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

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE289818 | GEO | 2025/03/01

REPOSITORIES: GEO

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