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NSUN2 is a glucose sensor suppressing cGAS/STING to maintain tumorigenesis and immunotherapy resistance
Tingjin Chen1, Zhi-Gang Xu2, Jie Luo1
1Department of Cancer Biology, Wake Forest Baptist Medical Center, Wake Forest University, Winston-Salem, NC 27157, USA.
Abstract:
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.
Insights
Glucose acts as a signaling molecule by activating methyltransferase NSUN2, promoting cancer growth and immunotherapy resistance. Inhibiting this glucose-NSUN2-TREX2 pathway suppresses tumors and enhances anti-PD-L1 therapy effectiveness.
Area of Science:
- Oncology
- Molecular Biology
- Immunology
Background:
- Glucose metabolism is crucial for cancer development.
- The role of glucose as a direct signaling molecule in oncogenesis is not fully understood.
Purpose of the Study:
- To investigate if glucose directly regulates oncoprotein activity for tumorigenesis.
- To identify glucose-sensing mechanisms in cancer progression.
Main Methods:
- Biochemical assays to study glucose binding to NSUN2.
- RNA methylation analysis.
- In vitro and in vivo models of tumorigenesis and immunotherapy resistance.
- Genetic manipulation of the glucose/NSUN2/TREX2 axis.
Main Results:
- Glucose binds to methyltransferase NSUN2, promoting its activation and oligomerization.
- Activated NSUN2 maintains m5C RNA methylation, stabilizing TREX2 and suppressing the cGAS/STING pathway, thus promoting tumorigenesis and anti-PD-L1 resistance.
- Disrupting glucose-NSUN2 interaction or deleting the axis inhibits tumor growth and overcomes immunotherapy resistance by reactivating cGAS/STING.
Conclusions:
- NSUN2 is a direct glucose sensor that drives tumorigenesis and immunotherapy resistance.
- The glucose-NSUN2-TREX2 axis represents a novel therapeutic target for cancer treatment and overcoming resistance to immune checkpoint inhibitors.
