Aberrant methylation limits antitumoral inflammation in lung adenocarcinoma by restricting RIPK3 expression
Evasion of programmed cell death is a critical hallmark of cancer. However, the contribution of inflammatory forms of cell death in lung carcinogenesis and their effects on the composition of the tumor-immune microenvironment remain unclear. Our multi-omics analyses of samples from patients with primary lung adenocarcinoma revealed that necrosome signaling is repressed because of reduced expression of receptor-interacting protein kinase 3 (<i>RIPK3</i>). Distinct methylation signatures, both in the <i>RIPK3</i> promoter and nonpromoter regions, correlated with lower transcription levels of <i>RIPK3</i>. This resulted in limited expression of inflammatory genes, advanced histologic features, reduced immune cell invasion, and decreased patient survival. Mechanistically, we confirmed the tumor-suppressive role of necrosome signaling through the genetic deletion of <i>Ripk3</i> in two independent, clinically relevant mouse models of lung adenocarcinoma. Functionally, RIPK3 shaped a diverse immune environment by promoting the invasion of innate and adaptive immune cells in patient samples and experimental mice. Thus, RIPK3-mediated inflammatory signaling enhances a diverse immune microenvironment and hinders progression in lung adenocarcinoma.
Authors
- M Anton
- F. Allmendinger (ORCID: https://orcid.org/0009-0000-1812-7198)
- Francisco José Fernández Hernández
- Vanessa Jäger (ORCID: https://orcid.org/0009-0003-7761-3606)
- Katarina Cisarova (ORCID: https://orcid.org/0000-0003-2711-0480)
- K. Steiger
- Sebastian Vosberg (ORCID: https://orcid.org/0000-0002-8464-1483)
- Eva C. Keller (ORCID: https://orcid.org/0000-0001-6146-9425)
- Enkhtsetseg Munkhbaatar (ORCID: https://orcid.org/0000-0002-2427-5952)
- Deepti Agrawal (ORCID: https://orcid.org/0000-0002-9541-1704)
- Adam Wahida (ORCID: https://orcid.org/0000-0002-8856-8834)
- Nadia Dandachi (ORCID: https://orcid.org/0000-0001-9093-0743)
- Michael A. Dengler (ORCID: https://orcid.org/0000-0002-1693-1761)
- Philipp J. Jost (ORCID: https://orcid.org/0000-0003-2454-0362)
- Tobias Stoeger (ORCID: https://orcid.org/0000-0002-2790-0389)
- Verena Haefner
- Marta Tonietto
- Anna-Lena Meinhardt
- Nicholas McGranahan
- Moritz Jesinghaus
Institutions
- Philipps University of Marburg (DE)
- German Cancer Research Center (DE)
- Medical University of Graz (AT)
- Heidelberg University (DE)
- University Hospital Heidelberg (DE)
- TUM Klinikum (DE)
- Helmholtz Zentrum München (DE)
- London Cancer (GB)
- Graz University Hospital (AT)
- National Center for Tumor Diseases (DE)
- BioTechMed-Graz (AT)
- German Center for Lung Research (DE)
- CRUK Lung Cancer Centre of Excellence (GB)
- Deutsches Konsortium für Translationale Krebsforschung (DE)
- University College London (GB)
- Technical University of Munich (DE)
- Ludwig-Maximilians-Universität München (DE)
Publication Details
- Journal
- Science Advances
- Published
- 2026-01-21
- DOI
- https://doi.org/10.1126/sciadv.adz9227
- Primary Topic
- interferon and immune responses
- Type
- article
- Field-Weighted Citation Impact
- 0.00