Necroptosis in both tumour and stromal compartments determines responsiveness to immunogenic cell death-based immunotherapy
Abstract
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.
Article Details
Authors (45)
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
Department of Chemistry
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 Meier