葡萄糖代谢已知能调节肿瘤发生。然而，葡萄糖是否作为信号分子直接调控癌基因蛋白活性从而促进肿瘤发生仍然不清楚。在这里，我们报告了葡萄糖是一种辅因子，结合到甲基转移酶NSUN2的氨基酸1-28，促进NSUN2的寡聚体化和激活。NSUN2的激活维持全局的m5C RNA甲基化，包括TREX2，并稳定TREX2，限制细胞质内双链DNA积累和cGAS / STING的活化，从而促进肿瘤发生和抗PD-L1免疫治疗抵抗。缺乏与葡萄糖结合或破坏葡萄糖/NSUN2相互作用的NSUN2突变体会完全废除NSUN2的活性和TREX2的诱导，从而导致cGAS / STING活化以进行肿瘤抑制。令人惊讶的是，通过cGAS / STING活化促进凋亡和CD8 + T细胞浸润，葡萄糖/NSUN2/TREX2轴的遗传删除抑制了肿瘤发生并克服了抗PD-L1免疫治疗抵抗与这些冷性肿瘤。我们的研究确定了NSUN2是一个直接的葡萄糖传感器，其通过葡萄糖的激活推动肿瘤的发生和免疫治疗抵抗，通过维持TREX2的表达来进行cGAS / STING的失活。版权©2023 Elsevier Inc. 保留所有权利。

Glucose metabolism is known to orchestrate oncogenesis. Whether glucose serves as a signaling molecule directly regulating oncoprotein activity for tumorigenesis remains elusive. Here, we report that glucose is a cofactor binding to methyltransferase NSUN2 at amino acid 1-28 to promote NSUN2 oligomerization and activation. NSUN2 activation maintains global m5C RNA methylation, including TREX2, and stabilizes TREX2 to restrict cytosolic dsDNA accumulation and cGAS/STING activation for promoting tumorigenesis and anti-PD-L1 immunotherapy resistance. An NSUN2 mutant defective in glucose binding or disrupting glucose/NSUN2 interaction abolishes NSUN2 activity and TREX2 induction leading to cGAS/STING activation for oncogenic suppression. Strikingly, genetic deletion of the glucose/NSUN2/TREX2 axis suppresses tumorigenesis and overcomes anti-PD-L1 immunotherapy resistance in those cold tumors through cGAS/STING activation to facilitate apoptosis and CD8+ T cell infiltration. Our study identifies NSUN2 as a direct glucose sensor whose activation by glucose drives tumorigenesis and immunotherapy resistance by maintaining TREX2 expression for cGAS/STING inactivation.Copyright © 2023 Elsevier Inc. All rights reserved.