Chunyan Yu, Xin Li, Xiaolong Qian, Haoke Zhang, Xueying Li, Bo Wang, Mantong Li, Zixuan Liu, Wei Du, Siqi Chen, Yuqing Ouyang, Xiaofan Feng, Tianhui He, Zihe Liu, Haixia Wu, Xiaoyan Zheng, Junru Liu, Hong Zhang, Yuanming Song, Chenying Liu, Jiazhen Li, Hongyan Guo, Shiwen Xu, Xiaojing Guo, Weimin Deng
T cell senescence significantly impairs the efficacy of immune checkpoint blockade (ICB) therapy in cancer. Metabolic reprogramming is a crucial factor in T cell senescence in tumor microenvironment (TME). Ovarian cancer (OvCa) patients derive limited benefit from ICB treatment, probably related to T cell senescence. OvCa cells metastasize to the abdominal cavity rich in omental fat and raise ascites, forming a unique TME, adipocyte-rich TME. In this study, we investigated the effects of adipocyte-rich TME on T cell senescence. Using the single-cell RNA sequencing of OvCa and clinical samples, we found that adipocyte-rich TME is strongly associated with the formation of senescence CD8 + T (CD8 + Tsen) cells. Mechanistically, adipocyte-derived factors (MATES) and oleic acid (OA)-the predominant fatty acid in OvCa ascites-promoted tumor-induced CD8 + Tsen formation by enhancing fatty acid (FA) uptake via FABP4, triggering lipid peroxidation rather than energy production. Inhibition of FABP4 (using the inhibitor BMS309403 or siRNA knockdown) blocked CD8 + Tsen cell formation, reduced lipid peroxidation, restored CD8 + T cell effector function, and suppressed immunosuppressive cytokines. Moreover, using an OvCa mouse model, we found that in OvCa mice BMS309403 treatment partially diminished CD8 + Tsen formation by reducing FA uptake, and improved anti-tumor immunity, and prolonged the survival time of OvCa mice when combined with chemotherapy. Our work suggests FABP4 -mediated FA metabolism as a therapeutic target to counteract T cell senescence in adipocyte-rich TME, providing a novel immunotherapeutic strategy for OvCa.