Roberto Vendramin, Hongchang Fu, Shanila Fernandez Patel, Yue Zhao, Danwen Qian, Lorena Ligammari, Osnat Bartok, Polina Greenberg, Ronen Levy, Andrea Castro, Krupa Thakkar, Jun Murai, Wei-Ting Lu, Christopher CT Sng, Chen Weller, Gordon Beattie, Amandeep Bhamra, Roc Farriol-Duran, Despoina Karagianni, Marcellus Augustine, Krijn K. Dijkstra, Christopher L. Pinder, Benjamin S. Simpson, Gordon Weng-Kit Cheung, Felipe Gálvez-Cancino, Petra Vlckova, Silvia Šurinová, Manuel Rodriguez-Justo, Mansi Shah, Nicholas McGranahan, Jeremy G. Carlton, Eva Grönroos, James L. Reading, Yardena Samuels, Charles Swanton, Sergio A. Quezada, Kevin Litchfield
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.