The Pleiotropic IL-9 Network in Asthma Pathogenesis and Targeted Therapy

Asthma is a heterogeneous chronic airway disease predominantly driven by type 2 inflammation. The functional effects of classic type 2 cytokines, such as interleukin (IL)-4, IL-5, and IL-13, have been extensively characterized. In contrast, the precise positioning of IL-9 within the asthmatic inflammatory network remains less clearly defined. Once viewed mainly as a T cell and mast cell growth factor, IL-9 is now recognized as a pleiotropic cytokine produced by diverse innate and adaptive immune cells, including Th9 cells and type 2 innate lymphoid cells (ILC2s). This review summarizes the expanding cellular sources of IL-9 and delineates its effector networks targeting immune and airway structural cells, highlighting its role as a context-dependent immune amplifier that may contribute to mucus hypersecretion, inflammatory persistence, and airway remodeling in specific disease contexts. We also dissect the spatiotemporal and endotype-specific roles of IL-9, ranging from early ILC2-associated innate inflammation and chronic Th9-associated remodeling processes to recall responses triggered by tissue-resident memory T (TRM) cells and mixed Th2/Th17 inflammation linked to steroid resistance. While preclinical models indicate that IL-9 blockade can mitigate specific inflammatory phenotypes, its therapeutic efficacy is highly context-dependent. Consequently, clinical trials have demonstrated variable efficacy in broadly selected populations, largely due to cytokine redundancy and disease heterogeneity. Future translational strategies may benefit from focusing on precision interventions within biomarker-defined endotypes and mechanistically complementary combination strategies.