Non-canonical open reading frame-derived antigens as emerging immune targets in cancer immunotherapy
Abstract
Background/ObjectivesCancer immunotherapy predominantly targets mutation-derived neoantigens, thereby limiting its efficacy in low-mutational-burden tumours such as pancreatic and paediatric cancers. Non-canonical open reading frames (ncORFs) generate a diverse repertoire of peptides, the dark immunopeptidome, including upstream ORFs, lncRNA-derived ORFs, and transposable element-derived ORFs, which are efficiently presented by MHC class I molecules.MethodsA narrative synthesis of peer-reviewed literature integrating ribosome profiling, immunopeptidomics, proteogenomics, and functional T-cell assays was conducted across multiple tumour types.ResultsEvidence demonstrates that ncORF-derived peptides are frequently tumour-enriched at the transcript or translation level, and a proportion has been directly identified at the peptide level by HLA-elution immunopeptidomics from primary tumour tissue; a subset can prime antigen-specific CD8+ T-cell responses ex vivo, with cytotoxic activity demonstrated against peptide-pulsed targets in vitro and, in selected cases, against endogenously processed tumour cells. These ncORF-derived antigens may partially evade, and direct human thymic immunopeptidome data are lacking.ConclusionsIncorporating ncORF-derived antigens into personalised cancer vaccine strategies could expand therapeutic targets, especially for low-mutational burden and therapy-resistant tumours, but requires further bioinformatic refinement and rigorous safety validation.
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BibTeX
@article{fierromonti2026noncanonical,
title = {{Non-canonical open reading frame-derived antigens as emerging immune targets in cancer immunotherapy}},
author = {Ivo Fierro-Monti},
journal = {Frontiers in Immunology},
year = {2026},
month = nov,
doi = {10.3389/fimmu.2026.1939091},
url = {https://www.frontiersin.org/articles/10.3389/fimmu.2026.1939091},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Non-canonical open reading frame-derived antigens as emerging immune targets in cancer immunotherapy
AU - Ivo Fierro-Monti
PY - 2026
DA - 2026/11/03
JO - Frontiers in Immunology
DO - 10.3389/fimmu.2026.1939091
UR - https://www.frontiersin.org/articles/10.3389/fimmu.2026.1939091
AB - Background/ObjectivesCancer immunotherapy predominantly targets mutation-derived neoantigens, thereby limiting its efficacy in low-mutational-burden tumours such as pancreatic and paediatric cancers. Non-canonical open reading frames (ncORFs) generate a diverse repertoire of peptides, the dark immunopeptidome, including upstream ORFs, lncRNA-derived ORFs, and transposable element-derived ORFs, which are efficiently presented by MHC class I molecules.MethodsA narrative synthesis of peer-reviewed literature integrating ribosome profiling, immunopeptidomics, proteogenomics, and functional T-cell assays was conducted across multiple tumour types.ResultsEvidence demonstrates that ncORF-derived peptides are frequently tumour-enriched at the transcript or translation level, and a proportion has been directly identified at the peptide level by HLA-elution immunopeptidomics from primary tumour tissue; a subset can prime antigen-specific CD8+ T-cell responses ex vivo, with cytotoxic activity demonstrated against peptide-pulsed targets in vitro and, in selected cases, against endogenously processed tumour cells. These ncORF-derived antigens may partially evade, and direct human thymic immunopeptidome data are lacking.ConclusionsIncorporating ncORF-derived antigens into personalised cancer vaccine strategies could expand therapeutic targets, especially for low-mutational burden and therapy-resistant tumours, but requires further bioinformatic refinement and rigorous safety validation.
SN - 1664-3224
ER -