Oncogenic KRAS-driven type I interferon signalling primes pancreatic cancer for necroptosis

作者：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 S. Gülcüler Balta, Fanyu Liu, Ali T. Abdallah, Christina M. Bebber, Moritz Reese, Jonathan Lim, Alexander Quaas, Johannes Brägelmann, Manolis Pasparakis, Filippo Beleggia, Siddharth Balachandran, Anna Trauzold, Gianmaria Liccardi, Igor Astsaturov, Maximilian Reichert, Ariadne Androulidaki, Silvia von Karstedt · 发表于：Nature Communications · 年份：2026 · DOI：10.1038/s41467-026-73189-8 · 研究领域：interferon and immune responses、Cell death mechanisms and regulation、NF-κB Signaling Pathways

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.