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

Fernando, W; WARD, G; Clucas, J; Rizzo, A; Singer, R; Goode, E; Tiu, C; Layzell, S; Konecnik, J; Wilson, R; Wicky John, S; Jouny, S; Guppy, N; Boulat, V; Mannion, J; Goicoechea, M; Tan, S; Lawson, S; Starling, C; Elshtein, G; Ravindran, N; Montgomery, AB; Andres-Ejarque, R; Allen, M; Lumbard, S; Wallberg, F; Betteridge, K; Scrimgeour, R; Robertson, D; Sims, M; Smyth, T; Samson, AL; Murphy, JM; Kolarevic Ivankovic, D; Arwert, EN; Calado, DP; Grigoriadis, A; Smalley, MJ; Melcher, A; Haider, S; Lawrence, T; Roxanis, I; Tutt, ANJ; Tenev, T; Meier, P

Author(s): Fernando, W; WARD, G; Clucas, J; Rizzo, A; Singer, R; Goode, E; Tiu, C; Layzell, S; Konecnik, J; Wilson, R; Wicky John, S; Jouny, S; Guppy, N; Boulat, V; Mannion, J; Goicoechea, M; Tan, S; Lawson, S; Starling, C; Elshtein, G; Ravindran, N; Montgomery, AB; Andres-Ejarque, R; Allen, M; Lumbard, S; Wallberg, F; Betteridge, K; Scrimgeour, R; Robertson, D; Sims, M; Smyth, T; Samson, AL; Murphy, JM; Kolarevic Ivankovic, D; Arwert, EN; Calado, DP; Grigoriadis, A; Smalley, MJ; Melcher, A; Haider, S; Lawrence, T; Roxanis, I; Tutt, ANJ; Tenev, T; Meier, P;
Details: Publication Year 2026-03-06,Volume 17,Issue #1,Page 3597
Journal Title: Nature Communications
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.
Publisher: Springer Nature
Keywords: *Necroptosis/immunology/drug effects/genetics; *Immunotherapy/methods; Humans; Animals; Receptor-Interacting Protein Serine-Threonine Kinases/genetics/metabolism; *Immunogenic Cell Death/immunology/drug effects; Mice; Stromal Cells/immunology/pathology/metabolism/drug effects; Female; *Triple Negative Breast Neoplasms/immunology/therapy/pathology/genetics; Cell Line, Tumor; Protein Kinases/genetics/metabolism; Immune Checkpoint Inhibitors/pharmacology/therapeutic use; Tumor Microenvironment/immunology; Programmed Cell Death 1 Receptor/antagonists & inhibitors/immunology; BRCA1 Protein/genetics; Mice, Knockout; Membrane Proteins/agonists/metabolism; Organoids; Mice, Inbred C57BL
Research Division(s): Inflammation
PubMed ID: 41792126
Publisher's Version: https://doi.org/10.1038/s41467-026-70133-8
Open Access at Publisher's Site: https://doi.org/10.1038/s41467-026-70133-8
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2026-03-16 01:38:27

Last Modified: 2026-04-27 03:54:31