An age-related decrease in leptin contributes to CD8+ T cell aging in the tumor microenvironment
T cell dysfunction with age underlies an increased incidence of cancer in elderly individuals; however, how T cell aging is triggered in the tumor microenvironment is unclear. Here, we show that an age-associated reduction in adipocyte-derived leptin contributes to the accumulation of tumor-infiltrating senescent CD8<sup>+</sup> T cells. Single-cell profiling of human and mouse cancer tissues reveals that the frequency of intratumoral senescent CD8<sup>+</sup> T cells increases with age, leading to a weak antitumor effect. Moreover, decreased levels of adipocyte-derived leptin are an indispensable factor for CD8<sup>+</sup> T cell aging. Leptin signaling prevents p38-dependent CD8<sup>+</sup> T cell senescence. Furthermore, plasma leptin levels are negatively related to intratumoral CD8<sup>+</sup> T cell senescence in cancer patients. Our findings identify an unappreciated interplay between metabolic perturbation and T cell aging and suggest that modulating adipocyte-derived leptin levels may be a promising therapeutic strategy for older cancer patients.
Authors
- Rujuan Bao (ORCID: https://orcid.org/0009-0000-5011-9542)
- Youqiong Ye (ORCID: https://orcid.org/0000-0001-8332-4710)
- Runchang Li
- Shuiyu Xu
- Haiyan Huang (ORCID: https://orcid.org/0000-0002-9903-5160)
- Junke Zheng (ORCID: https://orcid.org/0000-0002-7023-2400)
- Jiayuan Sun (ORCID: https://orcid.org/0000-0003-3158-3256)
- Qiaoqiao Han
- Yichuan Xiao (ORCID: https://orcid.org/0000-0001-7804-6971)
- Qiang Zou (ORCID: https://orcid.org/0000-0002-1362-2007)
- Hang Li (ORCID: https://orcid.org/0000-0002-8486-6631)
- Feixiang Wang (ORCID: https://orcid.org/0000-0003-3791-1695)
- Yuerong Zhang (ORCID: https://orcid.org/0000-0002-6699-375X)
- Ren Zhao (ORCID: https://orcid.org/0000-0002-2331-0007)
- Jie Wan (ORCID: https://orcid.org/0000-0003-1539-3284)
- Xian Du
- Guoqiang Chen (ORCID: https://orcid.org/0000-0003-4936-2363)
- Xingang Cui
- Wenyan Li (ORCID: https://orcid.org/0000-0002-7229-2466)
- Xinyu Ding (ORCID: https://orcid.org/0009-0006-3012-9579)
- Xiaoyan Yu (ORCID: https://orcid.org/0000-0002-0748-3522)
Institutions
- Shanghai Jiao Tong University (CN)
- XinHua Hospital (CN)
- Ruijin Hospital (CN)
- Shanghai Chest Hospital (CN)
- Shanghai Institute of Nutrition and Health (CN)
- Shanghai Cancer Institute (CN)
- Ministry of Education (TH)
- Shanghai Children's Hospital (CN)
- University of Chinese Academy of Sciences (CN)
- Hainan Medical University (CN)
Publication Details
- Journal
- Cell Reports Medicine
- Published
- 2025-08-25
- DOI
- https://doi.org/10.1016/j.xcrm.2025.102310
- Citations
- 3
- Primary Topic
- MicroRNA in disease regulation
- Type
- article
- Field-Weighted Citation Impact
- 2.81
Funders
- National Natural Science Foundation of China
- Science and Technology Commission of Shanghai Municipality
- National Key Research and Development Program of China