Gut microbiota-cGAS-STING axis in microsatellite stable colorectal cancer: From immune sensing to therapeutic opportunities

Microsatellite stable (MSS) colorectal cancer (CRC) accounts for approximately 85% of all CRC cases and is largely unresponsive to immune checkpoint inhibitors, making its resistance to immunotherapy one of the major challenges in current clinical oncology.The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway is a key initiator of antitumor innate immune responses.In MSS CRC, reduced cGAS and/or STING expression in tumor cells is associated with impaired type I interferon signaling and reduced CD8 + T-cell infiltration, contributing to an immunologically "cold" tumor microenvironment.Restoration of cGAS-STING activity may enhance antitumor immunity, but its effects are strongly dependent on the intensity, duration, and cellular context of activation.Transient and appropriately localized signaling can promote antigen presentation and T-cell recruitment, whereas sustained or excessive activation may shift signaling toward nuclear factor kappaB-driven inflammation, immune dysfunction, and tumor-promoting effects.The gut microbiota adds another layer of regulation to this pathway through microbial components and metabolites that can either activate or suppress cGAS-STING signaling.Yet direct evidence for microbiota-mediated regulation of cGAS-STING in human MSS CRC remains limited, and many mechanistic observations currently derive from preclinical CRC models, other tumor types, or inflammatory disease settings.This review therefore examines the gut microbiota-cGAS-STING axis with particular attention to the distinction between evidence established in MSS CRC and mechanisms inferred from related experimental systems.The bidirectional effects of probiotics, pathogenic bacteria, and microbial metabolites on cGAS-STING signaling are discussed alongside their consequences for the MSS CRC immune microenvironment, and the therapeutic potential and translational limitations of microbiota-based strategies for sensitizing MSS CRC to immunotherapy are critically evaluated.