Emerging role of cGAS-STING in the pathogenesis of allergic diseases

The cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) signaling pathway, classically recognized as a crucial cytosolic DNA-sensing mechanism in innate antiviral immunity, is now emerging as a pivotal regulator of sterile inflammation and immune dysregulation. Recent evidence has shifted the paradigm, revealing its significant involvement in the pathogenesis of various allergic diseases, including asthma, atopic dermatitis, and allergic rhinitis. Beyond its canonical role in infection, aberrant activation of cGAS by endogenous DNA from mitochondrial stress, cellular damage, or neutrophil extracellular traps (NETs) can drive pro-inflammatory cytokine responses and, depending on context, type I interferon responses; however, stimulus-induced type I interferon production is impaired in asthmatic airway epithelium and is further suppressed by type 2 inflammatory mediators. This review synthesizes current findings on how dysregulated cGAS-STING signaling contributes to allergic inflammation by amplifying Th2 responses, promoting airway remodeling, enhancing epithelial barrier dysfunction, and modulating the activity of key immune cells such as eosinophils, macrophages, mast cells, dendritic cells, and fibroblasts. We further explore the interplay between this pathway and other allergic signaling cascades, highlighting its role as an innate immune amplifier of allergic sensitization and chronicity Finally, we discuss the translational potential of targeting the cGAS-STING axis as an emerging therapeutic strategy for managing severe, steroid-resistant, or type-2-low allergic endotypes, while emphasizing the need for further validation, particularly in settings where type I interferon responses are impaired and where direct evidence for type-2-low endotypes remains limited.Understanding the emerging role of cGAS-STING provides critical insights into the complex immunobiology of allergic diseases and opens new avenues for intervention.