The airway epithelial-immune axis: mechanisms and therapeutic implications.

The airway epithelium is increasingly recognized not merely as a physical barrier, but as a central, active regulator of mucosal immunity. This review comprehensively summarizes the structural and functional basis of the airway epithelial-immune axis and its critical role in chronic respiratory diseases. Exposure to environmental allergens, pollutants, and respiratory pathogens disrupts epithelial tight junctions and triggers the rapid release of key alarmins, including TSLP, IL-33, and IL-25. These epithelial-derived cytokines participate in reciprocal epithelial-immune circuits, driving extensive crosstalk with both innate (ILC2s) and adaptive (Th2 cells) immune networks to establish self-perpetuating inflammatory loops. Such epithelial dysfunction can act as an important driver and amplifier in the pathogenesis of asthma, chronic obstructive pulmonary disease (COPD), and upper airway inflammatory disorders. Consequently, targeting this axis has emerged as a promising therapeutic strategy, shifting the focus toward alarmin-neutralizing biologics, upstream receptor inhibition, and barrier restoration. Furthermore, we highlight how emerging technologies-such as single-cell RNA sequencing, spatial transcriptomics, organoid models, and multi-omics integration-are decoding cellular heterogeneity and spatial niches, ultimately paving the way for precision medicine and long-term disease-modifying therapies in respiratory medicine.