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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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2
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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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5
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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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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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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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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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10
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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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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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12
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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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13
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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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14
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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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15
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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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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 2025:104767. [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 Cedex, 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
| | - 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
| | - Lisa Derosa
- Gustave Roussy Cancer Campus (GRCC), Clinicobiome, Villejuif Cedex, 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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18
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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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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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20
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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] [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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21
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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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22
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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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23
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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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24
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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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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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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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31
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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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32
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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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Yadav K, Das T, Lynn AM. Pancancer analysis of DNA damage repair gene mutations and their impact on immune regulatory gene expression. Sci Rep 2025; 15:15667. [PMID: 40325163 PMCID: PMC12052996 DOI: 10.1038/s41598-025-99965-y] [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: 02/13/2025] [Accepted: 04/24/2025] [Indexed: 05/07/2025] Open
Abstract
DNA damage is a key factor in many human disorders, including cancer, chronic inflammation, and early aging. Genes involved in DNA damage repair (DDR) not only maintain genomic stability but also contribute to immune responses by regulating the expression of antimicrobial peptides and ligands that activate immune receptors. Various components of the DNA damage response (DDR), including DNA damage sensors, transducer kinases, and effector proteins, are capable of activating diverse immunological signaling pathways. While DDR gene mutations are common in cancers, their effects on immune characteristics are not well understood. We investigated how mutations in DDR genes influence the expression of immune regulatory genes, including immune stimulators, inhibitors, and genes related to the major histocompatibility complex (MHC) pathway. Using gene expression data from The Cancer Genome Atlas (TCGA) and mutation data from cBioPortal, we analyzed 264 DDR-related genes and 66 immune regulatory genes. These genes were clustered and categorized using Metascape, an integrative bioinformatics tool that applies enrichment-based analysis to group functionally related genes into clusters. The clustered genes were further validated through a literature review and the GeneCards database. We scored the change in immune regulatory gene expression in response to DDR gene mutations to identify differentially expressed immune stimulators, inhibitors, and MHC-related genes. Our analysis revealed positive and negative correlations between DDR gene mutations and the expression of immune modulators. These findings could help guide future cancer treatments based on biomarkers and immunotherapy strategies.
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Affiliation(s)
- Kanchana Yadav
- School of Computational and Integrative Sciences, Jawaharlal Nehru University, New Delhi, 110067, India
| | - Trishala Das
- School of Computational and Integrative Sciences, Jawaharlal Nehru University, New Delhi, 110067, India
| | - Andrew M Lynn
- School of Computational and Integrative Sciences, Jawaharlal Nehru University, New Delhi, 110067, India.
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Jünemann W, Bley I, Rekowski L, Klokow M, Herppich S, Müller I, Cornils K. GD2-CAR NK-92 cell activity against neuroblastoma cells is insusceptible to TIGIT knockout. Cancer Immunol Immunother 2025; 74:191. [PMID: 40317320 PMCID: PMC12049354 DOI: 10.1007/s00262-025-04010-6] [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: 01/13/2025] [Accepted: 03/03/2025] [Indexed: 05/07/2025]
Abstract
Immunotherapy by inhibition of immune checkpoint (IC) molecules has emerged as an important cancer therapy. Among these lC, the poliovirus receptor/poliovirus receptor-like 2 protein (PVR/PVRL2)-TIGIT axis was discovered as potential target for various cancers. For neuroblastoma (NB), the most common extracranial solid cancer in children, no effective IC therapy has been established yet. To investigate the PVR/PVRL2-TIGIT IC axis as a new target for the treatment of NB, we analysed whether PVR and PVRL2 influence the survival of patients and verified the expression of the receptors on NB cell lines. To disrupt the checkpoint axis, we performed single and double knockouts of these receptors on NB cell lines and subsequently removed TIGIT, an inhibitory receptor on immune effector cells, from NK-92 cells. Finally, we combined checkpoint inhibition with GD2-CAR NK-92 cells and investigated changes in cytotoxicity. Using RNA-Seq data we showed that the expression of PVR and PVRL2 on NB cells correlates to a lower event-free survival of patients. CRISPR/Cas9 knockouts of PVR and PVRL2 showed no improved cytotoxic activity of NK-92 cells. We observed enhanced lysis of NB cells using TIGIT-deficient NK-92 cells. However, the cytotoxicity of GD2-CAR NK-92 was not significantly enhanced. In summary, we have shown that in addition to the interaction of PVR/PVRL2 and TIGIT on engineered immune effector cells against NB, pleiotropic ligands appear to be relevant. Deletion of TIGIT from immune effector cells is a promising approach to protect these cells from tumour-associated inhibitory signals but cannot enhance the effect of GD2-CAR-NK-92 cells.
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MESH Headings
- Humans
- Neuroblastoma/immunology
- Neuroblastoma/therapy
- Neuroblastoma/pathology
- Receptors, Immunologic/genetics
- Receptors, Immunologic/metabolism
- Receptors, Immunologic/immunology
- Killer Cells, Natural/immunology
- Killer Cells, Natural/metabolism
- Gangliosides/immunology
- Cell Line, Tumor
- Immunotherapy, Adoptive/methods
- Gene Knockout Techniques
- Receptors, Chimeric Antigen/immunology
- Receptors, Chimeric Antigen/genetics
- Receptors, Virus/genetics
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Affiliation(s)
- Wiebke Jünemann
- Children's Cancer Centre Research Institute Hamburg, Hamburg, Germany
- Division of Paediatric Stem Cell Transplantation and Immunology, Department of Paediatric Haematology and Oncology, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany
| | - Isabelle Bley
- Children's Cancer Centre Research Institute Hamburg, Hamburg, Germany
- Division of Paediatric Stem Cell Transplantation and Immunology, Department of Paediatric Haematology and Oncology, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany
| | - Laura Rekowski
- Children's Cancer Centre Research Institute Hamburg, Hamburg, Germany
- Division of Paediatric Stem Cell Transplantation and Immunology, Department of Paediatric Haematology and Oncology, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany
| | - Marianne Klokow
- Children's Cancer Centre Research Institute Hamburg, Hamburg, Germany
- Division of Paediatric Stem Cell Transplantation and Immunology, Department of Paediatric Haematology and Oncology, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany
| | - Susanne Herppich
- Children's Cancer Centre Research Institute Hamburg, Hamburg, Germany
- Division of Paediatric Stem Cell Transplantation and Immunology, Department of Paediatric Haematology and Oncology, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany
| | - Ingo Müller
- Children's Cancer Centre Research Institute Hamburg, Hamburg, Germany
- Division of Paediatric Stem Cell Transplantation and Immunology, Department of Paediatric Haematology and Oncology, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany
| | - Kerstin Cornils
- Children's Cancer Centre Research Institute Hamburg, Hamburg, Germany.
