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

Authors

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

Published in

Molecular cancer. Volume 25. Issue 1. Aug 27, 2026. Epub Aug 27, 2026.

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.

PMID:
42711693
Bibliographic data and abstract were imported from PubMed on 09 Sep 2026.

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