Lipid droplets impair anti-tumor immunity by disrupting IFNGR1 trafficking via TGN diacylglycerol depletion

Lipid droplets (LDs) are dynamic organelles that regulate cellular metabolism, yet their role in tumor immune evasion remains unclear. Here, we demonstrate that LDs impair anti-tumor immunity by disrupting the membrane localization of interferon-gamma receptor 1 (IFNGR1). Tumor cells with reduced LD content exhibit heightened susceptibility to immune-mediated cytotoxicity in vitro, in murine immunotherapy models, and in patients undergoing immune checkpoint blockade. Mechanistically, IFNGR1 trafficking to the plasma membrane is dependent on diacylglycerol (DAG) in the trans-Golgi network (TGN). However, LDs sequester DAG, impeding IFNGR1 trafficking and attenuating JAK2-STAT1 signaling. Notably, genetic or pharmacological depletion of LDs enhances tumor sensitivity to anti-PD-1 therapy. These findings establish LDs as immunosuppressive organelles that compromise interferon signaling, highlighting their potential as therapeutic targets to improve cancer immunotherapy outcomes. Overall design: RNA-seq of HT29 shCTRL and shFITM2 colon cancer cells.