The roles of cGAS-STING pathway in cancer

The cyclic guanosine monophosphate–adenosine monophosphate synthase (cGAS)-stimulator of interferon genes (STING) pathway is a crucial cytosolic DNA-sensing pathway that bridges innate and adaptive immunity. Extensive research has demonstrated the important roles of cGAS-STING signaling in various aspects, including antimicrobial defense, genomic stability, and immune homeostasis. However, this pathway has a double-edged effect in cancer. On the one hand, activation of the cGAS-STING pathway generates antitumor effects by enhancing antigen presentation via dendritic cells, reinforcing tumor immune surveillance, and promoting cytotoxic effects of CD8 + T cells and natural killer cells. In contrast, persistent stimulation of cGAS-STING signaling drives chronic inflammation, which results in immunosuppressive cell accumulation, enhanced angiogenesis, and tumor cell proliferation and metastasis. In the tumor microenvironment, the cGAS-STING pathway not only coordinates a complex network involving immune cells, cancer-associated fibroblasts, and endothelial cells but also engages in noncanonical regulatory functions in ferroptosis, pyroptosis, and nuclear DNA repair. These multifaceted effects identify cGAS-STING signaling as a potential driver of tumor adaptation and a promising immunotherapeutic target. Current clinical strategies for STING agonists or combination therapies with immune checkpoint inhibitors have shown encouraging, yet variable, outcomes, highlighting multiple challenges, including dose optimization, immune tolerance, and patient heterogeneity. A deeper mechanistic understanding and precise spatiotemporal regulation of this pathway are critical to fully harness its therapeutic value in cancer.