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, * and Marcia C. Haigis
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.