Nonsense-mediated mRNA decay inhibition reshapes the cancer immunopeptidome

DNA mutations are a well-characterized source of neoepitopes in immunotherapy. Here, we examined the contribution of dysregulated RNA processing to neoantigen production. Leveraging multi-omics and checkpoint inhibitor (CPI) response data from >1,000 patients, we identified reduced activity of the nonsense-mediated mRNA decay (NMD) pathway kinase SMG1 as a predictor of improved CPI response. NMD inhibition through SMG1 targeting stabilized transcripts containing premature termination codons, most of which were of non-mutational origin. This reshaped the major histocompatibility complex class I (MHC class I)-bound immunopeptidome and increased neoantigen abundance to levels comparable to high mutation burden tumors. Functionally, NMD inhibition drove antigen-dependent T cell-mediated tumor cell killing in vitro, promoted activation of tissue-resident T cells in patient-derived models ex vivo, and improved CPI efficacy in vivo. Our findings establish NMD inhibition as a strategy to harness a previously inaccessible source of canonical and non-canonical neoantigens, with the potential to increase tumor immunogenicity across cancers.

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Publication Details

Journal
Immunity
Published
2026-04-01
DOI
https://doi.org/10.1016/j.immuni.2026.02.005
Primary Topic
RNA and protein synthesis mechanisms
Type
article
Field-Weighted Citation Impact
0.00

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article

Nonsense-mediated mRNA decay inhibition reshapes the cancer immunopeptidome

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Immunity
RNA and protein synthesis mechanisms
article

Nonsense-mediated mRNA decay inhibition reshapes the cancer immunopeptidome

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article en

Abstract

DNA mutations are a well-characterized source of neoepitopes in immunotherapy. Here, we examined the contribution of dysregulated RNA processing to neoantigen production. Leveraging multi-omics and checkpoint inhibitor (CPI) response data from >1,000 patients, we identified reduced activity of the nonsense-mediated mRNA decay (NMD) pathway kinase SMG1 as a predictor of improved CPI response. NMD inhibition through SMG1 targeting stabilized transcripts containing premature termination codons, most of which were of non-mutational origin. This reshaped the major histocompatibility complex class I (MHC class I)-bound immunopeptidome and increased neoantigen abundance to levels comparable to high mutation burden tumors. Functionally, NMD inhibition drove antigen-dependent T cell-mediated tumor cell killing in vitro, promoted activation of tissue-resident T cells in patient-derived models ex vivo, and improved CPI efficacy in vivo. Our findings establish NMD inhibition as a strategy to harness a previously inaccessible source of canonical and non-canonical neoantigens, with the potential to increase tumor immunogenicity across cancers.

Immunity
The Francis Crick Institute (GB), Cancer Research UK (GB), London Cancer (GB), Oncode Institute (NL), Cancer Research Horizons (GB), CRUK Lung Cancer Centre of Excellence (GB), The Patients Association (GB), University College London (GB), Weizmann Institute of Science (IL), Universitat Politècnica de Catalunya (ES)
Cancer Research Institute, Breast Cancer Research Foundation, European Association for Cancer Research, Melanoma Research Alliance, Wellcome Trust, Mark Foundation For Cancer Research, Royal Marsden Cancer Charity, Cancer Research UK, National Institute for Health and Care Research, Royal Society, University College London, University of Oxford, Rosetrees Trust, Israel Science Foundation, Barcelona Supercomputing Center, Novo Nordisk Fonden, CRUK Lung Cancer Centre of Excellence, Medical Research Council, Biotechnology and Biological Sciences Research Council, European Research Council, University College London Hospitals Biomedical Research Centre, H2020 Marie Skłodowska-Curie Actions
Good health and well-being
Openalex Percentile: Top 26%
RNA and protein synthesis mechanisms
DOIOpen Access PDFOpenAlex
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