PCK1 deficiency promotes MASH-HCC progression by 12-HETE-induced CD8+ T cell dysfunction

Abnormal tumor microenvironment (TME) affects the efficacy of immunotherapies in metabolic dysfunction-associated steatohepatitis-induced hepatocellular carcinoma (MASH-HCC); however, the mechanisms underlying tumor metabolism modulating the TME remain obscure. This study reveals the pivotal role of the hepatic cell-intrinsic enzyme phosphoenolpyruvate carboxykinase 1 (PCK1) in mediating immunosuppression in MASH-HCC. Hepatocyte-specific Pck1 knockout promotes the development of MASH-HCC by inhibiting the effector function of CD8+ T cells in mice.

异常肿瘤微环境（TME）影响代谢功能障碍相关脂肪性肝炎诱导的肝细胞癌（MASH-HCC）中免疫疗法的疗效；然而，调节TME的肿瘤代谢机制尚不明确。本研究揭示了肝细胞内源性酶磷酸烯醇丙酮酸羧激酶1（PCK1）在介导MASH-HCC免疫抑制中的关键作用。特异性敲除肝细胞中的Pck1基因可促进MASH-HCC的发展，其机制是通过抑制小鼠中CD8+ T细胞的效应功能。