Neutralizing the IL-12/IL-23 p40 subunit prevents immune checkpoint blockade toxicity without compromising antitumor efficacy.

Authors

Christianne Groeneveldt, Disha Vadgama, Anne Onrust-van Schoonhoven, Declan Whyte, Maaike M Hofman, Nina E M Rozendaal, Menno van Nimwegen, Mike Eterman, Daphne W Dumoulin, Ron H J Mathijssen, Arjen Joosse, Astrid A M van der Veldt, Louis Boon, Michail Doukas, Janneke N Samsom, Ralph Stadhouders, Floris Dammeijer, Joachim G J V Aerts, Maria E Joosse

Published in

Cancer immunology research. Aug 31, 2026. Epub Aug 31, 2026.

Abstract

Immune checkpoint blockade (ICB) has markedly improved overall survival in various cancers, but is associated with severe and sometimes fatal immune-related adverse events (irAEs). Current management of irAEs involves discontinuation of ICB therapy and administration of immunosuppressive drugs, such as corticosteroids, which have been associated with decreased antitumor efficacy. Although irAE development is associated with ICB response, it is currently unknown whether their underlying mechanisms are shared or distinct. To identify early and targetable drivers of irAEs, we performed proteomic analyses on the serum of patients with cancer treated with anti-PD-1 and anti-CTLA-4 combination ICB. We identified a significantly increased concentration of p40, a subunit of IL-12/IL-23, shortly after the start of ICB but before the onset of clinically apparent irAEs. Importantly, increased p40 levels were not associated with ICB efficacy. Neutralizing p40 mitigated ICB-induced toxicity in various mouse models without impairing ICB-induced antitumor efficacy. In conclusion, we demonstrated that IL-12/IL-23p40 is a key mediator of ICB-induced toxicity while being redundant for ICB antitumor efficacy. This shows that the mechanisms underlying ICB toxicity and efficacy can be uncoupled and provides a rationale for p40 blockade in clinical trials with ICB treatment to prevent irAEs in patients.

PMID:
42671933
Bibliographic data and abstract were imported from PubMed on 01 Sep 2026.

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