REVIEW article
Front. Immunol.
Sec. Cancer Immunity and Immunotherapy
Volume 16 - 2025 | doi: 10.3389/fimmu.2025.1656733
Senescent Immune Cells in the Tumor Microenvironment: Emerging Insights into Cancer Immunotherapy Resistance
Provisionally accepted- 1Sheng Jing Hospital Affiliated, China Medical University, Shenyang, China
- 2New York University, New York, United States
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Cancer remains a leading cause of mortality worldwide, with rising incidence and death rates continuing to rise. While conventional treatments such as surgery, radiotherapy, and chemotherapy form the backbone of cancer care, they are often limited by adverse effects, recurrence risk, and incomplete tumor eradication. Tumor immunotherapy—particularly immune checkpoint inhibitors and chimeric antigen receptor (CAR) T cell therapy—has emerged as a transformative approach by activating and reprogramming anti-tumor immune responses. Despite these advances, significant challenges persist, including limited response rates to checkpoint inhibitors, the immunosuppressive nature of the tumor microenvironment (TME), and resistance mechanisms employed by tumor cells. Growing evidence suggests that immune cell senescence is a critical contributor to TME-driven immunosuppression. Senescent immune cells exhibit functional decline, elevated expression of inhibitory immune checkpoint molecules, and increased secretion of pro-inflammatory cytokines, collectively impairing anti-tumor immunity and reducing the efficacy of immunotherapy. This review highlights the role of immune cell senescence in shaping the immunosuppressive TME and driving resistance to immunotherapy. It further discusses emerging therapeutic strategies that combine immunotherapy with senescence-targeting interventions, aiming to provide novel insights into the development of more effective cancer treatment strategies.
Keywords: Tumor Microenvironment, immune cell senescence, Immunosuppression, Cancerimmunotherapy, Anti-aging therapy, cancer treatment strategies
Received: 30 Jun 2025; Accepted: 01 Oct 2025.
Copyright: © 2025 Gao, Kan, He, Sun, Tang and Yang. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence:
Siyu Sun, sunsy@sj-hospital.org
Lei Tang, tangl@sj-hospital.org
Fan Yang, yangfan@cmu.edu.cn
Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.