The cGAS-STING pathway and mitochondrial metabolism: from mechanistic insights to therapeutic potential in tumor

The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway serves as the core cytoplasmic DNA-sensing signaling pathway and represents a pivotal node within the immune-metabolic regulatory network through its coordination with mitochondrial metabolism. Emerging evidence suggests that the cGAS-STING pathway plays a dual role in the tumor microenvironment (TME), promoting both anti-tumor immunity and tumor progression. These opposing effects are governed by the spatiotemporal dynamics of STING activation and the metabolic state of mitochondria. Recent studies have revealed that the clinical efficacy of STING agonists is constrained not only by the induction of chronic inflammatory responses but also by tumor metabolic heterogeneity. A comprehensive understanding of the mechanistic crosstalk between the cGAS-STING pathway and mitochondrial metabolism could provide a robust theoretical foundation for developing novel STING-targeted therapeutic strategies based on metabolic modulation. This review provides a systematic overview of the interactive regulatory mechanisms connecting the cGAS-STING pathway with mitochondrial metabolism and assesses the translational potential of targeting this immune-metabolic axis in the context of precision oncology. The insights discussed herein are intended to support the rational optimization and clinical application of STING agonists.