particularly immune checkpoint inhibitors, providing valuable insights for future clinical practice and research directions in HNSCC treatment.
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Affiliation(s)
- Manzhu Jiang
- College of Life Sciences, Shandong Agricultural University, Tai’an, China
| | - Jiefu Li
- Guangzhou National Laboratory, Guangzhou, China
| | - Jianhua Wei
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, National Clinical Research Center for Oral Diseases, Shaanxi Key Laboratory of Stomatology, Department of Prosthodontics, School of Stomatology, The Fourth Military Medical University, Xi’an, China
| | - Xuerong Yang
- College of Life Sciences, Shandong Agricultural University, Tai’an, China
| | - Weiqi Wang
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, National Clinical Research Center for Oral Diseases, Shaanxi Key Laboratory of Stomatology, Department of Prosthodontics, School of Stomatology, The Fourth Military Medical University, Xi’an, China
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Li L, Sun Z, Sun W, Zhai Y, Ding N, Wang W. Associations between ionomic profile and metabolic abnormalities in a murine model of sodium sulfide induced alopecia areata. Front Pharmacol 2025; 16:1507348. [PMID: 40438604 PMCID: PMC12117264 DOI: 10.3389/fphar.2025.1507348] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2024] [Accepted: 04/28/2025] [Indexed: 06/01/2025] Open
Abstract
Background Alopecia areata (AA) is a common autoimmune disorder marked by non-scarring hair loss, which imposes significant psychosocial stress on patients. To investigate key metabolites and ions involved in AA's pathogenesis, we utilized gas chromatography-mass spectrometry (GC-MS) for non-targeted metabolomics and inductively coupled plasma mass spectrometry (ICP-MS) for ionomics. Methods A total of 36 six-week-old Kunming mice were divided into control (n = 12), an AA model (n = 12), and tofacitinib-treated groups (n = 12). A mouse model of AA was established by sodium sulfide (Na2S) induction in both the model and treatment groups, while the treatment group (n = 12) received tofacitinib treatment at a dose of 1 mg/kg. GC-MS was used to determine the metabolic profiling in serum samples, and ICP-MS was applied to assess ionomic changes in the serum samples. Potential metabolites and ions were identified using orthogonal partial least squares-discriminant analysis (OPLS-DA). Subsequently, MetaboAnalyst 5.0 and the Kyoto Encyclopedia of Genes and Genomes database (KEGG) were used to map the metabolic pathways. Spearman correlation analysis was conducted to identify relationships and potential regulatory interactions between differential metabolites and individual ions. Results Metabolomics analysis revealed that D-lactic acid, glycolic acid, linoleic acid, petroselinic acid, and stearic acid are key differential metabolites between the control, AA model, and tofacitinib groups. Pathway analysis highlighted that the biosynthesis of unsaturated fatty acids and linoleic acid metabolism are pivotal pathways implicated in the onset and progression of AA. Furthermore, ionomics analysis identified magnesium, aluminum, titanium, and nickel as differential ions among the three groups. The integrated metabolomics and ionomics analysis indicated that linoleic acid, a key differential metabolite according to the KEGG database, shows a positive correlation with phosphorus, vanadium, magnesium, and zinc. Among these, Mg2+ (Mg2+) play a crucial role in modulating CD8+ T cell infiltration, thereby influencing the disease progression in AA. Conclusion Tofacitinib inhibits CD8+ T cell infiltration in hair follicles affected by sodium sulfide-induced AA by modulating the linoleic acid metabolism-Mg2+ pathway. Our findings offer new insights and potential avenues for the clinical diagnosis and treatment of AA, suggesting that targeting metabolic and ionic pathways could enhance therapeutic outcomes.
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Affiliation(s)
- Luning Li
- Clinical Medical Laboratory Center, Jining First People’s Hospital, Jining, Shandong, China
| | - Zhen Sun
- Department of Clinical Pharmacy, Jining First People’s Hospital, Jining, Shandong, China
| | - Wenxue Sun
- Department of Clinical & Translational Medicine, Jining First People’s Hospital, Jining, Shandong, China
| | - Yujuan Zhai
- Department of Dermatology, Jining First People’s Hospital, Jining, Shandong, China
| | - Na Ding
- Department of Dermatology, Jining First People’s Hospital, Jining, Shandong, China
| | - Wei Wang
- Department of Dermatology, Jining First People’s Hospital, Jining, Shandong, China
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Pires de Oliveira Neto C, Nascimento GC, Damianse SDSP, Faria MDS. Recent advances in craniopharyngioma pathophysiology and emerging therapeutic approaches. Front Endocrinol (Lausanne) 2025; 16:1562942. [PMID: 40433410 PMCID: PMC12106005 DOI: 10.3389/fendo.2025.1562942] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/18/2025] [Accepted: 04/28/2025] [Indexed: 05/29/2025] Open
Abstract
Craniopharyngiomas are rare intracranial tumors originating from the Rathke's pouch, affecting the sellar and parasellar regions. Despite their benign nature, they cause significant morbidity and mortality due to their proximity to vital structures such as the optic pathways and the hypothalamic-pituitary axis, resulting in endocrine, visual, neurological impairment, and hypothalamic syndrome. Classified into adamantinomatous (ACP) and papillary (PCP), these tumors differ in epidemiology, histology, and pathophysiology. ACP, the most common type, presents a bimodal peak incidence between 5 and 15 years of age and 45 and 60 years of age, while PCP is more restricted to adults. Traditional treatments such as surgery and radiotherapy face significant challenges, including high recurrence rates. Intracystic chemotherapy is used in monocystic ACP but with limited efficacy and adverse effects related to toxicity. Recent advances in molecular biology have introduced targeted therapies, such as BRAF and MEK inhibitors, which show potential benefits in craniopharyngioma patients, particularly in the PCP. For ACP, however, therapeutic outcomes remain limited despite advances in molecular understanding, including mutations in the CTNNB1 gene and growth factors. Increasing investigation into the inflammatory microenvironment and immune response of these tumors presents new therapeutic possibilities and promising alternatives for tumor control, such as the use of anti-IL-6R, anti-VEGF agents and immune checkpoints inhibitors. This review aims to synthesize advancements in the pathophysiology of craniopharyngiomas and explore emerging therapeutic implications, focusing on precision medicine approaches for the management of this challenging disease.
