Nonsense-mediated mRNA decay inhibition reshapes the cancer immunopeptidome PMID: 41956098

ADC Targets in Oncology

2026-04-10

Nonsense-mediated mRNA decay inhibition reshapes the cancer immunopeptidome

Immunity. 2026 May 12;59(5):1398-1421.e20. doi: 10.1016/j.immuni.2026.02.005.

Roberto Vendramin ¹ , Hongchang Fu ² , Shanila Fernandez Patel ³ , Yue Zhao ⁴ , Danwen Qian ⁵ , Lorena Ligammari ⁵ , Osnat Bartok ⁶ , Polina Greenberg ⁶ , Ronen Levy ⁶ , Andrea Castro ⁵ , Krupa Thakkar ⁷ , Jun Murai ⁸ , Wei-Ting Lu ⁹ , Christopher C T Sng ⁵ , Chen Weller ⁶ , Gordon Beattie ¹⁰ , Amandeep Bhamra ¹¹ , Roc Farriol-Duran ¹² , Despoina Karagianni ¹³ , Marcellus Augustine ¹⁴ , Krijn K Dijkstra ¹⁵ , Christopher L Pinder ⁵ , Benjamin S Simpson ⁵ , Gordon Weng-Kit Cheung ¹⁶ , TRACERx Consortium , Felipe Galvez-Cancino ¹⁷ , Petra Vlckova ¹⁸ , Silvia Surinova ¹¹ , Manuel Rodriguez-Justo ¹⁹ , Mansi Shah ²⁰ , Nicholas McGranahan ²¹ , Jeremy G Carlton ²² , Eva Grönroos ²³ , James L Reading ²⁴ , Yardena Samuels ⁶ , Charles Swanton ²⁵ , Sergio A Quezada ²⁶ , Kevin Litchfield ²⁷

Affiliations

1. The Tumor Immunogenomics and Immunosurveillance Lab, University College London Cancer Institute, London, UK; Cancer Evolution and Genome Instability Lab, The Francis Crick Institute, London, UK; CRUK Lung Cancer Centre of Excellence, University College London Cancer Institute, London, UK. Electronic address: [email protected].
2. The Tumor Immunogenomics and Immunosurveillance Lab, University College London Cancer Institute, London, UK; CRUK Lung Cancer Centre of Excellence, University College London Cancer Institute, London, UK; Pre-Cancer Immunology Lab, University College London Cancer Institute, London, UK.
3. The Tumor Immunogenomics and Immunosurveillance Lab, University College London Cancer Institute, London, UK; CRUK Lung Cancer Centre of Excellence, University College London Cancer Institute, London, UK; Organelle Dynamics Lab, School of Cancer & Pharmaceutical Sciences, King's College London, London, UK; Organelle Dynamics Lab, the Francis Crick Institute, London, UK.
4. The Tumor Immunogenomics and Immunosurveillance Lab, University College London Cancer Institute, London, UK; CRUK Lung Cancer Centre of Excellence, University College London Cancer Institute, London, UK; Department of Thoracic Surgery, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
5. The Tumor Immunogenomics and Immunosurveillance Lab, University College London Cancer Institute, London, UK; CRUK Lung Cancer Centre of Excellence, University College London Cancer Institute, London, UK.
6. Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel.
7. The Tumor Immunogenomics and Immunosurveillance Lab, University College London Cancer Institute, London, UK; Cancer Evolution and Genome Instability Lab, The Francis Crick Institute, London, UK; CRUK Lung Cancer Centre of Excellence, University College London Cancer Institute, London, UK.
8. The Tumor Immunogenomics and Immunosurveillance Lab, University College London Cancer Institute, London, UK; CRUK Lung Cancer Centre of Excellence, University College London Cancer Institute, London, UK; Drug Discovery Technology Laboratories, Ono Pharmaceutical Co. Ltd., Osaka, Japan.
9. Cancer Evolution and Genome Instability Lab, The Francis Crick Institute, London, UK; CRUK Lung Cancer Centre of Excellence, University College London Cancer Institute, London, UK; Department of Oncology, Medical Sciences Division, University of Oxford, Oxford, UK.
10. CRUK City of London Centre Single Cell Genomics Facility, University College London Cancer Institute, London, UK; Bioinformatics Hub, University College London Cancer Institute, London, UK.
11. Proteomics Research Translational Technology Platform, University College London Cancer Institute, London, UK.
12. CRUK Lung Cancer Centre of Excellence, University College London Cancer Institute, London, UK; Barcelona Supercomputing Center (BSC), Barcelona, Spain; Cancer Genome Evolution Research Group, University College London Cancer Institute, London, UK.
13. CRUK Lung Cancer Centre of Excellence, University College London Cancer Institute, London, UK; Immune Regulation and Tumor Immunotherapy Group, University College London Cancer Institute, London, UK.
14. The Tumor Immunogenomics and Immunosurveillance Lab, University College London Cancer Institute, London, UK; Cancer Evolution and Genome Instability Lab, The Francis Crick Institute, London, UK; CRUK Lung Cancer Centre of Excellence, University College London Cancer Institute, London, UK; Division of Medicine, University College London, London, UK.
15. Cancer Evolution and Genome Instability Lab, The Francis Crick Institute, London, UK; CRUK Lung Cancer Centre of Excellence, University College London Cancer Institute, London, UK; Department of Molecular Oncology and Immunology, the Netherlands Cancer Institute, Amsterdam, the Netherlands; Oncode Institute, Utrecht, the Netherlands.
16. Research Department of Haematology, University College London Cancer Institute, London, UK.
17. CRUK Lung Cancer Centre of Excellence, University College London Cancer Institute, London, UK; Immune Regulation and Tumor Immunotherapy Group, University College London Cancer Institute, London, UK; Immune Regulation Lab, Centre for Immuno-Oncology, Nuffield Department of Medicine, University of Oxford, Oxford, UK.
18. Organoid Translational Technology Platform, University College London Cancer Institute, London, UK.
19. Department of Research Pathology, University College London Cancer Institute, London, UK.
20. CRUK City of London Explant and Patient-Derived Xenograft Core, London, UK.
21. CRUK Lung Cancer Centre of Excellence, University College London Cancer Institute, London, UK; Cancer Genome Evolution Research Group, University College London Cancer Institute, London, UK.
22. Organelle Dynamics Lab, School of Cancer & Pharmaceutical Sciences, King's College London, London, UK; Organelle Dynamics Lab, the Francis Crick Institute, London, UK.
23. Cancer Evolution and Genome Instability Lab, The Francis Crick Institute, London, UK.
24. CRUK Lung Cancer Centre of Excellence, University College London Cancer Institute, London, UK; Pre-Cancer Immunology Lab, University College London Cancer Institute, London, UK.
25. Cancer Evolution and Genome Instability Lab, The Francis Crick Institute, London, UK; CRUK Lung Cancer Centre of Excellence, University College London Cancer Institute, London, UK. Electronic address: [email protected].
26. CRUK Lung Cancer Centre of Excellence, University College London Cancer Institute, London, UK; Immune Regulation and Tumor Immunotherapy Group, University College London Cancer Institute, London, UK. Electronic address: [email protected].
27. The Tumor Immunogenomics and Immunosurveillance Lab, University College London Cancer Institute, London, UK; CRUK Lung Cancer Centre of Excellence, University College London Cancer Institute, London, UK. Electronic address: [email protected].

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.

Keywords

SMG1; cancer immunopeptidome; cancer immunotherapy; cryptic peptides; non-canonical neoantigens; nonsense-mediated mRNA decay; patient-derived fragments; tumor immunogenicity.