Research on cGAS STING Signaling Pathway

Abstract

The cGAS-STING signaling pathway serves as a pivotal component of innate immunity, enabling the detection of cytoplasmic DNA to initiate immune responses against pathogens, tumors, and cellular damage. This pathway is activated when cyclic GMP-AMP synthase (cGAS) binds to double-stranded DNA (dsDNA), catalyzing the synthesis of the second messenger 2′3′-cGAMP. cGAMP subsequently binds to the endoplasmic reticulum adaptor STING, triggering its oligomerization, translocation to the Golgi apparatus, and recruitment of TBK1 and IRF3. Phosphorylated IRF3 induces type I interferons (IFN-I), which orchestrate antiviral and antitumor responses. Recent studies highlight the dual roles of this pathway: it not only defends against viral infections (e.g., herpesvirus, poxvirus, and HIV) and suppresses tumorigenesis by recognizing genomic instability but also contributes to autoimmune disorders (e.g., systemic lupus erythematosus) due to aberrant self-DNA sensing. In cancer, cGAS-STING activation can paradoxically promote metastasis in certain contexts, underscoring its context-dependent complexity. Clinically, targeting this pathway has emerged as a therapeutic strategy, with cGAS inhibitors (e.g., aspirin-mediated acetylation) and STING agonists/antagonists under development. However, challenges persist, including systemic toxicity, drug delivery efficiency, and balancing immune activation versus suppression. This review synthesizes current advances, unresolved questions, and translational prospects of the cGAS-STING pathway in health and disease.