- Division of Paediatric Stem Cell Transplantation and Immunology, Department of Paediatric Haematology and Oncology, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany.
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35
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van Rijssen L, Nagtegaal IEC, Ploos van Amstel FK, Driessen CML, van Erp NP, Timmer-Bonte A, Verhoeff SR. Safety of accelerated infusion of nivolumab and pembrolizumab. Eur J Cancer 2025; 220:115373. [PMID: 40154211 DOI: 10.1016/j.ejca.2025.115373] [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: 01/31/2025] [Revised: 03/04/2025] [Accepted: 03/13/2025] [Indexed: 04/01/2025]
Abstract
Nivolumab and pembrolizumab are checkpoint inhibitors targeting programmed cell death-1, used for several types of cancer. The increased use of these drugs and the growing number of cancer patients place a significant burden on the hospital ward capacity. Safely reducing the infusion time of immune checkpoint inhibitors could improve capacity. The aim of this implementation project was to explore the safety of accelerated infusion time for nivolumab and pembrolizumab. Patients who received monotherapy nivolumab or pembrolizumab were included in the implementation project. The administration time according to label of nivolumab and pembrolizumab was reduced over 2-3 treatment cycles from 60 and 30-10 min. Vital signs were measured every 15 min from start until 30 min after completion of each administration. If a hypersensitivity reaction (HSR) occurred, infusion was interrupted, and its severity was graded. Between January 2023 and December 2024, 101 patients were enrolled (316 infusions). This included 72 patients with nivolumab and 29 with pembrolizumab treatment. Only grade 1 and 2 HSR were observed. In total 11 HSRs were observed during the administration of nivolumab. Nine HSRs occurred during the 30-minute and two during the 10-minute infusion. No HSR was recorded with pembrolizumab. The accelerated infusion of nivolumab and pembrolizumab in 10 min is safe and results in considerable time efficiency. This strategy is potentially feasible for more immune checkpoint inhibitors and should therefore be considered to facilitate the treatment of the increasing number of cancer patients.
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Affiliation(s)
- Loes van Rijssen
- Department of Medical Oncology, Radboudumc, Nijmegen, the Netherlands.
| | | | | | | | | | - Anja Timmer-Bonte
- Department of Medical Oncology, Radboudumc, Nijmegen, the Netherlands
| | - Sarah R Verhoeff
- Department of Medical Oncology, Radboudumc, Nijmegen, the Netherlands; Department of Medical Oncology, Zuyderland MC, Sittard-Geleen, the Netherlands
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Tan Z, Völler S, Sancho-Araiz A, Knibbe CAJ, Moes DJAR. A Systematic Evaluation of the Dosing Regimens for Approved Targeted Therapies and Immune Checkpoint Inhibitors in Metastatic Renal Cell Carcinoma From a Project OPTIMUS Perspective. J Clin Pharmacol 2025. [PMID: 40313197 DOI: 10.1002/jcph.70035] [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: 02/10/2025] [Accepted: 04/02/2025] [Indexed: 05/03/2025]
Abstract
Targeted therapies and immune checkpoint inhibitors (ICIs) have significantly improved survival outcomes in metastatic renal cell carcinoma (mRCC) but are often associated with high rates of adverse events, leading to dose reductions or treatment discontinuation. The FDA's recent initiative, Project OPTIMUS, emphasizes the importance of optimizing dosing regimens in oncology clinical development, and moves beyond the conventional maximum tolerated dose approach. In this study, we aimed to review and redefine the approved dosing strategies for targeted therapies and ICIs in mRCC from the Project OPTIMUS perspective, including pazopanib, axitinib, cabozantinib, sunitinib, everolimus, and nivolumab. A comprehensive summary of FDA clinical pharmacology reviews and clinical studies performed in routine clinical practice was conducted, alongside model-informed simulations of pharmacokinetic profiles with approved and alternative regimens. Results demonstrated that actual tolerated doses in clinical practice were 46.1% to 86% lower than the approved dosages, with up to 75% of patients requiring dose adjustments. Model-informed simulations suggested that for most targeted therapies, a 14%-50% dose reduction maintained comparable efficacy while improving tolerability. For nivolumab, simulations confirmed adequate drug exposure with the approved flat dose regimens, without an increase of adverse effects. In conclusion, we identified optimized dosing regimens that could improve drug tolerability while maintaining efficacy for approved targeted therapies and ICIs in mRCC. We suggest that these optimized dosing regimens should be considered for use in clinical practice and that the optimal exposure range be included in drug labels to support pharmacokinetically guided dose individualization in clinical practice.
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Affiliation(s)
- Zhiyuan Tan
- Division of Systems Pharmacology and Pharmacy, Leiden Academic Centre for Drug Research, Leiden University, Leiden, The Netherlands
- Department of Clinical Pharmacy and Toxicology, Leiden University Medical Center, Leiden, The Netherlands
| | - Swantje Völler
- Division of Systems Pharmacology and Pharmacy, Leiden Academic Centre for Drug Research, Leiden University, Leiden, The Netherlands
| | - Aymara Sancho-Araiz
- Division of Systems Pharmacology and Pharmacy, Leiden Academic Centre for Drug Research, Leiden University, Leiden, The Netherlands
| | - Catherijne A J Knibbe
- Division of Systems Pharmacology and Pharmacy, Leiden Academic Centre for Drug Research, Leiden University, Leiden, The Netherlands
- Department of Clinical Pharmacy, St Antonius Hospital, Nieuwegein, The Netherlands
| | - Dirk Jan A R Moes
- Department of Clinical Pharmacy and Toxicology, Leiden University Medical Center, Leiden, The Netherlands
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37
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Zhang D, Wang Z, Inuzuka H, Wei W. Proximity-induced membrane protein degradation for cancer therapies. RSC Med Chem 2025:d5md00141b. [PMID: 40365034 PMCID: PMC12066958 DOI: 10.1039/d5md00141b] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2025] [Accepted: 04/30/2025] [Indexed: 05/15/2025] Open
Abstract
The selective modulation of membrane proteins presents a significant challenge in drug development, particularly in cancer therapies. However, conventional small molecules and biologics often face significant hurdles in effectively targeting membrane-bound proteins, largely due to the structural complexity of these proteins and their involvement in intricate cellular processes. In light of these limitations, proximity-induced protein modulation has recently emerged as a transformative approach. It leverages molecule-induced proximity strategies to commandeer endogenous cellular machinery for precise protein manipulation. One of these modulatory strategies is protein degradation, wherein membrane-targeting degraders derived from proximity-induction approaches offer a unique therapeutic avenue by inducing the irreversible removal of key oncogenic and immune-regulatory proteins to combat cancer. This review explores the fundamental principles underlying proximity-driven membrane protein degradation, highlighting key strategies such as LYTACs, PROTABs, TransTACs, and IFLD that are reshaping targeted cancer therapy. We discuss recent technological advancements in the application of proximity-induced degraders across breast cancer, lung cancer, immunotherapy, and other malignancies, underscoring how these innovative approaches have demonstrated significant therapeutic potential. Lastly, while these emerging technologies offer significant promise, they still face substantial limitations, including drug delivery, selectivity, and resistance mechanisms that need to be addressed to achieve successful clinical translation.
