Cholesterol esterification blockade boosts immunotherapy and reduces liver cancer relapse
Gu, y.; Zhang, l.; Xu, c.; Wang, z.; Wang, g.
Show abstract
Recurrence after liver cancer resection and transplantation remains a critical clinical challenge, driven by immune evasion. However, effective immune-sensitizing targets for preventing or managing relapse remain limited. In this study, we integrated differential proteomic profiling of human liver cancer samples with or without subsequent recurrence and T cell killing assays to uncover a pivotal role for the cholesterol esterification enzyme SOAT1 in immune evasion and cancer recurrence. Genetic knockout or pharmacological inhibition of SOAT1 markedly sensitized both mouse and human cancer cells to immune surveillance and T cell-mediated killing. Mechanistically, blocking cholesterol esterification disrupted excessive cholesterol biosynthesis, impairing cancer cells antioxidant capacity and metabolic resilience under immune attack. Importantly, SOAT1 inhibition effectively suppressed tumor immune escape and improved the efficacy of anti-PD1 and CAR-T cell therapies, even in immunocompromised conditions. These findings highlight cholesterol esterification as a key driver of cancer cell redox metabolism resilience under immunosurveillance and position SOAT1 as a promising target to prevent cancer relapse and enhance immunotherapy outcomes.
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