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Affiliation(s)
- Clariano Pires de Oliveira Neto
- Post-Graduate Program in Health Sciences (PPGCS), Federal University of Maranhão (UFMA), São Luis, Brazil
- Service of Endocrinology, University Hospital of the Federal University of Maranhao (HUUFMA), São Luis, Brazil
- Research Group in Clinical and Molecular Endocrinology and Metabology (ENDOCLIM), Federal University of Maranhão (UFMA), São Luis, Brazil
- Clinical Research Center (CEPEC), University Hospital of the Federal University of Maranhao (HUUFMA), São Luís, Brazil
| | - Gilvan Cortês Nascimento
- Service of Endocrinology, University Hospital of the Federal University of Maranhao (HUUFMA), São Luis, Brazil
- Research Group in Clinical and Molecular Endocrinology and Metabology (ENDOCLIM), Federal University of Maranhão (UFMA), São Luis, Brazil
- Clinical Research Center (CEPEC), University Hospital of the Federal University of Maranhao (HUUFMA), São Luís, Brazil
- Department of Medicine I, Federal University of Maranhao (UFMA), São Luis, Brazil
| | - Sabrina da Silva Pereira Damianse
- Service of Endocrinology, University Hospital of the Federal University of Maranhao (HUUFMA), São Luis, Brazil
- Research Group in Clinical and Molecular Endocrinology and Metabology (ENDOCLIM), Federal University of Maranhão (UFMA), São Luis, Brazil
- Clinical Research Center (CEPEC), University Hospital of the Federal University of Maranhao (HUUFMA), São Luís, Brazil
| | - Manuel dos Santos Faria
- Post-Graduate Program in Health Sciences (PPGCS), Federal University of Maranhão (UFMA), São Luis, Brazil
- Service of Endocrinology, University Hospital of the Federal University of Maranhao (HUUFMA), São Luis, Brazil
- Clinical Research Center (CEPEC), University Hospital of the Federal University of Maranhao (HUUFMA), São Luís, Brazil
- Department of Medicine I, Federal University of Maranhao (UFMA), São Luis, Brazil
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Spadotto V, Ripamonti C, Ghiroldi A, Galbiati E, Pozzi P, Noberini R, Bonaldi T, Steinkühler C, Fossati G. HDAC6 inhibition by ITF3756 modulates PD-L1 expression and monocyte phenotype: insights for a promising immune checkpoint blockade co-treatment therapy. Front Immunol 2025; 16:1546939. [PMID: 40433358 PMCID: PMC12106391 DOI: 10.3389/fimmu.2025.1546939] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2024] [Accepted: 04/15/2025] [Indexed: 05/29/2025] Open
Abstract
Introduction Tumor immunotherapy has revolutionized cancer treatment, particularly through the use of immune checkpoint inhibitors targeting the PD-L1/PD-1 axis. While PD-L1 expression on tumor cells is an established predictive biomarker for therapeutic response, emerging evidence highlights the importance of PD-L1 expression on myeloid cells, both in the periphery and within the tumor microenvironment (TME). This study explores the immunomodulatory effects of the selective HDAC6 inhibitor ITF3756 on monocytes and dendritic cells (DCs). Methods Monocytes were stimulated with the pro-inflammatory cytokine TNF-α and treated with ITF3756. PD-L1 and CD40 expression levels were assessed by flow cytometry. Transcriptomic and proteomic analyses were performed to characterize changes in gene and protein expression profiles. T cell proliferation was evaluated in co-culture assays. Additionally, the impact of ITF3756 was assessed in an in vivo murine model of colon cancer. Results ITF3756 effectively downregulated PD-L1 expression in TNF-α-activated monocytes and enhanced their costimulatory capacity by increasing CD40 expression. Transcriptomic and proteomic analyses revealed that ITF3756 counteracted TNF-α pathway activation and downregulated multiple inhibitory immune checkpoint molecules, promoting a less immunosuppressive phenotype. In co-culture assays, ITF3756-treated monocytes and DCs significantly enhanced T cell proliferation. In vivo, ITF3756 treatment led to reduced tumor growth in a colon cancer model. Discussion These findings demonstrate that selective HDAC6 inhibition by ITF3756 modulates myeloid cell functionality by diminishing inhibitory signals and promoting T cell activation. Thus, ITF3756 represents a promising immunomodulatory agent that could enhance the efficacy of immune checkpoint blockade in cancer immunotherapy.
