An age-related decrease in leptin contributes to CD8+ T cell aging in the tumor microenvironment

作者：Feixiang Wang, Rujuan Bao, Shuiyu Xu, Wenyan Li, Haiyan Huang, Runchang Li, Xinyu Ding, Yuerong Zhang, Xiaoyan Yu, Qiaoqiao Han, Xian Du, Jie Wan, Hang Li, Yichuan Xiao, Ren Zhao, Xingang Cui, Youqiong Ye, Jiayuan Sun, Junke Zheng, Guoqiang Chen, Qiang Zou · 发表于：Cell Reports Medicine · 年份：2025 · DOI：10.1016/j.xcrm.2025.102310 · 被引用次数：5 · 研究领域：MicroRNA in disease regulation、Single-cell and spatial transcriptomics、Adipokines, Inflammation, and Metabolic Diseases

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 + T cells. Single-cell profiling of human and mouse cancer tissues reveals that the frequency of intratumoral senescent CD8 + T cells increases with age, leading to a weak antitumor effect. Moreover, decreased levels of adipocyte-derived leptin are an indispensable factor for CD8 + T cell aging. Leptin signaling prevents p38-dependent CD8 + T cell senescence. Furthermore, plasma leptin levels are negatively related to intratumoral CD8 + 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.