Targeting upstream alarmins (TSLP, IL-33, IL-25): a new frontier in treating type 2 chronic rhinosinusitis with nasal polyps

Chronic rhinosinusitis with nasal polyps (CRSwNP) affects 1%-4% of adults globally and imposes a substantial burden on quality of life. Despite endoscopic surgery, topical corticosteroids, and systemic glucocorticoids, postoperative recurrence exceeds 54% at five years. Even with the advent of biologics targeting downstream type 2 effectors, such as dupilumab, mepolizumab, and omalizumab, a meaningful subset of patients, particularly those with mixed or non-type 2 endotypes, remains inadequately controlled. The epithelial alarmins thymic stromal lymphopoietin (TSLP), interleukin-33 (IL-33), and interleukin-25 (IL-25) occupy the apex of the inflammatory cascade, functioning as proximal triggers that bridge innate barrier disruption to adaptive type 2 amplification. This review examines the shared and distinctive pathobiology of these three molecules in CRSwNP, compares the clinical trajectories of tezepelumab (Phase 3), anti-IL-33/ST2 agents (Phase 2/3), and emerging anti-IL-25 biologics (early-phase), and outlines a conceptual framework for future investigation. We propose that upstream alarmin inhibition offers a broader immunomodulatory scope than downstream cytokine blockade, yet its clinical translation hinges on three unresolved challenges: overcoming functional redundancy among alarmins, defining the long-term safety profile of sustained epithelial-immune suppression, and validating clinically accessible predictive biomarkers. The proposed algorithms and biomarker cut-offs remain exploratory and require prospective validation in CRSwNP-specific cohorts.