cGAS-STING signaling pathway in urogenital oncology: Regulation, resistance, and routes to response.

The cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway links cytosolic DNA sensing to tissue-level innate immunity and has emerged as a pivotal, yet paradoxical, determinant of tumor behavior in urogenital cancers. Recent work reveals multilayered regulation of this axis through phosphorylation and ubiquitination networks, epigenetic and transcriptional repression, and metabolic reprogramming that collectively shape tumor-immune communication. These insights are illuminating therapeutic strategies that exploit genomic instability, reactivate dormant STING signaling through cytotoxic or radiologic injury, or directly engage the pathway using engineered microbes, synthetic cyclic dinucleotides, and nanocarrier systems. Integration of cGAS-STING activation with immune checkpoint blockade and cellular therapies demonstrates potent synergy but also uncovers resistance circuits that remodel interferon competence and therapeutic responsiveness. Pathway-informed gene signatures, patient-derived models, and biomarker frameworks are beginning to guide clinical translation. Context-dependent, non-canonical signaling and intercellular cGAMP transport and clearance further define developmental vulnerabilities and pharmacodynamic anchors. Together, these advances position cGAS-STING as a double-edged axis in urogenital oncology-one that offers powerful opportunities for immune reactivation while demanding precision strategies to avert protumor adaptation.