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
  • 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: [email protected].
  • 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: [email protected].
  • 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: [email protected].
  • 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: [email protected].
  • 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: [email protected].
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.
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