The cGAS-STING pathway in ovarian cancer: from genomic instability to immunotherapeutic vulnerability

Ovarian cancer remains the most lethal gynecologic malignancy, a status largely attributable to late-stage diagnosis and inevitable chemoresistance. The cGAS-STING pathway, a cornerstone of innate immune surveillance, has emerged as a critical nexus linking genomic instability to antitumor immunity-a connection of particular relevance in ovarian cancer, where chromosomal instability is a defining hallmark. This review synthesizes current understanding of the cGAS-STING pathway in ovarian cancer, spanning molecular mechanisms to translational opportunities. We delineate the dualistic nature of STING signaling, which orchestrate robust T cell-mediated antitumor immunity under certain conditions yet paradoxically foster immunosuppression and tumor progression in others. Particular emphasis is placed on the intricate interplay between DNA damage repair deficiencies-especially in BRCA1/2 and homologous recombination-and STING-dependent immune activation, which forms the mechanistic basis for the immunomodulatory effects of PARP inhibitors. We critically examine the TME, where CAFs and myeloid cells integrate STING signals to either potentiate or constrain antitumor immunity. The landscape of STING-modulating therapeutic strategies is surveyed, encompassing direct agonists, nanoparticle-based delivery platforms, and rational combinations with immune checkpoint blockade and DNA-damaging agents. Finally, we identify key unresolved questions, including the need for predictive biomarkers, strategies to overcome resistance, and the challenge of balancing therapeutic efficacy against potential toxicities. By integrating recent discoveries with established paradigms and explicitly addressing the "double-edged sword" duality of STING signaling, the stromal response, and a proposed roadmap for biomarker-guided therapeutic development, this review aims to provide a framework that distinguishes itself from prior comprehensive reviews by integrating recent discoveries with established paradigms and explicitly addressing the 'double-edged sword' duality of STING signaling, the stromal response, and a proposed roadmap for biomarker-guided therapeutic development.