T细胞在抗肿瘤免疫中发挥重要作用。然而，鉴于肝细胞癌（HCC）肿瘤微环境对基于 T 细胞的免疫疗法产生耐药性，因此 HCC 的治疗迫切需要增强 T 细胞介导的抗肿瘤功效的新策略。在这里，我们发现前蛋白转化酶枯草杆菌蛋白酶/kexin 9 型 (PCSK9) 的高表达与 HCC 患者的总体生存率和 CD8 T 细胞标记物呈负相关。 PCSK9 的药理抑制增强了肿瘤特异性杀伤并下调了 AFP 特异性 TCR-T 的 PD-1 表达。抑制 PCSK9 可显着增强 TCR-T 细胞和体内抗 PD-1 免疫疗法的抗 HCC 功效。此外，PCSK9 抑制剂抑制依赖 CD8 T 细胞的 HCC 生长。从机械角度来看，PCSK9 的药理抑制促进了 CD8 T 细胞中低密度脂蛋白受体 (LDLR) 介导的 mTORC1 信号激活。 LDLR 缺陷会损害细胞 mTORC1 信号传导和 CD8 T 细胞的抗 HCC 功能。根据我们在本研究中的发现，我们提出了一种潜在的代谢干预策略，可用于增强 HCC 免疫治疗的抗肿瘤效果。© 作者。

T cells play important roles in antitumor immunity. However, given that the hepatocellular carcinoma (HCC) tumor microenvironment confers resistance to T cell-based immunotherapies, novel strategies to boost T cell-mediated antitumor efficacy are urgently needed for the treatment of HCC. Here, we show that high proprotein convertase subtilisin/kexin type9 (PCSK9) expression was negatively associated with HCC patient's overall survival and markers of CD8+ T cells. Pharmacological inhibition of PCSK9 enhanced tumor-specific killing and downregulated PD-1 expression of AFP-specific TCR-T. Inhibition of PCSK9 significantly enhances the anti-HCC efficacy of TCR-T cells and anti-PD-1 immunotherapy in vivo. Moreover, PCSK9 inhibitor suppressed HCC growth dependent on CD8+ T cells. Mechanically, pharmacological inhibition of PCSK9 promoted low-density lipoprotein receptor (LDLR)-mediated activation of mTORC1 signaling in CD8+ T cells. LDLR deficiency was shown to impair cellular mTORC1 signaling and the anti-HCC function of CD8 T cells. On the basis of our findings in this study, we propose a potential metabolic intervention strategy that could be used to enhance the antitumor effects of immunotherapy for HCC.© The author(s).