Journal Article

DKFZ-2026-02218

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png A targetable dependency on nonsense-mediated decay for cellular homeostasis and immune control in small cell lung cancer.

Torres-Fernández, L. A. ; Boehm, V. ; Kaufmann, J. ; Becker, J.DKFZ* ; Garcia-Marquez, M. ; de Bruijn, B. ; Rumińska, A. ; Müller, C. ; Bosco, G. ; Alavinejad, N. ; Lovric, L. ; Bihler, J. I. ; Schulte, H. ; Davoodi, P. ; Schöllhorn, A. ; Weihrauch, K. R. ; Kaiser, L. ; Ibruli, O. ; Liu, F. ; Androulidaki, A. ; Wobst, N. ; Schmiel, M. ; Valiulis, J. ; Maas, L. ; D'Rozario, J. ; Sakthivelu, V. ; Göbel, B. ; Touet, M. ; Brägelmann, J. ; Höpker, K. ; John, F. ; Wolf, J. ; Knapp, S. ; Quaas, A. ; Cartolano, M. ; von Karstedt, S. ; Beleggia, F. ; Rammensee, H.-G.DKFZ* ; Gouttefangeas, C.DKFZ* ; Schlößer, H. A. ; Riemer, A. B.DKFZ* ; Reinhardt, H. C. ; Gehring, N. H. ; Peifer, M. ; Thomas, R. K. ; George, J.

2026
Biomed Central London

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 TMBhigh cancers may depend on NMD to limit the accumulation of mutation-derived byproducts in order to maintain cellular homeostasis and evade immune recognition. In TMBhigh 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 TMBhigh 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 TMBhigh cancer - relies on NMD for survival and immune escape, uncovering a novel TMB-dependent tractable vulnerability for this devastating disease.

Keyword(s): Cancer genomics ; Cancer immunotherapy ; Frameshift mutations ; Genomic instability ; Neoantigen ; Nonsense mediated decay (NMD) ; Proteostasis ; RNA surveillance ; Small cell lung cancer (SCLC) ; Tumor mutational burden (TMB)

Note: 2026 Aug 27;25(1):210 / #DKTKZFB26# / #NCTZFB26#

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Contributing Institute(s):

1. Immuntherapie und -prävention (D410)
2. DKTK Koordinierungsstelle Tübingen (TU01)
3. Koordinierungsstelle NCT Heidelberg (HD02)

Research Program(s):

1. 314 - Immunologie und Krebs (POF4-314) (POF4-314)

Appears in the scientific report 2026

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Database coverage:
; ; Article Processing Charges ; BIOSIS Previews ; Biological Abstracts ; Clarivate Analytics Master Journal List ; Current Contents - Life Sciences ; DOAJ Seal ; Ebsco Academic Search ; Essential Science Indicators ; Fees ; IF >= 30 ; JCR ; PubMed Central ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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