The cGAS‒STING pathway in colorectal cancer: bridging innate immunity and therapeutic strategies.

Colorectal cancer (CRC) continues to be a predominant cause of cancer-related mortality worldwide, with existing therapies constrained by systemic toxicity, resistance, and inadequate tumor targeting. While immunotherapy has potential in specific CRC subtypes, its overall effectiveness is still limited. The cyclic GMP‒AMP synthase-stimulator of interferon genes (cGAS‒STING) pathway, an essential cytosolic DNA sensor that facilitates innate immune responses, has surfaced as a prospective target for cancer immunotherapy. Recent studies have demonstrated that it plays dual roles in CRC: on the one hand, it triggers antitumor immune responses, while on the other hand, it promotes intestinal inflammation. Accurate delivery of STING agonists made feasible by developments in nanotechnology offers novel ways to modify the TME and overcome resistance. The current understanding of the activation and function of the cGAS-STING pathway in CRC, its impact on the TME, and recent developments in STING-targeted therapeutic approaches, comprising monotherapy and combination strategies with chemotherapy, radiotherapy, and immune checkpoint inhibitors, is summarized in this review. We also review new nanomedicine approaches designed to increase STING activation. Understanding the complex roles of cGAS-STING in CRC could help guide the development of next-generation immunotherapies with improved selectivity and efficacy.