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Affiliation(s)
| | | | - Andrea Ghiroldi
- New Drug Incubator Department, Italfarmaco Group, Milan, Italy
| | | | - Pietro Pozzi
- Preclinical Drug Development Department, Italfarmaco Group, Milan, Italy
| | - Roberta Noberini
- Department of Experimental Oncology, IEO European Institute of Oncology IRCCS, Milan, Italy
| | - Tiziana Bonaldi
- Department of Experimental Oncology, IEO European Institute of Oncology IRCCS, Milan, Italy
- Department of Oncology and Hematology-Oncology (DIPO), University of Milan, Milan, Italy
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Kouhen F, El Ghanmi A, Inghaoun H, Miftah H, Ghazi B, Badou A. The promise of PD1/PDL1 targeted immunotherapy in locally advanced cervical cancer: a game-changer for patients outcome? Front Immunol 2025; 16:1573576. [PMID: 40433369 PMCID: PMC12106400 DOI: 10.3389/fimmu.2025.1573576] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2025] [Accepted: 04/14/2025] [Indexed: 05/29/2025] Open
Abstract
Locally advanced cervical cancer remains a significant therapeutic challenge, with high rates of recurrence and metastasis despite advances in chemoradiation. Immunotherapy, particularly immune checkpoint inhibitors targeting the PD-1/PD-L1 axis, has emerged as a promising strategy to enhance treatment efficacy. This review explores the integration of immunotherapy with standard chemoradiation, highlighting the potential of PD-1 inhibitors, such as pembrolizumab, in improving progression-free survival (PFS) among high-risk patients. Furthermore, the role of predictive biomarkers, including microsatellite instability (MSI) and tumor mutational burden (TMB), is examined to refine patient selection and personalize therapeutic approaches. Emerging strategies, including the use of nivolumab, ipilimumab, and maintenance immunotherapy, are also discussed. While preliminary clinical data are encouraging, further research is required to optimize treatment combinations, establish robust patient selection criteria, and enhance long-term outcomes in cervical cancer management.
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Affiliation(s)
- Fadila Kouhen
- Mohammed VI Faculty of Medicine, Mohammed VI University of Sciences and Health (UM6SS), Rabat, Morocco
- Laboratory of Neurooncology, Oncogenetic and Personalized Medicine, Faculty of Medicine, Mohammed VI University of Sciences and Health (UM6SS), Casablanca, Morocco
- Department of Radiotherapy, International University Hospital Cheikh Khalifa, Casablanca, Morocco
| | - Adil El Ghanmi
- Immunopathology-Immunotherapy-Immunomonitoring Laboratory, Faculty of Medicine, Mohammed VI University of Sciences and Health (UM6SS), Casablanca, Morocco
- Department of Gynecology and Obstetrics, Mohammed VI International University Hospital, Bouskoura, Morocco
| | - Hanane Inghaoun
- Laboratory of Neurooncology, Oncogenetic and Personalized Medicine, Faculty of Medicine, Mohammed VI University of Sciences and Health (UM6SS), Casablanca, Morocco
| | - Hayat Miftah
- Laboratory of Immunogenetics and Human Pathologies, Faculty of Medicine and Pharmacy, Casablanca, Morocco
| | - Bouchra Ghazi
- Immunopathology-Immunotherapy-Immunomonitoring Laboratory, Faculty of Medicine, Mohammed VI University of Sciences and Health (UM6SS), Casablanca, Morocco
- Department of Gynecology and Obstetrics, Mohammed VI International University Hospital, Bouskoura, Morocco
| | - Abdallah Badou
- Laboratory of Immunogenetics and Human Pathologies, Faculty of Medicine and Pharmacy, Casablanca, Morocco
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Didi-Zurinam S, Katzman E, Cohen CJ. Potentiating T cell tumor targeting using a combination of TCR with a Siglec-7 based CSR. Front Immunol 2025; 16:1536868. [PMID: 40433387 PMCID: PMC12106334 DOI: 10.3389/fimmu.2025.1536868] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2024] [Accepted: 04/11/2025] [Indexed: 05/29/2025] Open
Abstract
Introduction Tumors may utilize different strategies to escape T cell immunosurveillance. Besides the overexpression of checkpoint ligands (such as PDL1) or the secretion of immunosuppressive agents, several studies have shown that cancer aberrant sialylation can, through interaction with selected receptors such as those from the Siglec family, neutralize NK and T cell function. Methods Herein, we wanted to take advantage of the presence of inhibitory sialic acid ligands on the tumor cell surface to enhance T cell anti-tumor activity. To this end, we devised a novel chimeric receptor consisting of the extracellular portion of Siglec-7 and the intracellular portion of 41BB, which can convert inhibitory signals into stimulatory ones when expressed in human T-cells. Results This co-stimulatory chimeric switch receptor (CSR), when co-expressed with a tumor-specific TCR, facilitated higher cytokine secretion and activation profiles following co-culture with tumor cells. Additionally, T cells equipped with Siglec-7 CSR demonstrated improved anti-tumor function in vivo. Discussion Given the broad expression pattern of Siglec-7 ligands on tumor cells, our data suggest this CSR may act as a general adjuvant to boost TCR T cell function. Overall, this work provides an approach to improve engineered T-cell-based cancer treatment.