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Affiliation(s)
- Dingpeng Zhang
- Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School Boston MA 02215 USA
| | - Zhen Wang
- Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School Boston MA 02215 USA
| | - Hiroyuki Inuzuka
- Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School Boston MA 02215 USA
| | - Wenyi Wei
- Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School Boston MA 02215 USA
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38
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Zhang R, Zhang X, Lau HCH, Yu J. Gut microbiota in cancer initiation, development and therapy. SCIENCE CHINA. LIFE SCIENCES 2025; 68:1283-1308. [PMID: 39821827 DOI: 10.1007/s11427-024-2831-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/03/2024] [Accepted: 12/12/2024] [Indexed: 01/19/2025]
Abstract
Cancer has long been associated with genetic and environmental factors, but recent studies reveal the important role of gut microbiota in its initiation and progression. Around 13% of cancers are linked to infectious agents, highlighting the need to identify the specific microorganisms involved. Gut microbiota can either promote or inhibit cancer growth by influencing oncogenic signaling pathways and altering immune responses. Dysbiosis can lead to cancer, while certain probiotics and their metabolites may help reestablish micro-ecological balance and improve anti-tumor immune responses. Research into targeted approaches that enhance therapy with probiotics is promising. However, the effects of probiotics in humans are complex and not yet fully understood. Additionally, methods to counteract harmful bacteria are still in development. Early clinical trials also indicate that modifying gut microbiota may help manage side effects of cancer treatments. Ongoing research is crucial to understand better how gut microbiota can be used to improve cancer prevention and treatment outcomes.
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Affiliation(s)
- Ruyi Zhang
- Institute of Digestive Disease and Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, CUHK Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong, China
| | - Xiang Zhang
- Institute of Digestive Disease and Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, CUHK Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong, China
| | - Harry Cheuk Hay Lau
- Institute of Digestive Disease and Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, CUHK Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong, China
| | - Jun Yu
- Institute of Digestive Disease and Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, CUHK Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong, China.
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39
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Chen M, Zhou Y, Bao K, Chen S, Song G, Wang S. Multispecific Antibodies Targeting PD-1/PD-L1 in Cancer. BioDrugs 2025; 39:427-444. [PMID: 40106158 DOI: 10.1007/s40259-025-00712-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/26/2025] [Indexed: 03/22/2025]
Abstract
The development of immune checkpoint inhibitors has revolutionized the treatment of patients with cancer. Targeting the programmed cell death protein 1 (PD-1)/programmed cell death 1 ligand 1(PD-L1) interaction using monoclonal antibodies has emerged as a prominent focus in tumor therapy with rapid advancements. However, the efficacy of anti-PD-1/PD-L1 treatment is hindered by primary or acquired resistance, limiting the effectiveness of single-drug approaches. Moreover, combining PD-1/PD-L1 with other immune drugs, targeted therapies, or chemotherapy significantly enhances response rates while exacerbating adverse reactions. Multispecific antibodies, capable of binding to different epitopes, offer improved antitumor efficacy while reducing drug-related side effects, serving as a promising therapeutic approach in cancer treatment. Several bispecific antibodies (bsAbs) targeting PD-1/PD-L1 have received regulatory approval, and many more are currently in clinical development. Additionally, tri-specific antibodies (TsAbs) and tetra-specific antibodies (TetraMabs) are under development. This review comprehensively explores the fundamental structure, preclinical principles, clinical trial progress, and challenges associated with bsAbs targeting PD-1/PD-L1.
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Affiliation(s)
- Miaomiao Chen
- Department of Oncology, Shengjing Hospital of China Medical University, 36 Sanhao Road, Shenyang, 110004, China
| | - Yuli Zhou
- Department of Pathology, Shengjing Hospital of China Medical University, Shenyang, China
| | - Kaicheng Bao
- Department of Oncology, Shengjing Hospital of China Medical University, 36 Sanhao Road, Shenyang, 110004, China
| | - Siyu Chen
- Department of Oncology, Shengjing Hospital of China Medical University, 36 Sanhao Road, Shenyang, 110004, China
| | - Guoqing Song
- Department of Oncology, Shengjing Hospital of China Medical University, 36 Sanhao Road, Shenyang, 110004, China.
| | - Siliang Wang
- Department of Oncology, Shengjing Hospital of China Medical University, 36 Sanhao Road, Shenyang, 110004, China.
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40
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Jamouss KT, Damanakis AI, Cornwell AC, Jongepier M, Trujillo MA, Pflüger MJ, Kawalerski R, Maalouf A, Hirose K, Datta S, Sipes A, Pedro BA, Gudmundsson E, Assarzadegan N, Engle L, Scharpf RB, Kawamoto S, Thompson ED, Wood LD. Tumor immune microenvironment alterations associated with progression in human intraductal papillary mucinous neoplasms. J Pathol 2025; 266:40-50. [PMID: 40001347 DOI: 10.1002/path.6402] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2023] [Revised: 11/26/2024] [Accepted: 01/08/2025] [Indexed: 02/27/2025]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) poses a significant challenge due to late-stage diagnoses. To improve patient outcomes, early intervention in precursor lesions such as intraductal papillary mucinous neoplasm (IPMN) is crucial. However, early intervention must be balanced against overtreatment of low-risk lesions that are unlikely to progress, underscoring the need to better understand molecular alterations in neoplastic cells and changes in the tumor microenvironment (TME) that drive the progression of IPMNs. In this study, we characterized alterations in the TME of IPMNs as they progressed to high-grade dysplasia, using immunohistochemistry to quantify immune cell density and activation status in more than 100 well-characterized human IPMN samples. Analyses revealed progression to a more immunosuppressive TME in high-grade IPMN compared with low-grade IPMN, characterized by elevated expression of immune checkpoint molecules (PD-L1, TIM3, VISTA), increased density of macrophages, and decreased density of cytotoxic T cells. Intriguingly, the alterations in macrophages were limited to focal regions of high-grade dysplasia, while T-cell alterations affected the entire IPMN. Additionally, elevated VISTA expression was associated with poorer clinical outcome after IPMN resection in an independent cohort. These findings provide important insights into the interplay between the immune microenvironment and IPMN progression, highlighting potential targets to modify the TME for cancer interception. © 2025 The Pathological Society of Great Britain and Ireland.
