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

Cell Metab. 2023 Oct 3;35(10):1782-1798.e8. doi: 10.1016/j.cmet.2023.07.009. Epub 2023 Aug 15.


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.

Keywords: NSUN2; STING; T cell infiltration; TREX2; cGAS; glucose; immunotherapy resistance; m(5)C RNA methylation.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural

MeSH terms

  • Carcinogenesis
  • Humans
  • Immunotherapy
  • Methyltransferases / metabolism
  • Nucleotidyltransferases* / genetics
  • Nucleotidyltransferases* / metabolism
  • Signal Transduction* / genetics


  • Nucleotidyltransferases
  • NSUN2 protein, human
  • Methyltransferases