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MESH Headings
- Humans
- Animals
- T-Lymphocytes/immunology
- T-Lymphocytes/metabolism
- Lectins/genetics
- Lectins/immunology
- Lectins/metabolism
- Receptors, Antigen, T-Cell/immunology
- Receptors, Antigen, T-Cell/genetics
- Receptors, Antigen, T-Cell/metabolism
- Mice
- Cell Line, Tumor
- Antigens, Differentiation, Myelomonocytic/genetics
- Antigens, Differentiation, Myelomonocytic/immunology
- Antigens, Differentiation, Myelomonocytic/metabolism
- Lymphocyte Activation/immunology
- Receptors, Chimeric Antigen/genetics
- Receptors, Chimeric Antigen/immunology
- Immunotherapy, Adoptive/methods
- Cytokines/metabolism
- Neoplasms/immunology
- Neoplasms/therapy
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Affiliation(s)
| | | | - Cyrille J. Cohen
- Laboratory of Tumor Immunology and Immunotherapy, The Goodman Faculty of Life Sciences, Bar-Ilan University, Ramat Gan, Israel
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Murray NP. Immunomodulation and Immunotherapy for Patients with Prostate Cancer: An Up-to-Date Review. Biomedicines 2025; 13:1179. [PMID: 40427006 PMCID: PMC12109314 DOI: 10.3390/biomedicines13051179] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2025] [Revised: 05/07/2025] [Accepted: 05/08/2025] [Indexed: 05/29/2025] Open
Abstract
Immunotherapy alone or in combination with chemotherapy or radiotherapy is the frontline treatment for melanoma and lung cancer. However, its role in prostate cancer is usually as a fourth-line treatment. It is usually employed in patients with metastasis, after androgen blockade and chemotherapy. This article reviews the immunosuppressive effects of prostate cancer and possible uses of various types of immunotherapies. It also considers when would be the optimal time to employ this type of therapy.
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Affiliation(s)
- Nigel P. Murray
- Faculty of Medicine, Universidad Finis Terrae, Santiago 7501015, Chile;
- Department of Medicine, Hospital de Carabineros de Chile, Santiago 7770199, Chile
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Escors D, Chocarro L, Echaide M, Rodriguez-Neira C, Vilaplana B, Kochan G. Programmed Death-1 Ligand 1 Domain Organization, Signaling Motifs, and Interactors in Cancer Immunotherapy. Cancers (Basel) 2025; 17:1635. [PMID: 40427133 PMCID: PMC12110588 DOI: 10.3390/cancers17101635] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2025] [Revised: 04/29/2025] [Accepted: 05/09/2025] [Indexed: 05/29/2025] Open
Abstract
Immunotherapies targeting the programmed cell death-1 ligand 1 (PD-L1) and programmed cell death 1 (PD-1) pathway sparked a revolution in cancer treatment. These breakthrough therapies work by disrupting the interaction between PD-1-expressed on T cells-and its ligand PD-L1, commonly found on the surface of cancer cells. By using monoclonal antibodies to block this binding, the immune system is unleashed to fight cancer more effectively. However, PD-L1's role extends far beyond immune evasion. When situated on cancer cells, PD-L1 transmits inhibitory signals through PD-1, silencing the effector functions of T cells. However, PD-L1 also engages in reverse signaling, also called intrinsic signaling, delivering intracellular instructions that contribute to cancer cell survival, even in the absence of PD-1 binding. This signaling cascade shields cancer cells from apoptosis, drives proliferation, regulates DNA damage responses, and even functions as a co-transcriptional transactivator, amplifying cancer's ability to thrive. The intricate mechanisms behind PD-L1's intrinsic signaling are under intense investigation. In this review, we provide a historical perspective on the discoveries leading to PD-L1's structure, signaling motifs, and interacting partners, shedding light on its multifaceted roles and the promising therapeutic possibilities ahead.
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Affiliation(s)
- David Escors
- OncoImmunology Unit, Navarrabiomed-Fundacion Miguel Servet, Hospital Universitario de Navarra (HUN), Instituto de Investigación Sanitaria de Navarra (IdISNA), Universidad Publica de Navarra (UPNA), 31008 Pamplona, Spain (M.E.); (C.R.-N.); (B.V.)
| | | | | | | | | | - Grazyna Kochan
- OncoImmunology Unit, Navarrabiomed-Fundacion Miguel Servet, Hospital Universitario de Navarra (HUN), Instituto de Investigación Sanitaria de Navarra (IdISNA), Universidad Publica de Navarra (UPNA), 31008 Pamplona, Spain (M.E.); (C.R.-N.); (B.V.)
