Targeting cholesterol esterification sensitizes liver cancer to CD8+ T cell attack by impairing metabolic and redox resilience.

Recurrence after tumor resection and liver transplantation remains a major clinical challenge in hepatocellular carcinoma (HCC). We examined tumor samples from HCC liver transplant patients to identify drivers of disease recurrence. Integration of proteomic profiling of human HCC samples with or without recurrence and T cell killing assays linked the cholesterol esterification enzyme SOAT1 to immune evasion and cancer recurrence. Genetic or pharmacological inhibition of SOAT1 sensitized liver cancer cells to CD8+ T cell-mediated immunosurveillance, anti-programmed cell death 1 (anti-PD-1) therapy, and chimeric antigen receptor (CAR)-T cell therapy and increased intratumoral CD8+ T cell infiltration. Mechanistically, the inhibition of SOAT1-mediated cholesterol esterification disrupted intratumoral cholesterol and lipid metabolism and reduced unsaturated fatty acids and prostaglandin E2 production; this impaired the antioxidant capacity and metabolic resilience of cancer cells under immune attack. Accordingly, SOAT1 inhibition enhanced immunotherapy efficacy in obesity-associated tumors and under immunosuppressant-induced conditions. Thus, cholesterol esterification supports redox fitness and cancer cell resilience upon immune attack, suggesting a strategy to prevent recurrence and improve immunotherapy outcomes.