The cGAS–STING pathway in pulmonary infectious and sterile inflammation: differences, connections, and therapeutic implications

Abstract

The cyclic GMP–AMP synthase–stimulator of interferon genes (cGAS–STING) signaling pathway plays a pivotal role in mediating both infectious and sterile pulmonary inflammation, exhibiting distinct dynamic characteristics under different contexts. The activation kinetics of the cGAS–STING pathway are highly dependent on disease context. In many acute infections, the cGAS–STING pathway is often activated rapidly and induces a strong type I interferon (IFN-I) response, which helps control pathogens. In contrast, chronic sterile injury is usually associated with endogenous damage-associated molecular patterns (DAMPs), persistent low-level pathway activation, inflammatory remodeling, and fibrosis. However, these patterns should be viewed as two ends of a dynamic infectious–sterile continuum rather than as mutually exclusive categories. In many pulmonary diseases, including tuberculosis, chronic viral infection, chronic obstructive pulmonary disease (COPD) exacerbation, infection-associated acute respiratory distress syndrome (ARDS), and post-infectious fibrosis, infectious and sterile mechanisms may coexist, overlap, or occur sequentially. This review summarizes the similarities, differences, and mechanistic connections between cGAS–STING signaling in infectious and sterile lung inflammation. We focus on upstream triggers, signaling dynamics, cell-specific responses, intercellular cyclic GMP-AMP (cGAMP) transmission, inflammatory outcomes, biomarkers, and therapeutic implications. We also propose a temporal–intensity model of cGAS–STING signaling as a conceptual framework to better understand stage-specific pathway functions and support future translational research.