Non-canonical microproteins as targets for shared-antigen cancer immunotherapy
- 1European Molecular Biology Laboratory’s European Bioinformatics Institute (EMBL-EBI), Hinxton
- 2Biozentrum, University of Basel
Abstract
Recent research reveals that microproteins encoded by non-canonical open reading frames (ncORFs) substantially enrich the cancer immunopeptidome, driven by oncogenic stress, essential cellular functions, immune tolerance mechanisms, and antigen-processing biases. These microproteins, often critical for tumour survival, produce peptides presented on tumour cell surfaces, offering shared antigen targets for immunotherapy, particularly in tumours with low mutational burden. Here we integrate multi-level evidence demonstrating how translational reprogramming under stress, essentiality constraints limiting antigen loss, and selective antigen processing converge to promote ncORF-derived peptide presentation. While emerging data suggest immunogenicity of some microproteins, clinical validation remains pending. Advancing therapeutic applications requires development of specialised computational predictors, rigorous immunopeptidomics workflows, and prospective thymic peptide profiling to ensure efficacy and safety. This framework highlights ncORF-derived microproteins as promising yet complex targets, expanding the landscape of cancer immunotherapy beyond canonical neoantigens.
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BibTeX
@article{fierromonti2026noncanonical,
title = {{Non-canonical microproteins as targets for shared-antigen cancer immunotherapy}},
author = {Ivo Fierro-Monti},
journal = {Frontiers in Immunology},
year = {2026},
month = oct,
doi = {10.3389/fimmu.2026.1984200},
url = {https://www.frontiersin.org/articles/10.3389/fimmu.2026.1984200/full},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Non-canonical microproteins as targets for shared-antigen cancer immunotherapy
AU - Ivo Fierro-Monti
PY - 2026
DA - 2026/10/29
JO - Frontiers in Immunology
DO - 10.3389/fimmu.2026.1984200
UR - https://www.frontiersin.org/articles/10.3389/fimmu.2026.1984200/full
AB - Recent research reveals that microproteins encoded by non-canonical open reading frames (ncORFs) substantially enrich the cancer immunopeptidome, driven by oncogenic stress, essential cellular functions, immune tolerance mechanisms, and antigen-processing biases. These microproteins, often critical for tumour survival, produce peptides presented on tumour cell surfaces, offering shared antigen targets for immunotherapy, particularly in tumours with low mutational burden. Here we integrate multi-level evidence demonstrating how translational reprogramming under stress, essentiality constraints limiting antigen loss, and selective antigen processing converge to promote ncORF-derived peptide presentation. While emerging data suggest immunogenicity of some microproteins, clinical validation remains pending. Advancing therapeutic applications requires development of specialised computational predictors, rigorous immunopeptidomics workflows, and prospective thymic peptide profiling to ensure efficacy and safety. This framework highlights ncORF-derived microproteins as promising yet complex targets, expanding the landscape of cancer immunotherapy beyond canonical neoantigens.
SN - 1664-3224
ER -