Cancer-associated adipocytes mediate CD8+T cell dysfunction via FGF21-driven lipolysis

作者：Sumiya Dalangood, Cegui Hu, Chenwei Yuan, Xiang Li, Wen Qiao, Hanjun Li, Rongyu Zhang, Luying Li, Li Peng, Xiang Yu, Wenjin Yin, Jinsong Lu, Jun Gui · 发表于：Cell Reports · 年份：2025 · DOI：10.1016/j.celrep.2025.116526 · 被引用次数：8 · 研究领域：Adipokines, Inflammation, and Metabolic Diseases、Adipose Tissue and Metabolism、Fibroblast Growth Factor Research

Cancer-associated adipocytes (CAAs) reprogram the metabolic status of the tumor microenvironment (TME). The metabolic crosstalk between CAAs and CD8 + T cells in the TME remains unclear. Here, we report that CAAs undergo lipolysis, releasing free fatty acids that promote lipid peroxidation and disturb mitochondrial homeostasis in CD8 + T cells, leading to their functional exhaustion. Importantly, we uncover that fibroblast growth factor 21 (FGF21) drives CAA lipolysis in an autocrine manner by upregulating adipose triglyceride lipase (ATGL) via FGFR1/KLB-p38 signaling. FGF21 deletion in adipose tissue or ATGL inhibition impedes CAA lipolysis, mitigates lipid peroxidation, normalizes mitochondrial dynamics of CD8 + T cells, and restores their effector function, consequently blunting tumor growth. Moreover, FGF21 deficiency or ATGL inhibition enhances the anti-tumor activity of CD8 + T cells in response to anti-PD-1 treatment, yielding greater therapeutic efficacy. Our findings highlight the pivotal role of CAA lipolysis in CD8 + T cell dysfunction within the TME, suggesting that targeting CAA lipolysis represents a valuable avenue for improving cancer immunotherapy.