NSUN2 is a glucose sensor suppressing cGAS/STING to maintain tumorigenesis and immunotherapy resistance

Tingjin Chen, Zhi Gang Xu, Jie Luo, Rajesh Kumar Manne, Zhengyu Wang, Che Chia Hsu, Bo Syong Pan, Zhen Cai, Pei Jane Tsai, Yau Sheng Tsai, Zhong Zhu Chen, Hong yu Li, Hui Kuan Lin

Research output: Contribution to journalArticlepeer-review

8 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)1782-1798.e8
JournalCell Metabolism
Issue number10
StatePublished - Oct 3 2023
Externally publishedYes


  • NSUN2
  • T cell infiltration
  • TREX2
  • cGAS
  • glucose
  • immunotherapy resistance
  • mC RNA methylation

ASJC Scopus subject areas

  • Molecular Biology
  • Physiology
  • Cell Biology


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