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Peer-reviewedCC BY-NC-ND 4.0Molecular Cancer

T cell exhaustion in cancer: from functional decline to adaptive immune regulation

  • Yanyang Wang1
  • Yang Yu2,3
  • Jing Zhuang1,2,3,4
  • Ruijuan Liu1,3,4
  • Changgang Sun1,2,3,4
4 affiliations
  1. 1College of First Clinical Medicine, Shandong University of Traditional Chinese Medicine, Jinan, China
  2. 2Faculty of Chinese Medicine, State Key Laboratory of Quality Research in Chinese Medicines, Macau University of Science and Technology, Macau, China
  3. 3College of Traditional Chinese Medicine, Shandong Second Medical University, Weifang, China
  4. 4Department of Oncology, Weifang Traditional Chinese Hospital, Weifang, China
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Abstract

T cell exhaustion has traditionally been defined as a state of progressive functional impairment and specific epigenetic remodeling induced by chronic antigen stimulation. However, emerging multidisciplinary evidence indicates that exhaustion is not merely a terminal stage of functional failure; rather, it represents an evolutionarily conserved adaptive program designed to balance long-term immune surveillance with the limitation of excessive pathological damage. This review focuses on the positive regulatory roles of T cell exhaustion within the tumor microenvironment. It elucidates how the exhausted state avoids lethal inflammation by restraining excessive activation while preserving a durable progenitor pool, thereby ultimately establishing a homeostatic balance between sustained tumor control and host survival. Overall, a comprehensive understanding of the evolutionary principles underlying this adaptive program provides important guidance for the design of precision immunotherapies that balance efficacy and safety. Strategically targeting and harnessing these protective features may greatly optimize the clinical benefits of solid tumor treatment and guide the development of next-generation innovative immunotherapies.

Graphical Abstract:

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Cite

BibTeXRIS
BibTeX
@article{wang2026cell,
  title = {{T cell exhaustion in cancer: from functional decline to adaptive immune regulation}},
  author = {Yanyang Wang and Yang Yu and Jing Zhuang and Ruijuan Liu and Changgang Sun},
  journal = {Molecular Cancer},
  year = {2026},
  month = aug,
  doi = {10.1186/s12943-026-02767-7},
  url = {https://doi.org/10.1186/s12943-026-02767-7},
  note = {CC BY-NC-ND 4.0},
}
RIS
TY  - JOUR
TI  - T cell exhaustion in cancer: from functional decline to adaptive immune regulation
AU  - Yanyang Wang
AU  - Yang Yu
AU  - Jing Zhuang
AU  - Ruijuan Liu
AU  - Changgang Sun
PY  - 2026
DA  - 2026/08/06
JO  - Molecular Cancer
DO  - 10.1186/s12943-026-02767-7
UR  - https://doi.org/10.1186/s12943-026-02767-7
AB  - T cell exhaustion has traditionally been defined as a state of progressive functional impairment and specific epigenetic remodeling induced by chronic antigen stimulation. However, emerging multidisciplinary evidence indicates that exhaustion is not merely a terminal stage of functional failure; rather, it represents an evolutionarily conserved adaptive program designed to balance long-term immune surveillance with the limitation of excessive pathological damage. This review focuses on the positive regulatory roles of T cell exhaustion within the tumor microenvironment. It elucidates how the exhausted state avoids lethal inflammation by restraining excessive activation while preserving a durable progenitor pool, thereby ultimately establishing a homeostatic balance between sustained tumor control and host survival. Overall, a comprehensive understanding of the evolutionary principles underlying this adaptive program provides important guidance for the design of precision immunotherapies that balance efficacy and safety. Strategically targeting and harnessing these protective features may greatly optimize the clinical benefits of solid tumor treatment and guide the development of next-generation innovative immunotherapies.  Graphical Abstract:
SN  - 1476-4598
ER  -