A targetable dependency on nonsense-mediated decay for cellular homeostasis and immune control in small cell lung cancer

Abstract Small cell lung cancer (SCLC) is one of the most aggressive malignancies, characterized by rapid metastatic dissemination and poor overall survival. Despite harboring excessive alterations, expectedly resulting in immunogenic neoantigens, patients with SCLC remain largely refractory to immunotherapy. We found abundant frameshift mutations in SCLC, regarded as highly immunogenic, counterbalanced by a hyperactive nonsense-mediated decay (NMD) pathway, responsible for frameshift-mRNA degradation. NMD activity correlated with tumor mutational burden (TMB) across cancers, suggesting that SCLC and other TMB high cancers may depend on NMD to limit the accumulation of mutation-derived byproducts in order to maintain cellular homeostasis and evade immune recognition. In TMB high SCLC models, inhibition of NMD impaired cell proliferation and induced ER stress-dependent apoptosis due to the accumulation of misfolded proteins. Genetic and pharmacological NMD inhibition in vivo effectively controlled TMB high tumor growth without overt toxicity. By integrating genome and transcriptome sequencing with MHC-I immunopeptidomics and functional in vitro and in vivo assays, we identified that NMD inhibition boosted neoantigen expression and presentation by tumor cells and increased T cell recognition, thus enhancing overall tumor immunogenicity and further improving immunotherapy efficacy in vivo . Our work shows that SCLC – as a TMB high cancer – relies on NMD for survival and immune escape, uncovering a novel TMB-dependent tractable vulnerability for this devastating disease.

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Publication Details

Journal
Molecular Cancer
Published
2026-08-27
DOI
https://doi.org/10.1186/s12943-026-02750-2
Primary Topic
Lung Cancer Research Studies
Type
article
Field-Weighted Citation Impact
0.00

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article

A targetable dependency on nonsense-mediated decay for cellular homeostasis and immune control in small cell lung cancer

Justinas Valiulis, Cécile Gouttefangeas, Hans Christian Reinhardt, Silvia von Karstedt et al.
Molecular Cancer
Lung Cancer Research Studies
article

A targetable dependency on nonsense-mediated decay for cellular homeostasis and immune control in small cell lung cancer

Justinas Valiulis, Cécile Gouttefangeas, Hans Christian Reinhardt, Silvia von Karstedt, Marian Touet, Filippo Beleggia, Olta Ibruli, Ariadne Androulidaki, Hanna Schulte, Alexander Quaas, Anna Schöllhorn, Marcel Schmiel, Katja Höpker, Poorya Davoodi, Vignesh Sakthivelu, Martin Peifer, Nazanin Alavinejad, Lucia Torres Fernández, Beaunelle de Bruijn, Graziella Bosco, Maria Cartolano, Lukas Maas, Agnieszka Rumińska, Felix John, María García Márquez, Johanna Bihler, Nina Wobst, Laura Lovric, Kian R. Weihrauch, Bianca Göbel, Hans A. Schlößer, Roman K. Thomas, Julie George, Johannes Brägelmann, Angelika B. Riemer, Jonas P. Becker, Niels H. Gehring, Hans-Georg Rammensee, Christian Müller, Laura Kaiser, Jürgen Wolf, Volker Boehm, Stefan Knapp, Fanyu Liu, Joshua D’Rozario, Joel Kaufmann
article en

Abstract

Abstract Small cell lung cancer (SCLC) is one of the most aggressive malignancies, characterized by rapid metastatic dissemination and poor overall survival. Despite harboring excessive alterations, expectedly resulting in immunogenic neoantigens, patients with SCLC remain largely refractory to immunotherapy. We found abundant frameshift mutations in SCLC, regarded as highly immunogenic, counterbalanced by a hyperactive nonsense-mediated decay (NMD) pathway, responsible for frameshift-mRNA degradation. NMD activity correlated with tumor mutational burden (TMB) across cancers, suggesting that SCLC and other TMB high cancers may depend on NMD to limit the accumulation of mutation-derived byproducts in order to maintain cellular homeostasis and evade immune recognition. In TMB high SCLC models, inhibition of NMD impaired cell proliferation and induced ER stress-dependent apoptosis due to the accumulation of misfolded proteins. Genetic and pharmacological NMD inhibition in vivo effectively controlled TMB high tumor growth without overt toxicity. By integrating genome and transcriptome sequencing with MHC-I immunopeptidomics and functional in vitro and in vivo assays, we identified that NMD inhibition boosted neoantigen expression and presentation by tumor cells and increased T cell recognition, thus enhancing overall tumor immunogenicity and further improving immunotherapy efficacy in vivo . Our work shows that SCLC – as a TMB high cancer – relies on NMD for survival and immune escape, uncovering a novel TMB-dependent tractable vulnerability for this devastating disease.

Molecular Cancer
Goethe University Frankfurt (DE), German Cancer Research Center (DE), University of Cologne (DE), Heidelberg University (DE), University Hospital Heidelberg (DE), Düsseldorf University Hospital (DE), National Center for Tumor Diseases (DE), German Center for Infection Research (DE), Essen University Hospital (DE), Bernstein Center for Computational Neuroscience Tübingen (DE), Cologne Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases (DE), University Hospital Cologne (DE), Guided Therapeutics (United States) (US), Heinrich Heine University Düsseldorf (DE), University of Tübingen (DE)
Universitätsklinikum Köln
No poverty
Openalex Percentile: Top 14%
Lung Cancer Research Studies
DOIOpen Access PDFOpenAlex
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