What question did this study set out to answer?

The aim is to unpack the cGAS-STING signaling pathway's roles in immunity and its dual effects on health and disease.

June 7, 2026Open Access

Spotlight on cGAS-STING: role in disease pathogenesis and therapeutic potential

Key Points

The aim is to unpack the cGAS-STING signaling pathway's roles in immunity and its dual effects on health and disease.
Systematic integration of structural biology, nanotechnology, and clinical research findings.
Examination of cell-type-specific mechanisms and immune-metabolic interactions in various disease microenvironments.
Focus on the development of small molecule inhibitors and advanced delivery systems for therapeutic applications.
Identified dual roles of cGAS-STING in promoting both protective immunity and chronic inflammation.
Proposed new therapeutic strategies leveraging nanotechnology and combination immunotherapies for better disease outcomes.

Abstract

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.

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