Mogat1 drives metabolic adaptations to evade immune surveillance

Despite immune checkpoint blockades have achieved remarkable success, most patients with solid tumors do not respond or develop resistance, suggesting additional treatment strategies are needed. Concentrated efforts are directed toward revitalizing the IFN? pathway or amplifying antigen presentation capabilities, alternative mechanisms underlying immune evasion remain poorly understood. Using an unbiased whole-genome in vivo natural selection screen, we identified an uncharacterized role of Monoacylglycerol O-Acyltransferase 1 (Mogat1) as a critical modulator of tumor immune evasion. As tumors progress and expand, they undergo systemic metabolic adaptations to evade immune surveillance. Tumor cells exploit Mogat1 to sequester excess fatty acids into triglycerides, orchestrating metabolic reprogramming that simultaneously fuels tumor growth and creates an immunosuppressive microenvironment. Mogat1 inhibition suppresses tumor growth by promoting T-cell infiltration and cytotoxicity. Remarkably, Mogat1 loss facilitates the circumvention of PD-1 checkpoint blockade resistance. This heightened inflammatory response, characterized by increased interferon sensitivity, circumvents the need for conventional antigen presentation. Our findings reveal a novel lipid metabolism-centered mechanism of immune evasion and offer a potential strategy to enhance cancer immunotherapy efficacy. Overall design: To unveil the molecular underpinnings of tumor immune evasion and growth, we performed RNA sequencing on tumor cells or CD8T cells isolated at early (2 weeks), middle (3 weeks), and late (4 weeks) stages of tumor development in our MMTV-PyMT model.What's more,to elucidate the molecular mechanisms underlying Mogat1's effects, we performed RNA-seq on MMTV-PyMT cells or CD8T cells isolated from shCTRL and shMogat1 xenografts.