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Affiliation(s)
- Kevin T Jamouss
- Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Alexander Ioannis Damanakis
- Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Abigail C Cornwell
- Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Martine Jongepier
- Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Maria A Trujillo
- Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Michael Johannes Pflüger
- Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA
- Graduate School of Life Sciences, Utrecht University, Utrecht, The Netherlands
| | - Ryan Kawalerski
- Molecular Biology and Genetics, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Alexandre Maalouf
- Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Katsuya Hirose
- Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Shalini Datta
- Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Abigail Sipes
- Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Brian A Pedro
- Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Emma Gudmundsson
- Department of Physiology, University of Maryland, Baltimore, MD, USA
| | - Naziheh Assarzadegan
- Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA
- Department of Pathology, University of Florida, Gainesville, FL, USA
| | - Logan Engle
- Bloomberg Kimmel Institute, Tumor Microenvironment Technology Development Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Robert B Scharpf
- Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Satomi Kawamoto
- Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Elizabeth D Thompson
- Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Laura D Wood
- Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA
- Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA
- Department of Medicine, Division of Gastroenterology and Hepatology, Johns Hopkins University, Baltimore, MD, USA
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Matsuura H, Ishino T, Ninomiya T, Ninomiya K, Tachibana K, Honobe‐Tabuchi A, Muto Y, Inozume T, Ueda Y, Ohashi K, Maeda Y, Nagasaki J, Togashi Y. High Antigenicity for T reg Cells Confers Resistance to PD-1 Blockade Therapy via High PD-1 Expression in T reg Cells. Cancer Sci 2025; 116:1214-1226. [PMID: 40017103 PMCID: PMC12044662 DOI: 10.1111/cas.70029] [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: 10/22/2024] [Revised: 02/12/2025] [Accepted: 02/17/2025] [Indexed: 03/01/2025] Open
Abstract
Regulatory T (Treg) cells have an immunosuppressive function, and programmed death-1 (PD-1)-expressing Treg cells reportedly induce resistance to PD-1 blockade therapies through their reactivation. However, the effects of antigenicity on PD-1 expression in Treg cells and the resistance to PD-1 blockade therapy remain unclear. Here, we show that Treg cells gain high PD-1 expression through an antigen with high antigenicity. Additionally, tumors with high antigenicity for Treg cells were resistant to PD-1 blockade in vivo due to PD-1+ Treg-cell infiltration. Because such PD-1+ Treg cells have high cytotoxic T lymphocyte antigen (CTLA)-4 expression, resistance could be overcome by combination with an anti-CTLA-4 monoclonal antibody (mAb). Patients who responded to combination therapy with anti-PD-1 and anti-CTLA-4 mAbs sequentially after primary resistance to PD-1 blockade monotherapy showed high Treg cell infiltration. We propose that the high antigenicity of Treg cells confers resistance to PD-1 blockade therapy via high PD-1 expression in Treg cells, which can be overcome by combination therapy with an anti-CTLA-4 mAb.
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Affiliation(s)
- Hiroaki Matsuura
- Department of Tumor MicroenvironmentOkayama UniversityOkayamaJapan
- Department of Hematology, Oncology and Respiratory MedicineOkayama UniversityOkayamaJapan
| | - Takamasa Ishino
- Department of Tumor MicroenvironmentOkayama UniversityOkayamaJapan
| | | | - Kiichiro Ninomiya
- Department of Hematology, Oncology and Respiratory MedicineOkayama UniversityOkayamaJapan
| | - Kota Tachibana
- Department of Dermatology, Faculty of Medicine, Dentistry and Pharmaceutical SciencesOkayama UniversityOkayamaJapan
| | | | - Yoshinori Muto
- Department of DermatologyUniversity of YamanashiYamanashiJapan
| | - Takashi Inozume
- Department of DermatologyUniversity of YamanashiYamanashiJapan
- Department of DermatologyChiba UniversityChibaJapan
| | - Youki Ueda
- Department of Tumor MicroenvironmentOkayama UniversityOkayamaJapan
| | - Kadoaki Ohashi
- Department of Hematology, Oncology and Respiratory MedicineOkayama UniversityOkayamaJapan
| | - Yoshinobu Maeda
- Department of Hematology, Oncology and Respiratory MedicineOkayama UniversityOkayamaJapan
| | - Joji Nagasaki
- Department of Tumor MicroenvironmentOkayama UniversityOkayamaJapan
| | - Yosuke Togashi
- Department of Tumor MicroenvironmentOkayama UniversityOkayamaJapan
- Department of Allergy and Respiratory MedicineOkayama University HospitalOkayamaJapan
- Kindai University Faculty of MedicineOsakaJapan
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Almuradova E, Izzo D, Gandini S, Gaeta A, Giordano E, Valenza C, Antonarelli G, Trapani D, Curigliano G. From Dose-Finding to Dose-Optimization in Early-Phase oncology clinical trials. Cancer Treat Rev 2025; 136:102906. [PMID: 40157116 DOI: 10.1016/j.ctrv.2025.102906] [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: 01/22/2025] [Revised: 02/19/2025] [Accepted: 02/20/2025] [Indexed: 04/01/2025]
Abstract
Dose optimization in Phase I oncology trials balances therapeutic efficacy and patient safety. Traditional dose-escalation methods, such as the 3 + 3 design, primarily focus on safety, often resulting in prolonged exposure to subtherapeutic or excessively toxic doses. Additionally, these methods may fail to account for modern therapies' complex pharmacokinetics and pharmacodynamics, including targeted agents and immunotherapies. Contemporary approaches address these gaps by incorporating biomarkers, pharmacokinetic profiling, and patient-reported outcomes to guide personalized dosing strategies. Such methods improve the precision of dose selection and promote individualized cancer care. This review underscores the importance of distinguishing between dose-finding and dose optimization, advocating for designs that integrate patient perspectives and pharmacologic insights from early-phase trials. Additionally, we highlight the challenges of traditional methodologies and the importance of simplifying complex designs without compromising their scientific rigor. By embracing innovative approaches and patient-centered metrics, Phase I trials can evolve beyond safety assessments to expedite the delivery of effective and tailored cancer therapies.
