2. Academic Validation
  3. An age-related decrease in leptin contributes to CD8+ T cell aging in the tumor microenvironment

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

  • Cell Rep Med. 2025 Aug 20:102310. doi: 10.1016/j.xcrm.2025.102310.
Feixiang Wang 1,  Rujuan Bao 2,  Shuiyu Xu 3,  Wenyan Li 4,  Haiyan Huang 3,  Runchang Li 5,  Xinyu Ding 2,  Yuerong Zhang 2,  Xiaoyan Yu 2,  Qiaoqiao Han 2,  Xian Du 2,  Jie Wan 2,  Song Li 2,  Yichuan Xiao 6,  Ren Zhao 3,  Xingang Cui 4,  Youqiong Ye 7,  Jiayuan Sun 8,  Junke Zheng 9,  Guo-Qiang Chen 10,  Qiang Zou 11
Affiliations

Affiliations

  • 1 Institute of Pediatric Infection, Immunity, and Critical Care Medicine, Shanghai Children's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200062, China; Shanghai Institute of Immunology, Department of Immunology and Microbiology, State Key Laboratory of Systems Medicine for Cancer, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
  • 2 Shanghai Institute of Immunology, Department of Immunology and Microbiology, State Key Laboratory of Systems Medicine for Cancer, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
  • 3 Department of General Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
  • 4 Department of Urology, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China.
  • 5 Department of Respiratory Endoscopy, Department of Respiratory and Critical Care Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200030, China.
  • 6 CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
  • 7 Shanghai Institute of Immunology, Department of Immunology and Microbiology, State Key Laboratory of Systems Medicine for Cancer, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China. Electronic address: youqiong.ye@shsmu.edu.cn.
  • 8 Department of Respiratory Endoscopy, Department of Respiratory and Critical Care Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200030, China. Electronic address: xkyyjysun@163.com.
  • 9 Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Faculty of Basic Medicine, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China. Electronic address: zhengjunke@shsmu.edu.cn.
  • 10 Institute of Aging & Tissue Regeneration, Stress and Cancer Research Unit of Chinese Academy of Medical Sciences, State Key Laboratory of Systems Medicine for Cancer, Ren-Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China; School of Basic Medicine and Life Science, Hainan Academy of Medical Sciences, Hainan Medical University, Haikou, Hainan 571199, China. Electronic address: chengq@shsmu.edu.cn.
  • 11 Shanghai Institute of Immunology, Department of Immunology and Microbiology, State Key Laboratory of Systems Medicine for Cancer, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China. Electronic address: qzou1984@sjtu.edu.cn.
PMID: 40858107 DOI: 10.1016/j.xcrm.2025.102310
Abstract

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.

Keywords

CD8(+) T cells; T cell senescence; aging; antitumor immunity; leptin.

Figures
Products
Inhibitors & Agonists