Mitochondrial DNA release and cGAS-STING activation: Emerging insights into anti-tumor immunity

Mitochondrial DNA (mtDNA) leakage into the cytosol has emerged as a critical modulator of cancer immunity, bridging the gap between cellular stress and antitumor immune responses. Under genomic instability, metabolic stress, or therapy-induced damage, mtDNA escapes into the cytosol, where it activates the cGAS-STING pathway a central regulator of innate immunity. This pathway not only triggers type I interferon (IFN) responses but also influences dendritic cell maturation, T cell infiltration, and immunogenic cell death, shaping the tumor microenvironment (TME) toward immune activation or suppression. Recent studies reveal that mtDNA leakage is not merely a passive byproduct of mitochondrial dysfunction but is dynamically regulated by autophagy, mitochondrial outer membrane permeabilization (MOMP), and interactions with noncoding RNAs. Furthermore, tumors exploit mtDNA degradation mechanisms (e.g., TREX1 exonuclease) or STING silencing to evade immune detection, highlighting this axis as a therapeutic vulnerability. This review synthesizes current knowledge on mtDNA-driven cGAS-STING activation in cancer, its dual role in promoting inflammation versus immune escape, and the therapeutic potential of targeting mtDNA release or STING signaling to enhance immunotherapy. We also explore emerging strategies, such as mtDNA-stabilizing agents and STING agonists, in combination with checkpoint blockade. Deciphering the nuances of mtDNA sensing in different cancers may unlock novel biomarkers and precision immunotherapies for resistant malignancies.