IL-5 Biology and Eosinophil Regulation: Advances, Resistance Pathways and Future Directions.

Interleukin-5 (IL-5) is a central regulator of eosinophil differentiation, maturation, trafficking, activation and survival, and therapeutic targeting of the IL-5/IL-5 receptor alpha pathway has substantially changed the management of severe eosinophilic asthma and other eosinophil-associated disorders. However, clinical responses to anti-IL-5 and anti-IL-5Rα biologics remain heterogeneous, and persistent symptoms may reflect ongoing eosinophilic inflammation, partial clinical response, comorbidity-driven residual disease or inflammatory mechanisms not primarily dependent on IL-5. This narrative review summarizes current knowledge on IL-5 biology, eosinophil regulation and the pharmacological basis of IL-5 pathway inhibition, with particular focus on severe eosinophilic asthma, chronic rhinosinusitis with nasal polyps, eosinophilic granulomatosis with polyangiitis and hypereosinophilic syndromes. It also discusses eosinophil heterogeneity, biomarkers of response, IL-5-dependent and IL-5-independent pathways, epithelial alarmins, IL-4/IL-13 signalling, airway remodelling and treatable traits associated with residual symptoms. An illustrative retrospective real-world cohort of patients treated with mepolizumab or benralizumab is used to contextualize biomarker variability, clinical heterogeneity and comorbidity burden in routine severe-asthma care. Overall, interpretation of response to IL-5/IL-5Rα-targeted therapy should integrate blood eosinophils with clinical outcomes, lung function, corticosteroid exposure, sinonasal disease and other comorbidities. Future research should standardize definitions of remission, partial response and non-response, strengthen prospective real-world registries, and identify tissue-based or multi-omic biomarkers to guide biologic selection, sequencing and treatment optimization.