Cholesterol esterification blockade boosts immunotherapy and reduces liver cancer relapse

Liver cancer recurrence after resection and transplantation remains a major clinical challenge, with limited therapeutic targets to effectively prevent or manage relapse. In this study, we integrated differential proteomic analysis of human liver cancer samples, with or without subsequent recurrence, and T cell killing assays to uncover a pivotal role of the cholesterol esterification enzyme SOAT1 in promoting immune evasion and driving recurrence. Genetic knockout or pharmacological inhibition of SOAT1 markedly sensitized both mouse and human liver cancer cells to immune surveillance and T cell-mediated killing. Mechanistic studies revealed that inhibiting SOAT1 disrupts cholesterol biosynthesis, impairing cancer cells antioxidant capacity and metabolic resilience under immune attack. Importantly, SOAT1 inhibition effectively suppressed tumor immune escape and enhanced the efficacy of anti-PD1 and CAR-T cell therapies, even in immunosuppressive conditions. These findings underscore the critical role of cholesterol esterification in driving redox resilience under immunosurveillance and highlight SOAT1 as a promising target to prevent cancer relapse and improve immunotherapy outcomes.