Understanding the roles of interleukin-33: is there promise for therapeutic targeting?

IL-33 is a chromatin-associated alarmin of the IL-1 cytokine family involved in tissue homeostasis and immune responses following epithelial or endothelial injury. Although the IL-33/ST2 axis is an attractive therapeutic target, clinical outcomes with IL-33- or ST2-directed agents have varied across diseases and patient populations.

This review examines IL-33 biology and the clinical development of tozorakimab, itepekimab, astegolimab and emerging multispecific antibodies across COPD, asthma, atopic dermatitis, food allergy, diabetic kidney disease and viral pneumonia. Particular attention is given to IL-33 oxidation, RAGE/EGFR-associated signaling, soluble ST2, tissue compartment, therapeutic modality and trial design, and to the distinction between pathway activation and pathogenic dependence.

IL-33 remains a promising but context-dependent therapeutic target. Phase 3 COPD trials provide the strongest evidence, particularly for tozorakimab, whereas outcomes with other agents and indications remain inconsistent. Future development should define disease- and endotype-specific dependence on IL-33, clarify the relevance of ST2-independent signaling and soluble ST2, and validate predictive biomarkers using form-resolved assays. Structural differences among anti-IL-33 antibodies may also influence activity, but comparative clinical evidence is lacking. Multispecific approaches may broaden efficacy, but their advantages over established biologics remain to be demonstrated and require prospective evaluation in biomarker-defined patient populations.