Mitochondrial DNA-activated cGAS-STING pathway in cancer: Mechanisms and therapeutic implications

Mitochondrial DNA (mtDNA), a circular double-stranded DNA located within mitochondria, plays a pivotal role in mitochondrial-induced innate immunity, particularly via the cyclic GMP-AMP synthase (cGAS)-STING pathway, which recognizes double-stranded DNA and is crucial for pathogen resistance. Recent studies elucidate the interplay among mtDNA, the cGAS-STING pathway, and neutrophil extracellular traps (NETs) in the context of cancer. mtDNA uptake by recipient cells activates the cGAS-STING pathway, while mtDNA leakage reciprocally regulates NET release, amplifying inflammation and promoting NETosis, a mechanism of tumor cell death. Autophagy modulates these processes by clearing damaged mitochondria and degrading cGAS, thus preventing mtDNA recognition. Tumor microenvironmental factors, such as metabolic reprogramming and lipid accumulation, induce mitochondrial stress, ROS production, and further mtDNA leakage. This review explores strategies in cancer drug development that leverage mtDNA leakage to activate the cGAS-STING pathway, potentially converting ‘cold tumors’ into ‘hot tumors,’ while discussing advancements in targeted therapies and proposing new research methodologies.