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Kaufman B, Abu-Ahmad M, Radinsky O, Gharra E, Manko T, Bhattacharya B, Gologan D, Erlichman N, Meshel T, Nuta Y, Cooks T, Elkabets M, Ben-Baruch A, Porgador A. N-glycosylation of PD-L1 modulates the efficacy of immune checkpoint blockades targeting PD-L1 and PD-1. Mol Cancer 2025; 24:140. [PMID: 40346531 PMCID: PMC12065222 DOI: 10.1186/s12943-025-02330-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2025] [Accepted: 04/11/2025] [Indexed: 05/11/2025] Open
Abstract
BACKGROUND The PD-L1/PD-1 pathway is crucial for immune regulation and has become a target in cancer immunotherapy. However, in order to improve patient selection for immune checkpoint blockade (ICB) therapies, better selection criteria are needed. This study explores how the N-glycosylation of PD-L1 affects its interaction with PD-1 and ICB efficacy, focusing on its four N-linked glycosylation sites: N35, N192, N200, and N219. METHODS Human PD-L1 glycosylation mutants-at each individual site or at all four sites together (Nx4)-were tested for their functional interaction with PD-1 using an artificial immune checkpoint reporter assay (IcAR-PD1). The blocking efficacy of anti-PD-L1 and anti-PD-1 antibodies was evaluated using human breast cancer cell lines (MDA-MB231 and MCF7), as well as A375 melanoma and A549 lung carcinoma cells expressing the glycosylation mutants. Results were validated through ex vivo activation and cytotoxicity assays using human CD8+ T cells. RESULTS The binding of the PD-L1N35A mutant to PD-1 was not effectively blocked by anti-PD-L1 and anti-PD-1 ICBs. In contrast, high blocking efficacy of PD-L1 binding to PD-1 was obtained at minimal ICB concentrations when PD-L1 did not express any glycosylation site (PD-L1Nx4 mutant). The PD-L1N35A mutant produced elevated levels of PD-L1 as a soluble (sPD-L1) and extracellular vesicles (EV)-bound molecule; in contrast, the PD-L1Nx4 mutant had lower sPD-L1 and EV levels. PD-L1 glycosylation status influenced the ability of PD-L1 interactions with PD-1 to down-regulate T-cell activation and cytotoxicity, with the PD-L1N35A mutant showing the lowest levels of T cell functions and the PD-L1Nx4 mutant the highest. CONCLUSIONS The N-glycosylation of PD-L1 at all four sites interferes with the ability of anti-PD-L1 and anti-PD-1 ICBs to block PD-L1 interactions with PD-1; in contrast, glycosylation at the N35 site enhances ICB blocking efficacy. These effects are connected to the ability of sPD-L1 to compete with ICB binding to PD-L1 or PD-1. Thus, assessing PD-L1 glycosylation, beyond expression levels, could improve patient stratification and outcomes.
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Affiliation(s)
- Bar Kaufman
- The Shraga Segal Department of Microbiology, Immunology and Genetics, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, 84105, Israel
| | - Muhammad Abu-Ahmad
- The Shraga Segal Department of Microbiology, Immunology and Genetics, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, 84105, Israel
| | - Olga Radinsky
- The Shraga Segal Department of Microbiology, Immunology and Genetics, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, 84105, Israel
| | - Eman Gharra
- The Shraga Segal Department of Microbiology, Immunology and Genetics, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, 84105, Israel
| | - Tal Manko
- The Shraga Segal Department of Microbiology, Immunology and Genetics, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, 84105, Israel
| | - Baisali Bhattacharya
- The Shraga Segal Department of Microbiology, Immunology and Genetics, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, 84105, Israel
| | - Daniela Gologan
- The Shraga Segal Department of Microbiology, Immunology and Genetics, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, 84105, Israel
| | - Nofar Erlichman
- The Shmunis School of Biomedicine and Cancer Research, George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv, 6997801, Israel
| | - Tsipi Meshel
- The Shmunis School of Biomedicine and Cancer Research, George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv, 6997801, Israel
| | - Yoav Nuta
- The Shmunis School of Biomedicine and Cancer Research, George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv, 6997801, Israel
| | - Tomer Cooks
- The Shraga Segal Department of Microbiology, Immunology and Genetics, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, 84105, Israel
| | - Moshe Elkabets
- The Shraga Segal Department of Microbiology, Immunology and Genetics, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, 84105, Israel.
| | - Adit Ben-Baruch
- The Shmunis School of Biomedicine and Cancer Research, George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv, 6997801, Israel.
| | - Angel Porgador
- The Shraga Segal Department of Microbiology, Immunology and Genetics, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, 84105, Israel.
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Glapiński F, Zając W, Fudalej M, Deptała A, Czerw A, Sygit K, Kozłowski R, Badowska-Kozakiewicz A. The Role of the Tumor Microenvironment in Pancreatic Ductal Adenocarcinoma: Recent Advancements and Emerging Therapeutic Strategies. Cancers (Basel) 2025; 17:1599. [PMID: 40427098 PMCID: PMC12110676 DOI: 10.3390/cancers17101599] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2025] [Revised: 04/30/2025] [Accepted: 05/06/2025] [Indexed: 05/29/2025] Open
Abstract
Pancreatic cancer (PC), with pancreatic ductal adenocarcinoma (PDAC) comprising about 90% of all cases, is one of the most aggressive and lethal solid tumors. PDAC remains one of the most significant challenges of oncology to this day due to its inadequate response to conventional treatment, gradual rise in incidence since 2004, and poor five-year survival rates. As cancer cells are the primary adversary in this uneven fight, they remain the primary research target. Nevertheless, increasing attention is being paid to the tumor microenvironment (TME). The most crucial TME constellation components are immune cells, especially macrophages, stellate cells and lymphocytes, fibroblasts, bacterial and fungal microflora, and neuronal cells. Depending on the particular phenotype of these cells, the composition of the microenvironment, and the cell ratio, patients can experience different disease outcomes and varying vulnerability to treatment approaches. This study aims to present the current knowledge and review the most up-to-date scientific findings regarding the microenvironment of PC. It contains detailed information on the structure and cellular composition of the stroma, including its impact on disease development, metastasis, and response to treatment, as well as the therapeutic opportunities that arise from targeting this tissue.