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Affiliation(s)
- Elvina Almuradova
- Division of New Drugs and Early Drug Development for Innovative Therapies, European Institute of Oncology, IRCCS, Milan, Italy; Ege University Hospital, Department of Medical Oncology, Izmir, Turkey
| | - Davide Izzo
- Division of New Drugs and Early Drug Development for Innovative Therapies, European Institute of Oncology, IRCCS, Milan, Italy; Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy
| | - Sara Gandini
- Experimental Oncology, European Institute of Oncology, IRCCS, Milan, Italy
| | - Aurora Gaeta
- Experimental Oncology, European Institute of Oncology, IRCCS, Milan, Italy
| | - Edoardo Giordano
- Division of New Drugs and Early Drug Development for Innovative Therapies, European Institute of Oncology, IRCCS, Milan, Italy; Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy
| | - Carmine Valenza
- Division of New Drugs and Early Drug Development for Innovative Therapies, European Institute of Oncology, IRCCS, Milan, Italy; Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy; Harvard Chan School of Public Health, Harvard University, Boston, MA, USA
| | - Gabriele Antonarelli
- Division of New Drugs and Early Drug Development for Innovative Therapies, European Institute of Oncology, IRCCS, Milan, Italy; Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy
| | - Dario Trapani
- Division of New Drugs and Early Drug Development for Innovative Therapies, European Institute of Oncology, IRCCS, Milan, Italy; Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy.
| | - Giuseppe Curigliano
- Division of New Drugs and Early Drug Development for Innovative Therapies, European Institute of Oncology, IRCCS, Milan, Italy; Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy
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43
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Qureshi Z, Zaheer Z, Asghar Z, Bakhtiar M, Fatima E, Altaf F. Cardiovascular Risk Profile of Nivolumab Anti-cancer Therapy: A Review of Current Literature. Am J Clin Oncol 2025; 48:235-241. [PMID: 40008416 DOI: 10.1097/coc.0000000000001166] [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: 02/27/2025]
Abstract
OBJECTIVES Immune checkpoint inhibitors (ICI) upregulate host antitumor immunity, proving efficacy across diverse tumor types. Currently approved ICI treatment primarily targets the programmed cell death receptor 1 (PD-1) and its ligand PD-L1, and cytotoxic T lymphocyte-antigen 4 (CTLA-4). Nivolumab is a monoclonal antibody that targets the human PD-1 receptor and is an entirely human immunoglobulin G4 (IgG4), approved by the FDA for various cancers like advanced melanoma, metastatic renal cell carcinoma, Hodgkin lymphoma, and advanced lung carcinoma. This review will summarise and discuss the recent literature on cardiotoxicity associated with nivolumab therapy. METHODS We searched online databases like PubMed, Scopus, Google Scholar, and Embase for articles related to Nivolumab. RESULTS Cardiotoxicity with ICI use is most commonly represented as myocarditis. Patients present with complaints of shortness of breath, palpitations, edema, and fatigue. Takotsubo cardiomyopathy, or broken heart syndrome, is characterized by systolic dysfunction of the left ventricle, mimicking a myocardial infarction but without associated coronary ischemia and with minimal elevation of cardiac enzymes. In the CHECKMATE-037 trial, ventricular arrhythmias occurred in <10% of those who received nivolumab. In a retrospective analysis of patients treated with ICI (predominantly nivolumab monotherapy) for lung cancer, 11% of the patients developed major adverse cardiac events, including myocarditis, non-ST-segment elevated myocardial infarction, supraventricular tachycardia, and pericardial disorders. CONCLUSION Close collaboration between cardiology and oncology specialists is crucial for early detection and effective management of cardiac complications, enhancing the safety of nivolumab anticancer therapy.
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Affiliation(s)
- Zaheer Qureshi
- The Frank H. Netter M.D. School of Medicine at Quinnipiac University, Bridgeport, CT
| | | | - Zoha Asghar
- Department of Medicine, Ziauddin University, Karachi
| | | | - Eeshal Fatima
- Department of Medicine, Services Institute of Medical Sciences, Lahore, Pakistan
| | - Faryal Altaf
- Department of Internal Medicine, Icahn School of Medicine at Mount Sinai/BronxCare Health System, New York, NY
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44
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Yong C, Liang Y, Wang M, Jin W, Fan X, Wang Z, Cao K, Wu T, Li Q, Chang C. Alternative splicing: A key regulator in T cell response and cancer immunotherapy. Pharmacol Res 2025; 215:107713. [PMID: 40147681 DOI: 10.1016/j.phrs.2025.107713] [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: 12/27/2024] [Revised: 03/03/2025] [Accepted: 03/24/2025] [Indexed: 03/29/2025]
Abstract
Alternative splicing (AS), a key post-transcriptional regulatory mechanism, is frequently dysregulated in cancer, driving both tumor progression and immune modulation. Aberrant AS influences antigen presentation, T cell activation, immune checkpoint regulation, and cytokine signaling, contributing to immune evasion but also presenting unique therapeutic vulnerabilities. Targeting AS has emerged as a promising strategy in cancer immunotherapy. Splicing-derived neoantigens have been identified as potent inducers of CD8⁺ T cell responses, offering potential for personalized treatment. AS modulators such as PRMT5 inhibitor GSK3326595 enhance immunotherapy efficacy by upregulating MHC class II expression and promoting T cell infiltration, while RBM39 inhibitor indisulam induces tumor-specific neoantigens. Furthermore, combining AS-targeting drugs with immune checkpoint inhibitors (ICIs) has demonstrated synergistic effects, improved response rates and overcoming resistance in preclinical models. Despite these advances, challenges remain in optimizing drug specificity and minimizing toxicity. Future efforts should focus on refining AS-targeting therapies, identifying predictive biomarkers, and integrating these approaches into clinical applications. This review highlights the therapeutic potential of AS modulation in cancer immunotherapy and its implications for advancing precision oncology.
