A study of NSUN2 Is a Glucose Sensor Suppressing cGAS-STING to Maintain Tumorigenesis and Immunotherapy Resistance. Tingin Chen et al.
Description
Uncropped scans of all blots and all values used to generate graphs are included for the study of NSUN2 Is a Glucose Sensor Suppressing cGAS-STING to Maintain Tumorigenesis and Immunotherapy Resistance. Tingin Chen et al.. Any additional information required to reanalyze the data reported in this paper is available from the lead contact upon request. Glucose primarily acts through its metabolism 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 exonuclease to restrict cytosolic dsDNA accumulation and cGAS/STING activation for promoting tumorigenesis and anti-PD-L1 immunotherapy resistance. A 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 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.