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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\n                    <jats:sup>high<\/jats:sup>\n                    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\n                    <jats:sup>high<\/jats:sup>\n                    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\n                    <jats:italic>in vivo<\/jats:italic>\n                    effectively controlled TMB\n                    <jats:sup>high<\/jats:sup>\n                    tumor growth without overt toxicity. By integrating genome and transcriptome sequencing with MHC-I immunopeptidomics and functional\n                    <jats:italic>in vitro<\/jats:italic>\n                    and\n                    <jats:italic>in vivo<\/jats:italic>\n                    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\n                    <jats:italic>in vivo<\/jats:italic>\n                    . Our work shows that SCLC \u2013 as a TMB\n                    <jats:sup>high<\/jats:sup>\n                    cancer \u2013 relies on NMD for survival and immune escape, uncovering a novel TMB-dependent tractable vulnerability for this devastating disease.\n                  <\/jats:p>","DOI":"10.1186\/s12943-026-02750-2","type":"journal-article","created":{"date-parts":[[2026,8,27]],"date-time":"2026-08-27T13:16:23Z","timestamp":1787836583000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["A targetable dependency on nonsense-mediated decay for cellular homeostasis and immune control in small cell lung cancer"],"prefix":"10.1186","volume":"25","author":[{"given":"Lucia 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All animal experiments were approved by and conduced in accordance with the regulations of the State Agency for Consumer Protection and Nutrition of the State of North Rhine-Westphalia (LAVE,\n                      Landesamt f\u00fcr Verbraucherschutz und Ern\u00e4hrung, Nordrhein-Westfalen\n                      , AZ 81-02.04.2018.A002 and AZ 81-02.04.2022.A394).","order":1,"name":"Ethics","label":"Ethics approval and consent to participate","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"Not applicable","order":2,"name":"Ethics","label":"Consent for publication","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"RKT is founder and shareholder of PearlRiver Bio, now acquired by Centessa, a shareholder of Centessa, and founder and shareholder of DISCO Pharmaceuticals. JG is a consultant to DISCO Pharmaceuticals and Tessellate Bio, and received honoraria from MSD and Boehringer Ingelheim. AS is a shareholder of AID Autoimmun Diagnostika GmbH. JPB has received research funding from Bayer outside of the submitted work. HCR received consulting and lecture fees from Abbvie, Roche, KinSea, Vitis, Cerus, Lilly, Novartis, Takeda, AstraZeneca, Vertex, and Merck. HCR received research funding from AstraZeneca and Gilead Pharmaceuticals. HAS received funding for research by Astra Zeneca.","order":3,"name":"Ethics","label":"Competing interests","group":{"name":"EthicsHeading","label":"Declarations"}}],"article-number":"210"}}