Highlights d CD8 + T cell exhaustion is correlated with a high cholesterol level d Tumor microenvironment is enriched with cholesterol d Cholesterol in the tumor microenvironment induces CD8 + T cell exhaustion d ER stress-XBP1 pathway is required for cholesterol-induced CD8 + T cell exhaustion

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Tumor-associated macrophages (TAM) are important tumorpromoting cells. However, the mechanisms underlying how the tumor and its microenvironment reprogram these cells remain elusive. Here we report that lipids play a crucial role in generating TAMs in the tumor microenvironment (TME). Macrophages from both human and murine tumor tissues were enriched with lipids due to increased lipid uptake by macrophages. TAMs expressed elevated levels of the scavenger receptor CD36, accumulated lipids, and used fatty acid oxidation (FAO) instead of glycolysis for energy. High levels of FAO promoted mitochondrial oxidative phosphorylation, production of reactive oxygen species, phosphorylation of JAK1, and dephosphorylation of SHP1, leading to STAT6 activation and transcription of genes that regulate TAM generation and function. These processes were critical for TAM polarization and activity, both in vitro and in vivo. In summary, we highlight the importance of lipid metabolism in the differentiation and function of protumor TAMs in the TME.Significance: This study highlights the role of lipid metabolism in the differentiation and function of TAMs and suggests targeting TAM fatty acid oxidation as a potential therapeutic modality for human cancers. MiceC57BL/6J, CD36 À/À , and NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ (NSG) mice were purchased from The Jackson Laboratory. C57BL/ KaLwRij mice were purchased from Envigo. Mice were maintained in a temperature-and humidity-controlled environment and given unrestricted access to chow diet and acidified water. Detailed methods

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