D Yan, Jiaoyue Hu, Liu Z, Weijie Ouyang
The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) signaling pathway represents a cornerstone of innate immunity, functioning as the primary cytosolic DNA sensor in mammalian cells. Upon detecting pathogenic DNA or mislocalized self-DNA (such as leaked mitochondrial or micronuclear DNA), cGAS synthesizes the second messenger cGAMP, which subsequently activates endoplasmic reticulum-resident STING. This activation triggers an intricate signaling cascade involving liquid-liquid phase separation, dynamic organelle trafficking, and robust interferon and pro-inflammatory cytokine production, thereby bridging microbial defense, antitumor immunity, and cellular homeostasis. Despite these structural and functional insights, the pathway's context-dependent duality, dictating whether it activates protective acute immunity or drives pathological chronic inflammation, immunosuppression, and metabolic dysregulation, remains a critical, unresolved clinical challenge. This review systematically integrates recent breakthroughs across structural biology, nanotechnology, and clinical research to dissect the spatiotemporal dynamic regulation and non-canonical functions of the cGAS-STING axis. We comprehensively examine its cell-type-specific mechanisms and metabolic-immune crosstalk within the microenvironments of neurodegenerative diseases, oncology, and autoimmune disorders. Furthermore, we highlight emerging translational innovations, emphasizing the rational design of small molecule inhibitors, advanced nanocarrier delivery systems, and combination immunotherapies. By redefining the conventional understanding of cytosolic DNA sensing, this synthesis establishes a comprehensive roadmap for precision immunomodulation. Ultimately, it provides a crucial framework for developing next-generation, microenvironment-adaptive therapeutics that leverage spatiotemporal dynamics to treat cGAS-STING-related pathologies.