Non-canonical caspase-8 activation by cathepsin B drives anti-inflammatory human macrophage polarization
Anti-inflammatory monocyte-derived macrophages are essential to maintain tissue homeostasis but can also contribute to disease progression, notably in cancer and fibrosis. Deciphering the signaling pathways that govern their generation could therefore unlock new therapeutic opportunities. Here we uncover a previously unrecognized, non-apoptotic function of caspase-8 in driving both monocyte-to-macrophage differentiation and anti-inflammatory macrophages polarization. We identified cathepsin B as a novel upstream activator of caspase-8 through a non-canonical cleavage mechanism, conferring to caspase-8 an original activity profile distinct from its apoptotic role. Disruption of this cathepsin B-caspase-8 axis, either genetically or pharmacologically, not only impairs the generation of anti-inflammatory macrophages but also reprograms them towards a pro-inflammatory phenotype. Our findings position the cathepsin B-caspase-8 axis as an original critical regulatory node in macrophage fate decisions and a promising target for therapeutic reprogramming of human macrophages in cancer, inflammation and fibrotic diseases.
Authors
- Paul Chaintreuil (ORCID: https://orcid.org/0000-0002-4845-7304)
- Johanna Chiche (ORCID: https://orcid.org/0000-0001-5276-1125)
- Sonia Boulakirba (ORCID: https://orcid.org/0000-0001-7089-0860)
- Michael L. Loschi (ORCID: https://orcid.org/0000-0002-4460-5939)
- Emeline Kerreneur (ORCID: https://orcid.org/0009-0009-4349-1931)
- Maxence Bourgoin
- Stoyan Ivanov (ORCID: https://orcid.org/0000-0002-0527-2297)
- Arnaud Jacquel (ORCID: https://orcid.org/0000-0001-5062-8048)
- Patrick Auberger (ORCID: https://orcid.org/0000-0002-2481-8275)
- Adèle Rivault (ORCID: https://orcid.org/0009-0000-2773-6315)
- Guillaume Robert (ORCID: https://orcid.org/0000-0002-6350-2222)
- Anne Doye (ORCID: https://orcid.org/0000-0001-6466-9326)
- Jean‐François Peyron (ORCID: https://orcid.org/0000-0001-6113-916X)
- Amaury Aouad
- Alexandre Gallerand (ORCID: https://orcid.org/0000-0002-3127-1343)
- Thomas Cluzeau (ORCID: https://orcid.org/0000-0002-6745-1127)
- Nathalie M Droin (ORCID: https://orcid.org/0000-0002-6099-5324)
- Juba Bennour
- Laurent Boyer (ORCID: https://orcid.org/0000-0003-1229-6622)
- Cécile Favreau
- Chloe Delaby
- Morgane Fajolles
- Els Verhoeyen
Institutions
- Université Paris-Sud (FR)
- Centre National de la Recherche Scientifique (FR)
- Inserm (FR)
- Université Côte d'Azur (FR)
- Institut Gustave Roussy (FR)
- Centre Hospitalier Universitaire de Nice (FR)
- La Ligue Contre le Cancer (FR)
- Hôpital l'Archet (FR)
- Centre Méditerranéen de Médecine Moléculaire (FR)
Publication Details
- Journal
- Cell Death and Differentiation
- Published
- 2026-10-29
- DOI
- https://doi.org/10.1038/s41418-026-01896-2
- Primary Topic
- Immune cells in cancer
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Institut National de la Santé et de la Recherche Médicale
- Fondation ARC pour la Recherche sur le Cancer
- Institut National Du Cancer
- Institut Carnot Santé Animale