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Obesity is a major cancer risk factor, but how differences in systemic metabolism change the tumor microenvironment (TME) and impact anti-tumor immunity is not understood. Here, we demonstrate that high-fat diet (HFD)-induced obesity impairs CD8 + T cell function in the murine TME, accelerating tumor growth. We generate a single-cell resolution atlas of cellular metabolism in the TME, detailing how it changes with diet-induced obesity. We find that tumor and CD8 + T cells display distinct metabolic adaptations to obesity. Tumor cells increase fat uptake with HFD, whereas tumor-infiltrating CD8 + T cells do not. These differential adaptations lead to altered fatty acid partitioning in HFD tumors, impairing CD8 + T cell infiltration and function. Blocking metabolic reprogramming by tumor cells in obese mice improves anti-tumor immunity. Analysis of human cancers reveals similar transcriptional changes in CD8 + T cell markers, suggesting interventions that exploit metabolism to improve cancer immunotherapy.
Alison E Ringel,Jefte M Drijvers
Arlene H Sharpe,Marcia C Haigis
Alison E Ringel,Jefte M Drijvers,Gregory J Baker,Alessia Catozzi,Juan C García-Cañaveras,Brandon M Gassaway,Brian C Miller,Vikram R Juneja,Thao H Nguyen,Shakchhi Joshi,Cong-Hui Yao,Haejin Yoon,Peter T Sage,Martin W LaFleur,Justin D Trombley,Connor A Jacobson,Zoltan Maliga,Steven P Gygi,Peter K Sorger,Joshua D Rabinowitz,Arlene H Sharpe,Marcia C Haigis