Lipid droplets control anti-tumor immunity by depleting Golgi DAG and blocking IFNGR1 surface trafficking

Resistance to anti-PD-1 therapy remains a major challenge in colorectal cancer (CRC), particularly in microsatellite-stable tumors, yet the underlying mechanisms are incompletely understood. Here, we identify tumor lipid droplets (LDs) as a driver of immune evasion and anti-PD-1 resistance. In CRC patients receiving anti-PD-1 therapy, progressive disease correlates with high tumor LD content and reduced plasma membrane IFNGR1. Mechanistically, fat storage-inducing transmembrane protein 2 (FITM2)-driven LD biogenesis preferentially depletes trans-Golgi network (TGN) diacylglycerol (DAG) without altering total cellular DAG or other TGN lipids, thereby impairing IFNGR1 vesicular trafficking to the plasma membrane and attenuating JAK2-STAT1 signaling. Genetic (FITM2 knockdown) or pharmacological (DGAT1 inhibitor A922500) LD reduction restores TGN DAG pools, rescues IFNGR1 surface localization, reactivates IFN-γ signaling, and synergizes with anti-PD-1 therapy in orthotopic CRC models. These findings define LD-driven TGN DAG depletion as a mechanistic link between lipid metabolism and immunotherapy resistance and nominate LD biogenesis targeting as a strategy to overcome anti-PD-1 resistance.