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bioRxiv · 10.1101/2024.10.18.618991

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

Dalangood, S.·Hu, C.·Yuan, C.·Li, X.·Qiao, W.·Li, H.·Zhang, R.·Li, L.·Li, P.·Yu, X.·Yin, W.·Lu, J.·Gui, J.
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Abstract

Cancer-associated adipocytes (CAAs) reprogram metabolic status of tumor microenvironment (TME). The metabolic crosstalk between CAAs and CD8+T cells in 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) autocrinally drives CAA lipolysis through 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, combining ATGL inhibitor with anti-PD-1 therapy synergistically enhances the antitumor activity of CD8+T cells, yielding greater therapeutic efficacy. Our findings highlight the pivotal role of CAA lipol ysis in CD8+T cell dysfunction within TME, suggesting that targeting CAA lipolysis represents a valuable avenue for improving cancer immunotherapy.

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Dalangood, S., Hu, C., Yuan, C., Li, X., Qiao, W., Li, H., Zhang, R., Li, L., Li, P., Yu, X., Yin, W., Lu, J., Gui, J.. 2024-10-21. Cancer-associated adipocytes mediate CD8+T cell dysfunction via FGF21-driven lipolysis. https://doi.org/10.1101/2024.10.18.618991

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