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Affiliation(s)
- Franciszek Glapiński
- Students’ Scientific Organization of Cancer Cell Biology, Department of Oncological Propaedeutics, Medical University of Warsaw, 01-445 Warsaw, Poland
| | - Weronika Zając
- Students’ Scientific Organization of Cancer Cell Biology, Department of Oncological Propaedeutics, Medical University of Warsaw, 01-445 Warsaw, Poland
| | - Marta Fudalej
- Department of Oncological Propaedeutics, Medical University of Warsaw, 01-445 Warsaw, Poland; (M.F.); (A.D.)
- Department of Oncology, National Medical Institute of the Ministry of the Interior and Administration, 02-507 Warsaw, Poland
| | - Andrzej Deptała
- Department of Oncological Propaedeutics, Medical University of Warsaw, 01-445 Warsaw, Poland; (M.F.); (A.D.)
| | - Aleksandra Czerw
- Department of Health Economics and Medical Law, Medical University of Warsaw, 02-091 Warsaw, Poland;
- Department of Economic and System Analyses, National Institute of Public Health NIH—National Research Institute, 00-791 Warsaw, Poland
| | - Katarzyna Sygit
- Faculty of Health Sciences, Calisia University, 62-800 Kalisz, Poland
| | - Remigiusz Kozłowski
- Department of Management and Logistics in Healthcare, Medical University of Lodz, 90-131 Lodz, Poland
| | - Anna Badowska-Kozakiewicz
- Department of Oncological Propaedeutics, Medical University of Warsaw, 01-445 Warsaw, Poland; (M.F.); (A.D.)
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Zhang J, Song Z, Zhang Y, Zhang C, Xue Q, Zhang G, Tan F. Recent advances in biomarkers for predicting the efficacy of immunotherapy in non-small cell lung cancer. Front Immunol 2025; 16:1554871. [PMID: 40406096 PMCID: PMC12095235 DOI: 10.3389/fimmu.2025.1554871] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2025] [Accepted: 04/18/2025] [Indexed: 05/26/2025] Open
Abstract
Lung cancer continues to be the primary cause of cancer-related deaths globally, with non-small cell lung cancer (NSCLC) accounting for approximately 85% of all instances. Recently, immune checkpoint inhibitors (ICIs) have transformed the treatment approach for NSCLC, however, only a subset of patients experiences significant benefits. Therefore, identifying reliable biomarkers to forecast the efficacy of ICIs is crucial for ensuring the safety and effectiveness of treatments, becoming a major focus of current research efforts. This review highlights the recent advances in predictive biomarkers for the efficacy of ICIs in the treatment of NSCLC, including PD-L1 expression, tertiary lymphoid structures (TLS), tumor-infiltrating lymphocytes (TILs), tumor genomic alterations, transcriptional signatures, circulating biomarkers, and the microbiome. Furthermore, it underscores the pivotal roles of liquid biopsy, sequencing technologies, and digital pathology in biomarker discovery. Special attention is given to the predictive value of TLS, circulating biomarkers, and transcriptional signatures. The review concludes that the integration of multiple biomarkers holds promise for achieving more accurate efficacy predictions and optimizing personalized immunotherapy strategies. By providing a comprehensive overview of the current progress, this review offers valuable insights into biomarker-based precision medicine for NSCLC and outlines future research directions.
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Affiliation(s)
- Jiacheng Zhang
- Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Zehao Song
- Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Yuanjie Zhang
- Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- Department of Thoracic Surgery, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning, China
| | - Chentong Zhang
- Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Qi Xue
- Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Guochao Zhang
- Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Fengwei Tan
- Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- Department of Thoracic Surgery, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning, China
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Yan Z, Wang C, Wu J, Wang J, Ma T. TIM-3 teams up with PD-1 in cancer immunotherapy: mechanisms and perspectives. MOLECULAR BIOMEDICINE 2025; 6:27. [PMID: 40332725 PMCID: PMC12058639 DOI: 10.1186/s43556-025-00267-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2024] [Revised: 04/13/2025] [Accepted: 04/18/2025] [Indexed: 05/08/2025] Open
Abstract
Immunotherapy using immune checkpoint inhibitors (ICIs) has become a prominent strategy for cancer treatment over the past ten years. However, the efficacy of ICIs remains limited, with certain cancers exhibiting resistance to these therapeutic approaches. Consequently, several immune checkpoint proteins are presently being thoroughly screened and assessed in both preclinical and clinical studies. Among these candidates, T cell immunoglobulin and mucin-domain containing-3 (TIM-3) is considered a promising target. TIM-3 exhibits multiple immunosuppressive effects on various types of immune cells. Given its differential expression levels at distinct stages of T cell dysfunction in the tumor microenvironment (TME), TIM-3, along with programmed cell death protein 1 (PD-1), serves as indicators of T cell exhaustion. Moreover, it is crucial to carefully evaluate the impact of TIM-3 and PD-1 expression in cancer cells on the efficacy of immunotherapy. To increase the effectiveness of anti-TIM-3 and anti-PD-1 therapies, it is proposed to combine the inhibition of TIM-3, PD-1, and programmed death-ligand 1 (PD-L1). The efficacy of TIM-3 inhibition in conjunction with PD-1/PD-L1 inhibitors is being evaluated in a number of ongoing clinical trials for patients with various cancers. This study systematically investigates the fundamental biology of TIM-3 and PD-1, as well as the detailed mechanisms through which TIM-3 and PD-1/PD-L1 axis contribute to cancer immune evasion. Additionally, this article provides a thorough analysis of ongoing clinical trials evaluating the synergistic effects of combining PD-1/PD-L1 and TIM-3 inhibitors in anti-cancer treatment, along with an overview of the current status of TIM-3 and PD-1 antibodies.
