Proper metabolic activities facilitate T cell expansion and antitumor function; however, the mechanisms underlying disruption of the T cell metabolic program and function in the tumor microenvironment (TME) remain elusive. Here, we show a zinc finger protein 91–governed (ZFP91-governed) mechanism that disrupts the metabolic pathway and antitumor activity of tumor-infiltrating T cells. Single-cell RNA-Seq revealed that impairments in T cell proliferation and activation correlated with ZFP91 in tissue samples from patients with colorectal cancer. T cell–specific deletion of Zfp91 in mice led to enhanced T cell proliferation and potentiated T cell antitumor function. Loss of ZFP91 increased mammalian target of rapamycin complex 1 (mTORC1) activity to drive T cell glycolysis. Mechanistically, T cell antigen receptor–dependent (TCR-dependent) ZFP91 cytosolic translocation promoted protein phosphatase 2A (PP2A) complex assembly, thereby restricting mTORC1-mediated metabolic reprogramming. Our results demonstrate that ZFP91 perturbs T cell metabolic and functional states in the TME and suggest that targeting ZFP91 may improve the efficacy of cancer immunotherapy.

中文翻译：

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ZFP91干扰肿瘤浸润性T细胞的代谢适应性和抗肿瘤活性

适当的代谢活动促进 T 细胞扩增和抗肿瘤功能；然而，肿瘤微环境 (TME) 中 T 细胞代谢程序和功能的破坏机制仍然难以捉摸。在这里，我们展示了一种锌指蛋白 91 控制（ZFP91 控制）机制，该机制破坏了肿瘤浸润性 T 细胞的代谢途径和抗肿瘤活性。单细胞 RNA-Seq 显示，T 细胞增殖和活化的损害与结直肠癌患者组织样本中的 ZFP91 相关。Zfp91 的T 细胞特异性缺失在小鼠中导致增强的 T 细胞增殖和增强的 T 细胞抗肿瘤功能。ZFP91 的缺失增加了哺乳动物雷帕霉素复合物 1 (mTORC1) 的靶标，以驱动 T 细胞糖酵解。从机制上讲，T 细胞抗原受体依赖性（TCR 依赖性）ZFP91 胞质易位促进蛋白磷酸酶 2A (PP2A) 复合物组装，从而限制 mTORC1 介导的代谢重编程。我们的结果表明，ZFP91 会扰乱 TME 中的 T 细胞代谢和功能状态，并表明靶向 ZFP91 可能会提高癌症免疫疗法的疗效。