Non-canonical microproteins as targets for shared-antigen cancer immunotherapy

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.