Metabolic reprogramming drives a refractory mixed TH2/TH17 endotype in chronic rhinosinusitis with nasal polyps.

BACKGROUND

Chronic rhinosinusitis with nasal polyps (CRSwNP) exhibits significant endotypic heterogeneity. Although Western populations predominantly display type 2 (T2) inflammation, Asian cohorts, including those in the People's Republic of China, show a high prevalence of mixed, non-T2, and neutrophilic endotypes. A subset of patients with a mixed T-helper cell 2 and 17 (TH2/TH17) profile often remains refractory to standard therapies.

OBJECTIVE

We hypothesized that this mixed TH2/TH17 endotype is associated with distinct metabolic and structural alterations that differentiate it from purely T2-driven disease, and we aimed to characterize these features and their prognostic implications.

METHODS

Integrated transcriptomic and metabolomic analyses were performed on nasal tissue from 103 patients (78 with CRSwNP and 25 controls). Patients were stratified into high-TH17 and low-TH17 endotypes on the basis of a specific gene signature. Immunometabolic profiles, barrier remodeling markers, and postoperative disease control rates were compared across endotypes.

RESULTS

Approximately 30.8% of patients with CRSwNP were classified as high-TH17. These patients exhibited clinical features similar to those of TH2-dominant disease, including comparable elevations in serum immunoglobulin E and blood eosinophils. However, prognostic differences emerged: patients with a mixed "double-high" profile (concurrent TH2/TH17 elevation) showed a higher disease control rate than the "Pure TH2" subgroup (48% vs 25%). Multiomics integration revealed that the high-TH17 endotype was significantly associated with a shift toward aerobic glycolysis-like metabolism and the accumulation of proinflammatory lipid mediators. This metabolic reprogramming strongly correlated with transcriptomic markers of squamous metaplasia and barrier hyperkeratinization, suggesting a transition from an edematous to a structurally remodeled tissue state.

CONCLUSION

The high-TH17 endotype in CRSwNP represents a mixed inflammatory state with clinical overlap with T2 disease but with distinct biological trajectories. The observed association between mixed TH2/TH17 inflammation, enhanced glycolysis, and squamous metaplasia provides a potential molecular framework for understanding the recalcitrance of this subgroup, although further mechanistic validation is required.