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

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

  • Nat Commun. 2026 Jun 15;17(1):5288. doi: 10.1038/s41467-026-73189-8.
Sofya Tishina 1 2,  Alina Dahlhaus 1 2,  Marta Manik 1 2,  Lejla Mulalic 1 2,  Janine Murr 3 4,  Michael Kotliar 5,  Hassan Rakhsh-Khorshid 6,  Myrto Kostopoulou 1 2,  Florian Hocher 7,  Jenny Stroh 1 2,  Julia Beck 1 2,  Riley M Williams 8,  Gülce G Balta 1 2,  Fanyu Liu 1 2,  Ali T Abdallah 2 9,  Christina M Bebber 1 2,  Moritz Reese 1 2,  Jonathan K M Lim 10,  Alexander Quaas 11,  Johannes Brägelmann 1 2 12 13,  Manolis Pasparakis 2 13 14,  Filippo Beleggia 1 2,  Siddharth Balachandran 8,  Anna Trauzold 7 15,  Gianmaria Liccardi 6,  Igor Astsaturov 16,  Maximilian Reichert 3 5 17 18,  Ariadne Androulidaki 1 2,  Silvia von Karstedt 19 20 21
Affiliations

Affiliations

  • 1 University of Cologne, Faculty of Medicine and University Hospital Cologne, Department of Translational Genomics, Cologne, Germany.
  • 2 CECAD Cluster of Excellence, Faculty of Medicine and University Hospital Cologne, Cologne, Germany.
  • 3 Translational Pancreatic Cancer Research Centre, TUM School of Medicine and Health, Department of Clinical Medicine - Clinical Department for Internal Medicine II, TUM University Hospital, Technical University of Munich, Munich, Germany.
  • 4 Centre for Organoid Systems (COS), Technical University Munich (TUM), Garching, Germany.
  • 5 Cincinnati Children's Hospital Medical Center, Division of Allergy and Immunology, Cincinnati, OH, USA.
  • 6 University of Cologne, Faculty of Medicine and University Hospital Cologne, Centre for Biochemistry, Cologne, Germany.
  • 7 University of Kiel, Institute for Experimental Cancer Research, Kiel, Germany.
  • 8 Fox Chase Cancer Center, Cancer Signaling and Microenvironment Program, Philadelphia, PA, USA.
  • 9 Institute of Medical Statistics and Computational Biology, Faculty of Medicine, University of Cologne, Cologne, Germany.
  • 10 Heinrich Heine University, Medical Faculty and University Hospital Düsseldorf, Institute of Neuropathology, Düsseldorf, Germany.
  • 11 University of Cologne, Faculty of Medicine and University Hospital Cologne, Institute of Pathology, Cologne, Germany.
  • 12 University Hospital Cologne, Mildred Scheel School of Oncology, Cologne, Germany.
  • 13 University Hospital Cologne, Centre for Molecular Medicine Cologne (CMMC), Cologne, Germany.
  • 14 University of Cologne, Institute for Genetics, Cologne, Germany.
  • 15 University Hospital Schleswig-Holstein (UKSH), Department of Gynecology and Obstetrics, Campus Kiel, Kiel, Germany.
  • 16 Fox Chase Cancer Center, Molecular Therapeutics Program, Philadelphia, PA, USA.
  • 17 German Cancer Consortium (DKTK), partner site Munich, a partnership between DKFZ and TUM University Hospital, Munich, Germany.
  • 18 Bavarian Cancer Research Centre (BZKF), Munich, Germany.
  • 19 University of Cologne, Faculty of Medicine and University Hospital Cologne, Department of Translational Genomics, Cologne, Germany. [email protected].
  • 20 CECAD Cluster of Excellence, Faculty of Medicine and University Hospital Cologne, Cologne, Germany. [email protected].
  • 21 University Hospital Cologne, Centre for Molecular Medicine Cologne (CMMC), Cologne, Germany. [email protected].
PMID: 42297776 DOI: 10.1038/s41467-026-73189-8
Abstract

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.

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