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Agrawal, D.* ; Cisarova, K.* ; Vosberg, S.* ; Allmendinger, F.* ; Munkhbaatar, E.* ; Dandachi, N.* ; Fernandez Hernandez, F.J.* ; Tonietto, M.* ; Jäger, V.* ; Anton, M.* ; Keller, E.C.* ; Jesinghaus, M.* ; Meinhardt, A.L.* ; Haefner, V. ; Stöger, T. ; Steiger, K.* ; McGranahan, N.* ; Dengler, M.A.* ; Wahida, A. ; Jost, P.J.*

Aberrant methylation limits antitumoral inflammation in lung adenocarcinoma by restricting RIPK3 expression.

Sci. Adv. 12:eadz9227 (2026)

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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 (RIPK3). Distinct methylation signatures, both in the RIPK3 promoter and nonpromoter regions, correlated with lower transcription levels of RIPK3. 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 Ripk3 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.

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Publication type Article: Journal article

Document type Scientific Article

Keywords Cell-death; Molecular Switch; Necroptosis; Cancer; Kinases; Events

ISSN (print) / ISBN 2375-2548

e-ISSN 2375-2548

Journal Science Advances

Quellenangaben Volume: 12, Issue: 4, Article Number: eadz9227

Publisher American Association for the Advancement of Science (AAAS)

Publishing Place Washington, DC [u.a.]

Reviewing status Peer reviewed

Institute(s) Institute of Metabolism and Cell Death (MCD)
Institute of Lung Health and Immunity (LHI)

Grants Deutsche Krebshilfe
German Research Foundation)
German Consortium for Translational Cancer Research (DKTK)
ZAP Cancer EU HORIZON-WIDERA-2023-ACCESS-02
Austrian Science Fund
EUnetCCC EU4H-2023-JA-3-IBA
INTERACT2 EU4H-2022-PJ-3
DFG (German Research Foundation)
Wellcome Trust
Royal Society
Cancer Research UK Lung Cancer Centre of Excellence
Rosetrees
NIHR BRC at University College London Hospitals
Deutsche Forschungsgemeinschaft (DFG