cGAS-STING Pathway in Gastrointestinal Malignancies: Mechanistic Insights and Translational Therapeutic Opportunities

An important regulator of tumor immunosurveillance and innate immune activation in gastrointestinal (GI) malignancies is the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway. The release of type I interferons, dendritic cell (DC) maturation, and cytotoxic T lymphocyte recruitment are the final steps of a pathway that is typically set in motion by aberrant DNA damage, microbiome-derived DNA, or mitochondrial stress.

Tumour has it that immunologically "cold" gastrointestinalcancers can be made more sensitive to immune-checkpoint blockade (ICB), radiation, and chemotherapy by therapeutically activating the cGAS-STING pathway, which turns them into inflamed, T-cell-permissive niches.

Progress in nanomedicine, small-molecule STING agonists, and tumour-microenvironment-responsive drug delivery systems has broadened the translational scope of this pathway across colorectal, gastric, and pancreatic malignancies. However, tumour-intrinsic heterogeneity, the dual immunostimulatory and immunosuppressive functions of chronic STING signalling, and delivery-related toxicities continue to pose substantial challenges.

This review consolidates current mechanistic insights, preclinical evidence, and emergent clinical data regarding the cGAS-STING pathway in gastrointestinal cancers, while emphasising biomarker-guided patient stratification and AI-powered predictive tools that could facilitate the precise application of STING-targeted therapies.