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

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.