Leticia Martín‐Cruz, Andrés de la Rocha‐Muñoz, Isabel María Peñalver-Fernández, Angel Maldonado, Sofía Sirvent, Óscar Palomares
ABSTRACT Background Thymic stromal lymphopoietin (TSLP) is a key epithelial alarmin involved in the initiation and maintenance of type 2 inflammatory airway diseases. Although tezepelumab, the first approved anti‐TSLP monoclonal antibody, has shown robust clinical efficacy in asthma and CRSwNP, the molecular mechanisms underlying its mode of action remain incompletely defined. Objective To determine whether TSLP induces a pathogenic immunometabolic program in human type 2 conventional dendritic cells (cDC2s) and whether tezepelumab can directly reverse this process. Methods Purified human circulating cDC2s from healthy non‐atopic donors were stimulated with TSLP in the presence or absence of tezepelumab. cDC2 phenotype, function, metabolism, and T‐cell polarization capacity were assessed. Pathogenic Th2 responses, Treg generation, suppressive function, and metabolic fitness were analyzed. Results TSLP induced a metabolic rewiring in human cDC2s characterized by increased glycolysis and mitochondrial oxidative phosphorylation. This metabolic hyperactivation was associated with the acquisition of a pro‐type 2 phenotype and required for the induction of pathogenic T‐cell responses. TSLP‐activated cDC2s generated pathogenic Th2 cells and FOXP3 + Tregs with impaired suppressive function and an altered metabolic profile. Tezepelumab effectively reversed TSLP‐induced metabolic and functional reprogramming in cDC2s, thereby limiting pathogenic Th2 polarization while restoring the functional and metabolic properties of induced Tregs. Conclusions We identify immunometabolic rewiring as a key mechanism of the TSLP–cDC2 axis and provide mechanistic insight into how tezepelumab reshapes pathogenic adaptive immune responses. These results support upstream epithelial alarmin blockade as a strategy to interfere with early disease‐driving immune programs in type 2 inflammatory airway diseases.