Summary T cell metabolic fitness plays a pivotal role in anti-tumor immunity and metabolic deregulation causes T cell dysfunction (i.e., ‘exhaustion’) in cancer. We identify that the scavenger receptor CD36 limits anti-tumor CD8 + T cell effector functions through lipid peroxidation. In murine tumors, oxidized phospholipids (OxPLs) were highly abundant and CD8 + TILs increased uptake and accumulation of lipids and lipid peroxidation. Functionally ‘exhausted’ CD8 + TILs substantially increased CD36 expression and CD36-deficient CD8 + TILs had more robust anti-tumor activity and cytokine production than wild-type cells. We further show that CD36 promotes uptake of oxidized low-density lipoproteins (OxLDL) and induces lipid peroxidation in CD8 + TILs, and OxLDL inhibits CD8 + T cell functions in a CD36-dependent manner. Moreover, glutathione peroxidase 4 (GPX4) over-expression lowers lipid peroxidation and restores functionalities in CD8 + TILs. These results define a key role for an oxidized lipid-CD36 axis in promoting intratumoral CD8 + T cell dysfunction.

Oxidized Lipids and CD36-Mediated Lipid Peroxidation in CD8 T Cells Suppress Anti-Tumor Immune Responses