Context-Dependent Rewiring of the cGAS-STING Pathway in Cancer: Implications for Immunotherapy and Therapeutic Resistance.

The cGAS-STING pathway is a critical cytosolic DNA-sensing system that bridges innate and adaptive immunity, which detects double-stranded DNA from nuclear, mitochondrial, or pathogen sources, triggering the production of 2'3'-cGAMP thereby activating the Stimulator of Interferon Genes (STING), inducing type I interferons and pro-inflammatory cytokines. In its canonical role, this axis facilitates dendritic cell maturation, antigen cross-presentation, and the recruitment of cytotoxic T and natural killer (NK) cells, converting "cold" tumors into "hot" immune-responsive lesions. This review posits that cGAS-STING is a context-dependent regulator. While acute activation bolsters anti-tumor surveillance, chronic or misdirected signaling within the tumor microenvironment (TME) paradoxically promotes progression and treatment resistance. In genomically unstable or therapy-exposed tumors, persistent cGAS-STING activity drives chronic inflammation, upregulates checkpoints like PD-L1, and expands immunosuppressive populations, such as myeloid-derived suppressor cells (MDSCs) and regulatory T cells (Tregs). The pathway's output is further shaped by metabolic and epigenetic reprogramming. The review also discusses the development of next-generation agonists and antagonists, alongside precision delivery systems designed for pulsed or compartment-restricted activation. Harnessing the immunostimulatory potential of cGAS-STING while mitigating its role in adaptive resistance is essential for improving clinical outcomes across diverse cancer types.