Cryptic peptides and the hidden cancer immunopeptidome: Emerging drivers of tumor–immune interactions and therapeutic opportunities

Recent advances in immunopeptidomics, proteogenomics, and translatomics have shown that the repertoire of antigens presented in cancer extends well beyond canonical protein-coding regions. Cryptic peptides arising from non-canonical translation events — including alternative reading frames, aberrant splicing, non-coding RNAs, endogenous retroelements, and unconventional initiation mechanisms — are increasingly recognized as important contributors to tumor antigenicity and immune recognition. These observations challenge the traditional view of the cancer immunopeptidome as a product of mutated protein-coding genes alone, and they reframe how the immune system perceives malignant cells. Across diverse tumor types, non-canonical antigens are emerging as a previously underappreciated layer of immune regulation, with implications for both fundamental tumor–immune biology and the design of next-generation immunotherapies.This Research Topic seeks to provide a comprehensive overview of how cryptic peptides shape cancer immunobiology, from antigen processing and presentation to immune surveillance, tumor immune evasion, and therapeutic exploitation. We welcome Original Research, Reviews, Mini-Reviews, Methods, and Perspective articles addressing, but not limited to, the following themes:Experimental discovery of cryptic and non-canonical antigens (immunopeptidomics, ribosome profiling, proteogenomics).Computational prediction and prioritization of non-canonical HLA ligands.Functional validation of immunogenicity and T cell recognition.Contribution of endogenous retroelements, non-coding RNAs, and aberrant splicing to the tumor antigen pool.Clinical translation, including cancer vaccines, adoptive cell therapies, and biomarkers of response to immunotherapy.Cryptic antigens in tumors with low mutational burden.The central problem this Research Topic aims to address is the incomplete map of the cancer antigen landscape: most current immunotherapies target mutated protein-coding neoantigens, leaving many patients — particularly those with low mutational burden tumors — without effective options. Recent work has shown that peptides derived from non-coding regions can substantially expand the tumor antigen repertoire and provide novel immunotherapeutic targets. By bringing together contributions from basic immunology, cancer biology, computational science, and translational research, this Topic seeks to consolidate current knowledge, benchmark discovery and prediction strategies, and clarify which classes of non-canonical antigens are most promising for clinical exploitation. The goal is to accelerate the translation of cryptic peptide biology into actionable diagnostics and therapies, and to establish non-canonical antigens as a recognized pillar of cancer immunology alongside classical neoantigens.This Research Topic accepts submissions in the following formats: Brief Research Report, Case Report, Classification, Clinical Trial, Editorial, FAIR² Data, General Commentary, Hypothesis and Theory, Methods, Mini Review, Opinion, Original Research, Perspective, Review, Study Protocol, Systematic Review, and Technology and Code. All published articles will undergo rigorous external peer review and may be subject to publication fees.Please note that manuscripts consisting solely of bioinformatics or computational analysis of public genomic or transcriptomic databases which are not accompanied by robust and relevant validation (clinical cohort or biological validation in vitro or in vivo) are out of scope for this Research Topic. Manuscripts focusing solely on cost-effectiveness studies are also not considered for publication in this journal. Topic editors: Angel Vizoso-Vázquez, Paula Díez, Adnane Achour Source: https://www.frontiersin.org/research-topics/79294/cryptic-peptides-and-the-hidden-cancer-immunopeptidome-emerging-drivers-of-tumor-immune-interactions-and-therapeutic-opportunities