Epithelial-immune interface in asthma: Mechanistic insights driving novel therapeutic strategies

Asthma is a heterogeneous chronic respiratory syndrome driven by complex interactions between environmental triggers and the host immune system while biologic therapies targeting downstream type 2 cytokines (e.g., anti-IL-5, anti-IL-4Rα) have improved outcomes, the recent success of upstream epithelial-targeting agents like Tezepelumab highlights the potential of targeting disease at its source. Accordingly, recent conceptual advances have redefined the airway epithelium from a passive structural shield to an active immunometabolic hub. This review provides a concise synthesis of emerging mechanistic insights into how airway epithelial cells (AECs) orchestrate both innate and adaptive immune responses. We systematically map the bidirectional crosstalk between the epithelium and diverse immune populations, highlighting how metabolic reprogramming, vesicle-mediated intercellular communication, and neuro-immune circuitry act synergistically to sustain chronic airway inflammation. Furthermore, we explore how these dynamic networks dictate distinct asthma endotypes, ranging from classic type 2 to non-type 2 phenotypes. By delineating these underlying pathobiological mechanisms, this article underscores the translational potential of targeting upstream epithelial signaling. Ultimately, advancing our understanding of this epithelial-immune interface paves the way for emerging precision therapeutics aimed at modifying disease progression and restoring airway homeostasis.