Metabolic Regulation of cGAS-STING Signaling in the Tumor Microenvironment: Dual Immune Roles and Therapeutic...

The cGAS-STING pathway, a cytosolic DNA-sensing mechanism, plays a context-dependent pivotal role in tumor immunity and tumor microenvironment (TME) remodeling. Acute activation of this pathway promotes type I interferon (IFN-I) and pro-inflammatory responses, including dendritic cell (DC) maturation and cytotoxic T cell recruitment, whereas chronic stimulation paradoxically drives immunosuppression and tumor progression through mechanisms such as PD-L1 upregulation and regulatory T cell activation. Tumor metabolic reprogramming-encompassing hypoxia, glycolysis, Krebs cycle metabolites, amino acids, lipids, TME acidity and redox species -emerges as a critical modulator of cGAS-STING activity. For instance, hypoxia suppresses cGAS-STING via TET1-mediated induction of miR-25 and miR-93, while oxygen supplementation reactivates antitumor immunity. Glucose flux exerts dual regulatory effects: NSUN2-dependent TREX2 stabilization limits cytosolic DNA accumulation, whereas glycolysis ATP fuels STING-dependent DC activation. Beyond tumor cells, cGAS-STING signaling in cancer-associated fibroblasts promotes chemoresistance via DNA damage repair, and endothelial STING activation normalizes tumor vasculature to alleviate TME hypoxia and improve T cell infiltration. Current therapeutic strategies prioritize isoform-specific agonists (e.g. cyclic dinucleotides like ADU-S100; non-CDNs like diABZI) and precision delivery systems, such as nanoparticles and engineered bacteria, to address challenges like short half-life and systemic toxicity. Synergistic approaches-including ACLY inhibition to amplify mitochondrial DNA release or pH-responsive nanoparticles co-delivering STING/TLR4 agonists-enhance efficacy when combined with checkpoint inhibitors and radiotherapy. However, the pathway's dual roles, particularly its tumor-promoting effects in advanced malignancies, necessitate context-dependent modulation. This review integrates preclinical insights and clinical trial data to outline strategies for harnessing cGAS-STING signaling in cancer immunotherapy while balancing its immunostimulatory and immunosuppressive outputs.