Abstract Small cell lung cancer (SCLC) is a highly aggressive cancer with one of the highest tumor mutational burden (TMB), but patients show only limited response to immunotherapy. The nonsense-mediated decay (NMD) pathway is responsible for the degradation of mutant transcripts thereby enabling tumors to cope with somatic alterations and contributing to immune evasion. We therefore hypothesized that inhibition of NMD in TMBhigh tumors such as SCLC may disrupt cellular homeostasis while promoting anti-tumor immunity. We have profiled the mutational landscape of 400 SCLC patients and generated 100 patient-derived xenotransplant models. Analysis of NMD activity in our SCLC cohort and across all cancers within the TCGA revealed a hyperactive NMD pathway in SCLC and other TMBhigh tumors, suggesting that an increased NMD efficiency may be required to cope with such an elevated mutational load. Inhibition of NMD in SCLC led to a massive accumulation of faulty transcripts resulting in cell cycle arrest and ER stress-dependent apoptosis, with the degree of cell death vulnerability correlating with the samples’ TMB. Accordingly, non-neoplastic cells and TMBlow tumors exhibited greater tolerance to NMD inhibition, whereas induction of hypermutation in TMBlow tumors rendered them susceptible to NMD inhibition, supporting a potential therapeutic index for in vivo treatment. Pharmacological NMD inhibition in immunocompromised mice successfully decreased tumor growth of TMBhigh tumors without overt toxicity, demonstrating for the first time a tumor-specific cell-autonomous vulnerability to NMD inhibition. We furthermore evaluated neoantigen expression and presentation after NMD inhibition in SCLC. Genome sequencing followed by transcriptome sequencing and HLA-I-binding modeling predicted an upregulation of hundred-thousands of neoantigens per sample upon NMD inhibition. HLA-I ligandomics revealed substantial changes in the presented peptidome of NMD inhibited samples, and in vitro assays confirmed a remarkably high immunogenicity of NMD-regulated neoantigens as well as an enhanced HLA-I-dependent T cell-mediated tumor killing upon NMD inhibition. Tumor-targeted inhibition of NMD in immunocompetent (C57BL/6) and immunocompromised mouse models (NSG and RAG1-KO) confirmed increased T cell infiltration and a T cell-dependent control of tumor growth in vivo, accompanied by a greater clonotype diversity as determined by single-cell TCR sequencing, consistent with an expanded neoantigen repertoire. We thus demonstrate for the first time a critical dependency of TMBhigh tumors on enhanced NMD activity to manage mutation-derived byproducts and sustain tumor growth. NMD inhibition in SCLC led to an unbearable accumulation of mutant transcripts which, on the one hand, triggered ER stress and cell-intrinsic apoptosis, and on the other hand, translated into neoantigens that enhanced tumor immunogenicity. This dual TMB-dependent vulnerability to NMD inhibition offers an opportunity for developing novel tumor-targeted therapies in SCLC and potentially other TMBhigh tumors. Citation Format: Lucia A. Torres Fernández, Volker Boehm, Joel Kaufmann, Agnieszka Rumińska, Jonas P. Becker, Maria Garcia Marquez, Beaunelle de Bruijn, Christian Müller, Nazanin Alavinejad, Laura Lovric, Johanna Bihler, Kian R. Weihrauch, Laura Kaiser, Marcel Schmiel, Lukas Maas, Filippo Beleggia, Olta Ibruli, Bianca Göbel, Vignesh Sakthivelu, Graziella Bosco, Liu Fanyu, Ariadne Androulidaki, Silvia von Karstedt, Maria Cartolano, Johannes Brägelmann, Justinas Valiulis, Joshua D’Rozario, Nina Wobst, Katja Höpker, Felix John, Jürgen Wolf, Alexander Quaas, Stefan Knapp, Poorya Davoodi, Anna Schöllhorn, Cécile Gouttefangeas, Hans-Georg Rammensee, Angelika B. Riemer, Hans C. Reinhardt, Hans A. Schlößer, Niels H. Gehring, Martin Peifer, Roman K. Thomas, Julie George. Inhibition of nonsense-mediated decay in small cell lung cancer promotes tumor cell-intrinsic death and T cell cytotoxicity abstract. In: Proceedings of the AACR Immuno-Oncology Conference (AACR IO): Discovery and Innovation in Cancer Immunology: Revolutionizing Treatment through Immunotherapy; 2026 Feb 18-21; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Immunol Res 2026;14(2 Suppl):Abstract nr A073.
Fernández et al. (Wed,) studied this question.