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Affiliation(s)
- Caiyu Yong
- School of Pharmacy, Hangzhou Normal University, Hangzhou 311121, PR China; Key Laboratory of Elemene Class Anti-Cancer Chinese Medicines, Engineering Laboratory of Development and Application of Traditional Chinese Medicines, Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, School of Pharmacy, Hangzhou Normal University, Hangzhou 311121, PR China
| | - Yexin Liang
- School of Pharmacy, Hangzhou Normal University, Hangzhou 311121, PR China; Key Laboratory of Elemene Class Anti-Cancer Chinese Medicines, Engineering Laboratory of Development and Application of Traditional Chinese Medicines, Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, School of Pharmacy, Hangzhou Normal University, Hangzhou 311121, PR China
| | - Minmin Wang
- School of Pharmacy, Hangzhou Normal University, Hangzhou 311121, PR China; Key Laboratory of Elemene Class Anti-Cancer Chinese Medicines, Engineering Laboratory of Development and Application of Traditional Chinese Medicines, Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, School of Pharmacy, Hangzhou Normal University, Hangzhou 311121, PR China
| | - Weiwei Jin
- School of Pharmacy, Hangzhou Normal University, Hangzhou 311121, PR China; Key Laboratory of Elemene Class Anti-Cancer Chinese Medicines, Engineering Laboratory of Development and Application of Traditional Chinese Medicines, Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, School of Pharmacy, Hangzhou Normal University, Hangzhou 311121, PR China
| | - Xuefei Fan
- School of Pharmacy, Hangzhou Normal University, Hangzhou 311121, PR China; Key Laboratory of Elemene Class Anti-Cancer Chinese Medicines, Engineering Laboratory of Development and Application of Traditional Chinese Medicines, Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, School of Pharmacy, Hangzhou Normal University, Hangzhou 311121, PR China
| | - Zhengwen Wang
- School of Pharmacy, Hangzhou Normal University, Hangzhou 311121, PR China; Key Laboratory of Elemene Class Anti-Cancer Chinese Medicines, Engineering Laboratory of Development and Application of Traditional Chinese Medicines, Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, School of Pharmacy, Hangzhou Normal University, Hangzhou 311121, PR China
| | - Kui Cao
- School of Pharmacy, Hangzhou Normal University, Hangzhou 311121, PR China; Key Laboratory of Elemene Class Anti-Cancer Chinese Medicines, Engineering Laboratory of Development and Application of Traditional Chinese Medicines, Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, School of Pharmacy, Hangzhou Normal University, Hangzhou 311121, PR China
| | - Tong Wu
- School of Pharmacy, Hangzhou Normal University, Hangzhou 311121, PR China; Key Laboratory of Elemene Class Anti-Cancer Chinese Medicines, Engineering Laboratory of Development and Application of Traditional Chinese Medicines, Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, School of Pharmacy, Hangzhou Normal University, Hangzhou 311121, PR China
| | - Qian Li
- School of Pharmacy, Hangzhou Normal University, Hangzhou 311121, PR China; Key Laboratory of Elemene Class Anti-Cancer Chinese Medicines, Engineering Laboratory of Development and Application of Traditional Chinese Medicines, Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, School of Pharmacy, Hangzhou Normal University, Hangzhou 311121, PR China
| | - Cunjie Chang
- School of Pharmacy, Hangzhou Normal University, Hangzhou 311121, PR China; Key Laboratory of Elemene Class Anti-Cancer Chinese Medicines, Engineering Laboratory of Development and Application of Traditional Chinese Medicines, Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, School of Pharmacy, Hangzhou Normal University, Hangzhou 311121, PR China.
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Hao B, Lin S, Liu H, Xu J, Chen L, Zheng T, Zhang W, Dang Y, Reiter RJ, Li C, Zhai H, Xia Q, Fan L. Baicalein tethers CD274/PD-L1 for autophagic degradation to boost antitumor immunity. Autophagy 2025; 21:917-933. [PMID: 39710370 PMCID: PMC12013432 DOI: 10.1080/15548627.2024.2439657] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2023] [Revised: 12/02/2024] [Accepted: 12/04/2024] [Indexed: 12/24/2024] Open
Abstract
Immune checkpoint inhibitors, especially those targeting CD274/PD-L1yield powerful clinical therapeutic efficacy. Thoughmuch progress has been made in the development of antibody-basedCD274 drugs, chemical compounds applied for CD274degradation remain largely unavailable. Herein,baicalein, a monomer of traditional Chinese medicine, isscreened and validated to target CD274 and induces itsmacroautophagic/autophagic degradation. Moreover, we demonstrate thatCD274 directly interacts with MAP1LC3B (microtubule associatedprotein 1 light chain 3 beta). Intriguingly, baicalein potentiatesCD274-LC3 interaction to facilitate autophagic-lysosomal degradationof CD274. Importantly, targeted CD274. degradation via baicaleininhibits tumor development by boosting T-cell-mediated antitumorimmunity. Thus, we elucidate a critical role of autophagy-lysosomalpathway in mediating CD274 degradation, and conceptually demonstratethat the design of a molecular "glue" that tethers the CD274-LC3interaction is an appealing strategy to develop CD274 inhibitors incancer therapy.Abbreviations: ATTECs: autophagy-tethering compounds; AUTACs: AUtophagy-TArgeting Chimeras; AUTOTACs: AUTOphagy-TArgeting Chimeras; AMPK: adenosine 5'-monophosphate (AMP)-activated protein kinase; BiFC: bimolecular fluorescence complementation; BafA1: bafilomycin A1; CD274/PD-L1/B7-H1: CD274 molecule; CQ: chloroquine; CGAS: cyclic GMP-AMP synthase; DAPI: 4'6-diamino-2-phenylindole; FITC: fluorescein isothiocyanate isomer; GFP: green fluorescent protein; GZMB: granzyme B; IHC: immunohistochemistry; ICB: immune checkpoint blockade; KO: knockout; KD: equilibrium dissociation constant; LYTAC: LYsosome-TArgeting Chimera; LIR: LC3-interacting region; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MST: microscale thermophoresis; NFAT: nuclear factor of activated T cells; NFKB/NF-kB: nuclear factor kappa B; NSCLC: non-small-cell lung cancer; PDCD1: programmed cell death 1; PROTACs: PROteolysis TArgeting Chimeras; PRF1: perforin 1; PE: phosphatidylethanolamine; PHA: phytohemagglutinin; PMA: phorbol 12-myristate 13-acetate; STAT: signal transducer and activator of transcription; SPR: surface plasmon resonance; TILs: tumor-infiltrating lymphocyte; TME: tumor microenvironment.
