清华大学潘登、曾泽贤和汪付兵研究组发现，肿瘤有氧糖酵解通过TNF-α调节对T细胞介导的旁观者杀伤的敏感性，从而赋予免疫逃避。该研究于2023年7月27日发表于国际一流学术期刊《细胞—代谢》杂志上。

通过在与细胞毒性T细胞(CTLs)共培养的小鼠肿瘤细胞中进行全基因组CRISPR筛选，他们发现缺乏两种重要的糖酵解酶，Glut1(葡萄糖转运蛋白1)和Gpi1(葡萄糖-6-磷酸异构酶1)，导致CTL对肿瘤细胞的杀伤增强。从机制上讲，Glut1失活导致代谢重新布线向氧化磷酸化，从而产生过量的活性氧(ROS)。积累的ROS以caspase-8和Fadd依赖的方式增强肿瘤坏死因子α (TNF-α)介导的肿瘤细胞死亡。

Glut1基因和药理学失活使肿瘤对抗肿瘤免疫增敏，并通过TNF-α途径与抗PD-1治疗协同作用。肿瘤内糖酵解与TNF-α-诱导的杀伤之间的机制相互作用为增强抗肿瘤免疫提供了新的治疗策略。

研究人员表示，糖酵解的代谢重编程是恶性肿瘤的一个标志。肿瘤糖酵解途径促进免疫逃避的分子机制仍有待阐明。

附：英文原文

Title: Tumor aerobic glycolysis confers immune evasion through modulating sensitivity to T cell-mediated bystander killing via TNF-α

Author: Lijian Wu, Yiteng Jin, Xi Zhao, Kaiyang Tang, Yaoning Zhao, Linjie Tong, Xuerong Yu, Ke Xiong, Ce Luo, Jiajun Zhu, Fubing Wang, Zexian Zeng, Deng Pan

Issue&Volume: 2023-07-27

Abstract: Metabolic reprogramming toward glycolysis is a hallmark of cancer malignancy. Themolecular mechanisms by which the tumor glycolysis pathway promotes immune evasionremain to be elucidated. Here, by performing genome-wide CRISPR screens in murinetumor cells co-cultured with cytotoxic T cells (CTLs), we identified that deficiencyof two important glycolysis enzymes, Glut1 (glucose transporter 1) and Gpi1 (glucose-6-phosphateisomerase 1), resulted in enhanced killing of tumor cells by CTLs. Mechanistically,Glut1 inactivation causes metabolic rewiring toward oxidative phosphorylation, whichgenerates an excessive amount of reactive oxygen species (ROS). Accumulated ROS potentiatetumor cell death mediated by tumor necrosis factor alpha (TNF-α) in a caspase-8- andFadd-dependent manner. Genetic and pharmacological inactivation of Glut1 sensitizestumors to anti-tumor immunity and synergizes with anti-PD-1 therapy through the TNF-αpathway. The mechanistic interplay between tumor-intrinsic glycolysis and TNF-α-inducedkilling provides new therapeutic strategies to enhance anti-tumor immunity.

DOI: 10.1016/j.cmet.2023.07.001

Source: https://www.cell.com/cell-metabolism/fulltext/S1550-4131(23)00251-6