Cancer cells exhibit distinct metabolic states, notably enhanced aerobic glycolysis (Warburg effect), which supports cancer stem cell maintenance, progression, metastasis, and drug resistance. Elevated glucose uptake, driven by increased glucose transporter expression, fuels glycolysis, supplying energy, biosynthetic precursors, and redox balance essential for tumor growth.

Beyond metabolism, glucose promotes oncogenic activity via glycolysis and the TCA cycle, while regulating histone acetylation through acetyl-CoA production. Emerging evidence suggests glucose may also act as a signaling molecule, potentially binding directly to target proteins. Prior studies showed glucose can activate signaling pathways independently of metabolism, indicating the presence of specific glucose sensors. This study demonstrates that glucose directly binds and activates NSUN2, maintaining m5C RNA methylation to drive oncogenesis and immunotherapy resistance.

This invention identifies NSUN2 as a previously unrecognized glucose sensor and therapeutic target in cancer, revealing a direct molecular link between glucose metabolism, RNA methylation, oncogenesis, and immunotherapy resistance. By targeting the glucose-NSUN2 signaling axis, researchers may be able to develop novel cancer therapies that suppress tumor growth, overcome treatment resistance, and enhance responses to immunotherapy. The discovery also provides new opportunities for biomarker development and therapeutic intervention across multiple cancer types characterized by dysregulated glucose metabolism. 

Technology Overview

Current Challenges

Glucose functions as a cofactor, binding the N-terminal region (aa 1–28) of the methyltransferase NSUN2, promoting its oligomerization and activation. Activated NSUN2 sustains global m5C RNA methylation, including TREX2, which limits dsDNA accumulation and suppresses cGAS/STING signaling, thereby promoting tumorigenesis and resistance to anti-PD-L1 immunotherapy.

Our Innovation

Disrupting the glucose–NSUN2 interaction via mutant NSUN2 or a TAT-N28 peptide abolishes NSUN2 activity, reduces TREX2, activates cGAS/STING, and inhibits tumor growth. Targeting this glucose/NSUN2/TREX2 axis suppresses tumors and overcomes resistance in “cold” tumors by promoting apoptosis and CD8+ T cell infiltration.

NSUN2 is identified as a direct glucose sensor driving cancer progression via TREX2-mediated suppression of cGAS/STING. The N28 peptide effectively blocks this interaction, restoring immune activation and improving therapeutic response.

The glucose/NSUN2/TREX2 axis regulates dsDNA accumulation and cGAS/STING activation, with TREX2 acting as a key downstream effector. This pathway also presents potential as a companion diagnostic for cGAS/STING-targeted therapies.

Additionally, inhaled NP-cGAMP enhances radiotherapy in lung metastasis models, inducing systemic anti-tumor immunity and abscopal effects through APC-mediated immune activation.

Benefits of this Technology

  • cGAS/STING is a critical pathway in tumor suppression and cancer immunity
  • Identifies glucose as a signaling molecule activating NSUN2 to suppress cGAS/STING and promote cancer progression
  • Provides new strategies to study glucose signaling in biology
  • Enables methods for cancer treatment and reducing immunotherapy resistance via NSUN2 inhibition

Stage of Development

Proof-of-concept data confirm NSUN2 acts as a glucose sensor that suppresses cGAS/STING signaling and contributes to immunotherapy resistance