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Affiliation(s)
- Bingjie Hao
- Institute of Energy Metabolism and Health, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai, China
- Department of Respiratory Medicine, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai, China
| | - Shumeng Lin
- Institute of Energy Metabolism and Health, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai, China
- Department of Respiratory Medicine, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai, China
| | - Haipeng Liu
- Clinical Translational Research Center, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China
| | - Junfang Xu
- Clinical Translational Research Center, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China
| | - Li Chen
- Clinical Translational Research Center, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China
| | - Tiansheng Zheng
- Department of Respiratory Medicine, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai, China
| | - Wen Zhang
- Department of Respiratory Medicine, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai, China
| | - Yifang Dang
- Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China
| | - Russel J. Reiter
- Department of Cell Systems and Anatomy, University of Texas Health San Antonio, San Antonio, TX, USA
| | - Chaoqun Li
- Institute of Energy Metabolism and Health, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai, China
| | - Hong Zhai
- Department of Respiratory Medicine, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai, China
| | - Qing Xia
- Institute of Energy Metabolism and Health, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai, China
| | - Lihong Fan
- Institute of Energy Metabolism and Health, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai, China
- Department of Respiratory Medicine, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai, China
- Department of Respiratory Medicine, Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai Jiao Tong University, Shanghai, P.R. China
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Ning Y, Li H, Song Y, He Y, Liu S, Liu Y. Predictive value of CPS combined with inflammatory markers for pathological remission of locally advanced head and neck squamous cell carcinoma after adjuvant immunochemotherapy. Front Mol Biosci 2025; 12:1593742. [PMID: 40376264 PMCID: PMC12078134 DOI: 10.3389/fmolb.2025.1593742] [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: 03/14/2025] [Accepted: 04/17/2025] [Indexed: 05/18/2025] Open
Abstract
Objective To explore the predictive value of the combined positive score (CPS) and the neutrophil-to- platelet count ratio (NPR) for surgical pathological remission in patients with locally advanced head and neck squamous cell carcinoma (LAHNSCC) who have undergone neoadjuvant immunotherapy combined with chemotherapy (NICC). Method Patients with LAHNSCC who underwent NICC and surgery from May 2021 to September 2023 were retrospectively analyzed. CPS, NPR and other clinically relevant parameters were collected, which includes gender, age, tumor types, multiple cancer, differentiation, T staging, N staging, immunotherapy cycles and postoperative pathological remission degree. Result Patients with a higher CPS were significantly associated with a higher pathological complete response (PCR) of the primary site (PPCR) (P = 0.034) and a higher PCR of the lymph nodes (LPCR) (P = 0.085). Specifically, patients with a CPS of ≥20 demonstrated a higher rate of severe pathologic tumor response (PTR), with values of 80.8% compared to 66.7% and 50%. Notably, even patients with a CPS <1 had a relatively high severe PTR rate of 66.7%. Moreover, patients with NPR <0.024 exhibited a higher severe PTR, regardless of the CPS subgroups (P < 0.05). Conclusion Higher CPS can be considered a good predictor of higher PCR after NICC in patients with LAHNSCC. Patients with CPS <1 can still achieve a higher PTR. Patients with NPR <0.024 can help achieve a higher severe PTR in patients with LAHNSCC regardless of the CPS.CPS combined with NPR may have a better predicted value for surgical PTR of HNSCC after NICC.
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Affiliation(s)
| | | | | | | | | | - Yang Liu
- *Correspondence: Shaoyan Liu, ; Yang Liu,
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Huang YE, Zhou S, Chen S, Chen J, Zhou X, Hou F, Liu H, Yuan M, Jiang W. Mutational signature-based biomarker to predict the response of immune checkpoint inhibitors therapy in cancers. Int J Biol Macromol 2025; 308:142585. [PMID: 40154701 DOI: 10.1016/j.ijbiomac.2025.142585] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2024] [Revised: 03/23/2025] [Accepted: 03/25/2025] [Indexed: 04/01/2025]
Abstract
Patients have a limited response rate to immune checkpoint inhibitors (ICIs) therapy. Although several biomarkers have been proposed, their ability to accurately predict the response to ICIs therapy remains unsatisfactory. In addition, mutational signatures were validated to be associated with ICIs therapy. Therefore, we developed a mutational signature-based biomarker (MS-bio) to predict the response to ICIs therapy. Based on differentially mutated genes, we extracted six mutational signatures (single-base substitution (SBS)-A, SBS-B, SBS-C, SBS-D, double-base substitution (DBS)-A, and DBS-B) as MS-bio, and constructed a random forest (RF) model to predict the response. Internal and external validations consistently demonstrated the excellent predictive capability of MS-bio, with an accuracy reaching up to 0.82. Moreover, MS-bio exhibited superior performance compared to existing biomarkers. To further validate the accuracy of MS-bio, we explored its performance in The Cancer Genome Atlas (TCGA) cohort and found that the predicted responders were immunologically "hot". Finally, we found that SBS-C had the highest importance in prediction and was related to T cell differentiation. Overall, here we introduced MS-bio as a novel biomarker for accurately predicting the response to ICIs therapy, thereby contributing to the advancement of precision medicine.
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Affiliation(s)
- Yu-E Huang
- Fujian Provincial Key Laboratory of Precision Medicine for Cancer, the First Affiliated Hospital, Fujian Medical University, Fuzhou 350005, China; National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou 350212, China; Guizhou Institute of Precision Medicine, the Affiliated Hospital of Guizhou Medical University, Guiyang 550004, China; Department of Biomedical Engineering, Nanjing University of Aeronautics and Astronautics, Nanjing 211106, China
| | - Shunheng Zhou
- School of Computer Sciences, University of South China, Hengyang 421001, China
| | - Sina Chen
- Department of Biomedical Engineering, Nanjing University of Aeronautics and Astronautics, Nanjing 211106, China
| | - Jiahao Chen
- Fujian Provincial Key Laboratory of Precision Medicine for Cancer, the First Affiliated Hospital, Fujian Medical University, Fuzhou 350005, China
| | - Xu Zhou
- Department of Biomedical Engineering, Nanjing University of Aeronautics and Astronautics, Nanjing 211106, China
| | - Fei Hou
- Department of Biomedical Engineering, Nanjing University of Aeronautics and Astronautics, Nanjing 211106, China
| | - Haizhou Liu
- Fujian Provincial Key Laboratory of Precision Medicine for Cancer, the First Affiliated Hospital, Fujian Medical University, Fuzhou 350005, China; National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou 350212, China
| | - Mengqin Yuan
- Department of Biomedical Engineering, Nanjing University of Aeronautics and Astronautics, Nanjing 211106, China
| | - Wei Jiang
- Fujian Provincial Key Laboratory of Precision Medicine for Cancer, the First Affiliated Hospital, Fujian Medical University, Fuzhou 350005, China; National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou 350212, China.