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Affiliation(s)
- Zhuohong Yan
- Department of Cancer Research Center, Beijing Chest Hospital, Capital Medical University, Beijing Tuberculosis and Thoracic Tumor Research Institute, Beijing, 101149, China
| | - Chunmao Wang
- Department of Thoracic Surgery, Beijing Chest Hospital, Capital Medical University, Beijing, 101149, China
| | - Jinghong Wu
- Department of Cancer Research Center, Beijing Chest Hospital, Capital Medical University, Beijing Tuberculosis and Thoracic Tumor Research Institute, Beijing, 101149, China
| | - Jinghui Wang
- Department of Cancer Research Center, Beijing Chest Hospital, Capital Medical University, Beijing Tuberculosis and Thoracic Tumor Research Institute, Beijing, 101149, China
| | - Teng Ma
- Department of Cancer Research Center, Beijing Chest Hospital, Capital Medical University, Beijing Tuberculosis and Thoracic Tumor Research Institute, Beijing, 101149, China.
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Zhou P, Huang R, Cheng Y, Yang Y, Qian D, Ming X, Wang AZ, Chen X, Min Y. Nanotherapeutic Wee1 Inhibition Sensitizes Tumor Ferroptosis to Promote Cancer Immunotherapy and Abscopal Effect. ACS NANO 2025; 19:16307-16326. [PMID: 40263774 DOI: 10.1021/acsnano.4c13218] [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: 04/24/2025]
Abstract
The major issue with cancer immunotherapy is the low response rate. So, development of therapeutics enhancing immune responses is an urgent need. Tumor ferroptosis could produce immunogenic cancer cell death, which may improve cancer immunotherapy. However, current ferroptosis inducers may be limited to specific genetic backgrounds of cancer cells. Therefore, sensitization to ferroptosis inducers has also been highly pursued. Here, we found that Wee1 expression was negatively associated with drug sensitivity and positively correlated with an immunosuppressive microenvironment. Further investigation demonstrated that Wee1 inhibition could result in changes of ferroptosis and iron ion homeostasis, regardless of p53 status. Our in vitro results demonstrated the underlying mechanism that Wee1 inhibition primed cancer cells to ferroptosis through mitochondria reactive oxygen species and labile iron-dependent pathways. In order to decrease side effects, we developed an acidic responsive nanoformulation of the Wee1 inhibitor, which can sensitize tumor ferroptosis in vivo and also improve the response of cancer immunotherapy. Combining immunotherapy, nanotherapeutic Wee1 inhibition also produced abscopal effect with up to 55% mice cured that has not been seen before. In summary, nanotherapeutic Wee1 inhibition sensitized ferroptosis to enhance cancer immunotherapy and abscopal effect.
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Affiliation(s)
- Peijie Zhou
- Department of Radiation Oncology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230026, China
| | - Ruijie Huang
- Department of Chemistry, University of Science and Technology of China, Hefei 230026, China
| | - Yong Cheng
- Department of Radiation Oncology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230026, China
| | - Yidong Yang
- Department of Radiation Oncology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230026, China
- School of Physical Sciences and Ion Medical Research Institute, University of Science and Technology of China, Hefei 230026, China
| | - Dong Qian
- Department of Radiation Oncology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230026, China
| | - Xin Ming
- Department of Cancer Biology and Department of Biomedical Engineering, Wake Forest University School of Medicine, Winston Salem, North Carolina 27157, United States
| | - Andrew Z Wang
- Department of Radiation Oncology, Simmons Comprehensive Cancer Center, UT Southwestern Medical Center, Dallas, Texas 75390, United States
| | - Xiaoyuan Chen
- Departments of Diagnostic Radiology, Surgery, Chemical and Biomolecular Engineering, and Biomedical Engineering, Yong Loo Lin School of Medicine and College of Design and Engineering, National University of Singapore, Singapore 119074, Singapore
- Clinical Imaging Research Centre, Centre for Translational Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117599, Singapore
- Nanomedicine Translational Research Program, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597, Singapore
- Institute of Molecular and Cell Biology, Agency for Science, Technology, and Research (A*STAR), 61 Biopolis Drive, Proteos, Singapore 138673, Singapore
| | - Yuanzeng Min
- Department of Radiation Oncology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230026, China
- Department of Chemistry, University of Science and Technology of China, Hefei 230026, China
- Department of Endocrinology, Division of Life Sciences and Medicine, The First Affiliated Hospital of USTC, University of Science and Technology of China, Hefei 230026, China
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Liu L, Wuyun T, Sun X, Zhang Y, Cha G, Zhao L. Therapeutic efficacy of TMTP1-modified EVs in overcoming bone metastasis and immune resistance in PIK3CA mutant NSCLC. Cell Death Dis 2025; 16:367. [PMID: 40328748 PMCID: PMC12055990 DOI: 10.1038/s41419-025-07685-y] [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: 10/20/2024] [Revised: 04/08/2025] [Accepted: 04/17/2025] [Indexed: 05/08/2025]
Abstract
