The interplay of cGAS-STING and autophagy: bidirectional regulation and pathophysiological implication

Abstract

The cGAS-STING pathway is a fundamental cytosolic DNA-sensing mechanism that activates innate immune responses through the production of type I interferons (IFNs) and other cytokines. Autophagy, a conserved intracellular degradation system, plays crucial roles in maintaining cellular homeostasis by clearing damaged organelles, protein aggregates, and pathogens. This review elucidates the intricate bidirectional crosstalk between autophagy and the cGAS-STING pathway. On one hand, cGAS-STING activation induces multiple forms of autophagy, including canonical macroautophagy and non-canonical LC3 lipidation on single-membrane compartments, through mechanisms involving Beclin-1 interaction, LC3 binding, putative liquid-liquid phase separation, and ER stress-mTOR signaling. On the other hand, autophagy serves as a comprehensive negative feedback mechanism, attenuating cGAS-STING signaling by clearing cytosolic DNA, selectively degrading pathway components (cGAS, STING, TBK1, IRF3), and preventing mitochondrial DNA (mtDNA) release via mitophagy. This reciprocal regulation has profound implications across various diseases: it enhances antiviral defense and pathogen clearance, but its dysregulation contributes to autoimmune diseases like systemic lupus erythematosus (SLE), cancer progression, and neurodegenerative disorders. In cancer, the axis exhibits dual roles—promoting antitumor immunity while also supporting tumor survival under stress. In neurodegeneration, impaired autophagy coupled with cGAS-STING hyperactivation exacerbates neuroinflammation. Understanding the nuanced interplay between cGAS-STING and autophagy is essential for developing targeted therapies against infections, autoimmune diseases, cancer, and neurological conditions.