Oncogenic KRAS-driven type I interferon signalling primes pancreatic cancer for necroptosis
- Sofya Tishina
- Alina Dahlhaus
- Marta Manik
- Lejla Mulalic
- Janine Murr
- Michael Kotliar
- Hassan Rakhsh-Khorshid
- Myrto Kostopoulou
- Florian Hocher
- Jenny Stroh
- Julia Beck
- Riley M. Williams
- Gülce G. Balta
- Fanyu Liu
- Ali T. Abdallah
- Christina M. Bebber
- Moritz Reese
- Jonathan K. M. Lim
- Alexander Quaas
- Johannes Brägelmann
- Manolis Pasparakis
- Filippo Beleggia
- Siddharth Balachandran
- Anna Trauzold
- Gianmaria Liccardi
- Igor Astsaturov
- Maximilian Reichert
- Ariadne Androulidaki
- Silvia von Karstedt
2026-06-15
Pancreatic ductal adenocarcinoma (PDAC) is projected to become the second leading cause of cancer-related death within this decade. Here, we show that its major driver oncogene KRAS activates the cGAS-STING-TBK1 axis, inducing a type I interferon (IFN) response that primes PDAC cells for necroptosis. Using genetically engineered mouse models, we find that cancer cell-specific deletion of caspase-8 is sufficient to trigger necroptotic cell death, eliminating most pancreatic precursor lesions. Mechanistically, KRAS-driven IFN signalling induces ISGF3-dependent expression of necroptosis-related interferon-stimulated genes, including MLKL. This renders PDAC cells selectively vulnerable to necroptosis upon caspase-8 inhibition. Therapeutically, pharmacologic caspase inhibition reduces tumour burden in aggressive PDAC models and human patient-derived organoids. A pan-cancer transcriptomic analysis links necroptosis gene expression with Ras pathway activity and IFN signatures across multiple tumour types. These findings reveal a KRAS-induced IFN program that sensitises tumour cells to necroptosis, highlighting a therapeutic vulnerability in PDAC with broader relevance across IFN-activated cancers.