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Nakatsukasa T, Muraoka D, Deng S, Yasui K, Sawada SI, Shimoda A, Matsushita H, Matsumoto K, Nagayasu T, Harada N, Akiyoshi K, Ikeda H. Antitumor immune response elicited by M2 TAM-specific DDS via C-type lectin CD209b using cholesteryl pullulan nanogel as a protein drug carrier. Biomater Sci 2025; 13:2340-2350. [PMID: 40094910 DOI: 10.1039/d5bm00342c] [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: 03/19/2025]
Abstract
Many cancer patients develop resistance to immunotherapy, highlighting the urgent need for novel therapeutic strategies. Various factors contribute to tumor resistance to immunotherapy, among which tumor-associated macrophages (TAMs) are critical regulators of tumor sensitivity. Therefore, combining cancer immunotherapies with drug delivery systems (DDSs) targeting TAMs has become an intriguing treatment strategy. However, the target molecules used in DDSs are limited to a few receptors expressed on TAMs. Therefore, the identification of novel target molecules for TAM-specific DDS is urgently needed. The current study evaluated the ability of a cholesteryl pullulan (CHP) nanogel to target TAMs via mDC-SIGN (CD209b). This nanogel encapsulated the cytotoxic protein drug Pseudomonas exotoxin A and was injected into a tumor-bearing mouse model. This treatment significantly reduced the abundance of CD209b-positive M2 TAMs and enhanced antitumor immune responses. Ultimately, tumor growth was suppressed, even in a low-immunogenic tumor model. Hence, CD209b is an effective target molecule for M2 TAM-specific DDSs that can be used to develop novel cancer therapies.
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Affiliation(s)
- Takaaki Nakatsukasa
- Department of Oncology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki 852-8523, Japan.
- Department of Surgical Oncology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki 852-8501, Japan
| | - Daisuke Muraoka
- Department of Oncology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki 852-8523, Japan.
- Division of Translational Oncoimmunology, Aichi Cancer Center Research Institute, Nagoya 464-8681, Japan.
| | - Situo Deng
- Department of Oncology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki 852-8523, Japan.
| | - Kiyoshi Yasui
- Department of Oncology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki 852-8523, Japan.
| | - Shin-Ichi Sawada
- Synergy Institute for Futuristic Mucosal Vaccine Research and Development (cSIMVa), Chiba University, Chiba 260-8670, Japan
| | - Asako Shimoda
- Department of Immunology, Graduate School of Medicine, Kyoto University, Yoshida-Konoe-cho, Sakyo-ku, Kyoto, 606-8501, Japan
- The Hakubi Center for Advanced Research, Kyoto University, Kyoto, Japan
| | - Hirokazu Matsushita
- Division of Translational Oncoimmunology, Aichi Cancer Center Research Institute, Nagoya 464-8681, Japan.
| | - Keitaro Matsumoto
- Department of Surgical Oncology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki 852-8501, Japan
| | - Takeshi Nagayasu
- Department of Surgical Oncology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki 852-8501, Japan
| | | | - Kazunari Akiyoshi
- Department of Immunology, Graduate School of Medicine, Kyoto University, Yoshida-Konoe-cho, Sakyo-ku, Kyoto, 606-8501, Japan
| | - Hiroaki Ikeda
- Department of Oncology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki 852-8523, Japan.
- Leading Medical Research Core Unit, Nagasaki University Graduate School of Biomedical Science, Nagasaki 852-8523, Japan
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Bess SN, Smart GK, Muldoon TJ. Quantifying treatment response to a macrophage-targeted therapy in combination with immune checkpoint inhibitors after exposure to conventional chemotherapy. Front Immunol 2025; 16:1565953. [PMID: 40356923 PMCID: PMC12066502 DOI: 10.3389/fimmu.2025.1565953] [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: 01/24/2025] [Accepted: 04/04/2025] [Indexed: 05/15/2025] Open
Abstract
Background Conventional chemotherapeutic agents, such as 5-fluorouracil (5-FU), can exert anti-tumor effects through immunogenic cell death (ICD) induction. Researchers have found hallmarks that quantify ICD (such as the translocation of HMGB1 and calreticulin). Although chemotherapeutic agents can induce ICD, they increase the expression of immune checkpoints, limiting their effectiveness. Studies have emphasized the importance of investigating the heterogeneous responses of cells co-localized in a solid tumor (macrophages, tumor cells, etc.) to ICD induction. However, these studies were performed in vivo, which limits the collection of information on cell-cell interactions due to model complexity. Methods In this study, we used a multicellular spheroid model in conjunction with single spheroid imaging to understand the structural and metabolic changes of a simulated solid tumor model. In addition to using the spheroid model, conventional 2D co-culture monolayers were used to quantify ICD hallmarks and changes in macrophage functional behavior while correlating immune responses after exposure to the combinatory regimen of immune checkpoint inhibitors and an ICD inducer. Results Results indicate that the combination of two immune checkpoint inhibitors in addition to a chemotherapy agent reduced spheroid growth (~46%) and reduced M2 macrophage expression and cellular proliferation while modulating cellular metabolism, ICD hallmarks, and phagocytic function. Conclusions Overall, this study not only quantified microregional metabolic and structural changes in a simulated spheroid model but also quantified changes in ICD hallmarks and macrophage functional behavior. It was also found that correlations between spheroid structure and ICD hallmarks through immunofluorescence markers could exist after exposure to the combinatory regimen of immune checkpoint inhibitors and an ICD inducer.
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Affiliation(s)
| | | | - Timothy J. Muldoon
- Department of Biomedical Engineering, University of Arkansas,
Fayetteville, AR, United States
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50
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Liu R, Jiang X, Dong R, Zhang Y, Gai C, Wei P. Revealing the mechanisms and therapeutic potential of immune checkpoint proteins across diverse protein families. Front Immunol 2025; 16:1499663. [PMID: 40356928 PMCID: PMC12066663 DOI: 10.3389/fimmu.2025.1499663] [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: 09/21/2024] [Accepted: 03/28/2025] [Indexed: 05/15/2025] Open
Abstract
Host immune responses to antigens are tightly regulated through the activation and inhibition of synergistic signaling networks that maintain homeostasis. Stimulatory checkpoint molecules initiate attacks on infected or tumor cells, while inhibitory molecules halt the immune response to prevent overreaction and self-injury. Multiple immune checkpoint proteins are grouped into families based on common structural domains or origins, yet the variability within and between these families remains largely unexplored. In this review, we discuss the current understanding of the mechanisms underlying the co-suppressive functions of CTLA-4, PD-1, and other prominent immune checkpoint pathways. Additionally, we examine the IgSF, PVR, TIM, SIRP, and TNF families, including key members such as TIGIT, LAG-3, VISTA, TIM-3, SIRPα, and OX40. We also highlight the unique dual role of VISTA and SIRPα in modulating immune responses under specific conditions, and explore potential immunotherapeutic pathways tailored to the distinct characteristics of different immune checkpoint proteins. These insights into the unique advantages of checkpoint proteins provide new directions for drug discovery, emphasizing that emerging immune checkpoint molecules could serve as targets for novel therapies in cancer, autoimmune diseases, infectious diseases, and transplant rejection.
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Affiliation(s)
| | | | | | | | - Cong Gai
- School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China
| | - Peng Wei
- School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China
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