Non-small cell lung cancer (NSCLC) with PIK3CA mutations demonstrates significant challenges in treatment due to enhanced bone metastasis and immune checkpoint resistance. This study investigates the efficacy of tumor-targeting peptide 1-modified cancer stem cell-derived extracellular vesicles (TMTP1-TSRP-EVs) in reshaping the tumor microenvironment and reversing immune checkpoint resistance in NSCLC. By integrating TMTP1-TSRP into EVs, we aim to specifically deliver therapeutic agents to NSCLC cells, focusing on inhibiting the PI3K/Akt/mTOR pathway, a crucial driver of oncogenic activity and immune evasion in PIK3CA-mutated cells. Our comprehensive in vitro and in vivo analyses show that TMTP1-TSRP-EVs significantly inhibit tumor growth, reduce PD-L1 expression, and enhance CD8+ T cell infiltration, effectively reversing the immune-suppressive microenvironment. Moreover, the in vivo models confirm that our approach not only suppresses bone metastases but also overcomes primary resistance to immune checkpoint inhibitors by modulating the expression of key immunological markers. These findings suggest that targeted delivery of TMTP1-TSRP-EVs could provide a novel therapeutic strategy for treating PIK3CA-mutant NSCLC, offering significant improvements over traditional therapies by directly targeting the molecular pathogenesis of tumor resistance and metastasis. Molecular Mechanisms Reshaping the TME to Halt PI3K-Mutant Bone Metastasis of NSCLC and Overcoming Primary ICI Resistance. (Created by BioRender).
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Affiliation(s)
- Liwen Liu
- Department of Radiology, Harbin Medical University Cancer Hospital, Harbin, China
| | - Tanghesi Wuyun
- The Second Department of Respiratory, Harbin Medical University Cancer Hospital, Harbin, China
| | - Xin Sun
- The Second Department of Respiratory, Harbin Medical University Cancer Hospital, Harbin, China
| | - Yu Zhang
- The Second Department of Respiratory, Harbin Medical University Cancer Hospital, Harbin, China
| | - Geqi Cha
- Department of Radiation Oncology, Harbin Medical University Cancer Hospital, Harbin, China
| | - Ling Zhao
- The Second Department of Respiratory, Harbin Medical University Cancer Hospital, Harbin, China.
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50
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Elder AM, Fairchild HR, Kines KT, Cozzens LM, Becks AR, Slansky JE, Anderson SM, Lyons TR. Semaphorin7A and PD-L1 cooperatively drive immunosuppression during mammary involution and breast cancer. Cell Rep 2025; 44:115676. [PMID: 40333186 DOI: 10.1016/j.celrep.2025.115676] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2024] [Revised: 02/06/2025] [Accepted: 04/16/2025] [Indexed: 05/09/2025] Open
Abstract
Postpartum mammary gland remodeling after a pregnancy/lactation cycle is characterized by mechanisms of cell death and inflammation. Here, we show that SEMA7A promotes PD-L1 expression in immune cells of the mammary tissue during involution. These same phenotypes are mimicked in the microenvironment of SEMA7A-expressing tumors, which partially respond to αPD-1/αPD-L1 treatments in vivo. However, cells that remain after treatment are enriched for SEMA7A expression. Therefore, we tested a monoclonal antibody that directly targets SEMA7A-expressing tumors, in part, by reducing SEMA7A-mediated upregulation of PD-L1. In vivo, the SEMA7A monoclonal antibody reduces tumor growth and/or promotes complete regression of mouse mammary tumors, reduces some immunosuppressive phenotypes in the tumor microenvironment, and restores cytotoxic T cells, suggesting that SEMA7A may be a candidate for immune-based therapy for breast cancer patients.
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Affiliation(s)
- Alan M Elder
- Division of Medical Oncology, Department of Medicine, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA; Cancer Biology Graduate Training Program, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
| | - Heather R Fairchild
- Division of Medical Oncology, Department of Medicine, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
| | - Kelsey T Kines
- Division of Medical Oncology, Department of Medicine, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA; Cancer Biology Graduate Training Program, University of Colorado Anschutz Medical Campus, Aurora, CO, USA; Medical Scientist Training Program, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
| | - Lauren M Cozzens
- Division of Medical Oncology, Department of Medicine, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA; Cancer Biology Graduate Training Program, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
| | - Alexandria R Becks
- Division of Medical Oncology, Department of Medicine, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA; Cancer Biology Graduate Training Program, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
| | - Jill E Slansky
- University of Colorado Cancer Center, Aurora, CO, USA; Department of Immunology and Microbiology, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
| | | | - Traci R Lyons
- Division of Medical Oncology, Department of Medicine, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA; University of Colorado Cancer Center, Aurora, CO, USA; Young Women's Breast Cancer Translational Program, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
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