Mogat1 drives metabolic adaptations to evade immune surveillance

Using an unbiased genome-wide in vivo natural selection screen, we identified the uncharacterized role of monoacylglycerol O-acyltransferase 1 (Mogat1) as a key modulator of tumor immune evasion. As tumors progress and expand, they undergo systemic metabolic adaptation to evade immune surveillance. Tumor cells use Mogat1 to sequester excess fatty acids into triglycerides, coordinating metabolic reprogramming while promoting tumor growth and creating an immunosuppressive microenvironment. Mogat1 inhibition inhibits tumor growth by promoting T cell infiltration and cytotoxicity. Notably, the loss of Mogat1 contributes to the circumvention of PD-1 checkpoint blocking resistance. This enhanced inflammatory response, characterized by increased interferon sensitivity, circumvents the need for routine antigen presentation. Our findings reveal a novel lipid metabolism-centered immune evasion mechanism, providing a potential strategy for improving the efficacy of cancer immunotherapy.