Necroptosis in both tumour and stromal compartments determines responsiveness to immunogenic cell death-based immunotherapy

Fernando, Winnie, Clucas, Jarama, Singer, Ramsey, Goode, Emily, Tiu, Crescens, Layzell, Scott, Konecnik, Joshua, Wilson, Rebecca, John, Sidonie Wicky, Jouny, Samuel, Guppy, Naomi, Boulat, Victoria, Mannion, Jonathan, Goicoechea, Maria, Tan, Shaun, Lawson, Sam, Starling, Chris, Elshtein, Gabrielle, Ravindran, Nivedita and Smalley, Matthew J. ORCID: https://orcid.org/0000-0001-9540-1146 2026. Necroptosis in both tumour and stromal compartments determines responsiveness to immunogenic cell death-based immunotherapy. Nature Communications 10.1038/s41467-026-70133-8

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Abstract

Immunotherapy has transformed cancer treatment, including early triple-negative breast cancer (TNBC), yet most patients with advanced TNBC fail to respond to immune checkpoint blockade (ICB) plus chemotherapy. Durable control likely requires not only tumour cell killing but also immunogenic cell death (ICD) that activates antitumour immunity. Using a Brca1⁻/⁻p53⁻/⁻ organoid-derived TNBC model that recapitulates the immune landscapes of basal-like tumours, we show that RIPK1-driven ICD synergises with anti-PD-1 therapy to induce durable tumour control and immune memory in immune-infiltrated tumours. Mechanistically, both tumour-intrinsic and stromal necroptosis are required. Deletion of Ripk1 or Mlkl in tumour cells, or Mlkl in the stromal compartment, markedly impairs therapeutic efficacy. Moreover, immunologically “cold” tumours can be rendered responsive to ICD-based therapy by STING agonists. These findings demonstrate that the benefit of IAP antagonism with checkpoint blockade critically depends on coordinated necroptosis in both tumour and stromal cells, underscoring the need to integrate tumour microenvironmental context when designing ICD-targeted immunotherapies.

Item Type:	Article
Date Type:	Published Online
Status:	In Press
Schools:	Schools > Biosciences
Additional Information:	Full author list: Winnie Fernando, Jarama Clucas, Alberto Rizzo, Ramsay Singer, Emily Goode, Crescens Tiu, Scott Layzell, Joshua Konecnik, Rebecca Wilson, Sidonie Wicky John, Samuel Jouny, Naomi Guppy, Victoire Boulat, Jonathan Mannion, Maria Goicoechea, Shaun Tan, Sam Lawson, Chris Starling, Gabrielle Elshtein, Nivedita Ravindran, Anna B. Montgomery, Rosa Andres-Ejarque, Mark Allen, Steven Lumbard, Fredrik Wallberg, Kai Betteridge, Ross Scrimgeour, David Robertson, George Ward, Martin Sims, Tomoko Smyth, Andre L. Samson, James M. Murphy, Daniela Kolarevic Ivankovic, Esther N. Arwert, Dinis P. Calado, Anita Grigoriadis, Matthew J. Smalley, Alan Melcher, Syed Haider, Toby Lawrence, Ioannis Roxanis, Andrew N. J. Tutt, Tencho Tenev & Pascal Meie.
Publisher:	Nature Research
ISSN:	2041-1723
Date of First Compliant Deposit:	16 March 2026
Date of Acceptance:	19 February 2026
Last Modified:	16 Mar 2026 11:15
URI:	https://orca.cardiff.ac.uk/id/eprint/185756

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