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.