BACKGROUND Eosinophilic chronic rhinosinusitis (eCRS) is a refractory type 2 inflammatory disease characterized by nasal polyp formation and eosinophilic infiltration. Although dupilumab, an IL-4Rα-blocking antibody, demonstrates clinical efficacy, its cellular mechanisms within nasal polyps remain unclear. OBJECTIVE To define the cell type-specific effects of dupilumab in eCRS, we examined IL-4/IL-13 receptor-dependent transcriptional responses in tissue-resident immune cells. METHODS Nasal polyp and peripheral blood samples were collected from five patients with eCRS before and after dupilumab treatment. Single-cell RNA sequencing on four paired cases, spatial transcriptomics, and immunostaining were performed. In vitro stimulation of human conventional dendritic cells (cDCs) validated IL-4/IL-13-regulated pathways. RESULTS Dupilumab improved symptoms and attenuated eosinophilic inflammation. Across annotated populations, the number of differentially expressed genes correlated positively with pre-treatment IL13RA1 expression. Accordingly, myeloid cells, particularly cDCs, which predominantly express type II IL-4/IL-13 receptors, showed the broadest transcriptional changes, including downregulation of ALOX15; ALOX15 inhibition abrogated IL-4/IL-13-induced CCL13 and CCL22 expression in cDCs. After treatment, pathogenic Th2 cell subset expressed lower IL1RL1 and AREG. IGHE and IL4R expression in CD23-positive B cells declined, as did PRDM1 and ELL2 in plasma cells. In one paired case, spatial analysis identified fewer TLS-like aggregates and lower detection of ALOX15 and IGHE transcripts after treatment. CONCLUSION Dupilumab preferentially remodels type II IL-4/IL-13 receptor-expressing immune cells, particularly polyp cDCs, while selectively reprogramming Th2, B, and plasma cells. Identification of ALOX15 as a candidate mediator in cDCs provides mechanistic insight that may inform optimization of type 2-targeted therapy in eCRS.
