Immunopeptidomics: advances in antigen discovery and therapy

Immunopeptidomics, the mass spectrometry based characterization of peptide ligands presented by major histocompatibility complex (MHC) class I and class II molecules, has emerged as a foundational discipline within contemporary T cell immunology, central to the rational design of personalized neoantigen vaccines, T cell receptor engineered adoptive cell therapies, peptide based vaccines, and stratification strategies for immune checkpoint blockade. The field has been transformed by three convergent developments: substantial gains in mass spectrometry sensitivity enabling low input and single cell scale profiling; the systematic integration of deep learning across the analytical pipeline, materially advancing the predictive modeling of MHC class II antigen presentation; and the discovery of an extensive non canonical, or "dark", immunopeptidome derived from cryptic open reading frames, long non coding RNAs, and defective ribosomal products, which is redefining the targetable antigen space, particularly in malignancies with low tumor mutational burden.The goal of this Research Topic is to consolidate recent methodological and conceptual advances across the immunopeptidomics field and to provide an integrative reference spanning fundamental discovery, enabling technology, and clinical translation. By bringing together contributions on high sensitivity and single cell scale mass spectrometry workflows, deep learning driven analytical pipelines, and the characterization of the non canonical, or "dark", immunopeptidome, this collection aims to clarify how MHC class I and class II ligands, including those derived from cryptic open reading frames and other non canonical sources, are generated, presented, and recognized by CD8⁺ and CD4⁺ T lymphocytes. We further aim to evaluate the translational potential of these peptides as biomarkers and therapeutic targets in cancer, infectious disease, and immune mediated disorders.This Research Topic invites contributions advancing the immunopeptidomics field across fundamental discovery, enabling technology, and clinical translation. Specific themes of interest include, but are not limited to:• The non canonical, or "dark", immunopeptidome, including cryptic peptides from non canonical open reading frames, lncRNA and smORF derived HLA ligands, and integration of Ribo-seq with mass spectrometry for confident identification of non canonical antigens.• Artificial intelligence and deep learning across the immunopeptidomics workflow, including spectrum and retention time prediction, de novo sequencing, peptide spectrum match rescoring of DIA datasets, immunogenicity modeling, and TCR–pMHC recognition.• MHC class II immunopeptidomics, including workflows, prediction tools, CD4⁺ T cell antigen discovery, and characterization of the class II ligandome of professional antigen presenting cells within the tumor microenvironment.• Post translationally modified MHC ligands, including phosphopeptides, glycopeptides, and citrullinated antigens, together with open modification search strategies for their discovery.• Single cell and low input immunopeptidomic workflows, including microfluidic HLA peptide enrichment for minimal input clinical samples.• Clinical translation, including lessons from personalized cancer vaccine trials and immunopeptidomics guided target selection for TCR engineered T cell therapy.• Pathogen immunopeptidomics, including HLA ligandomes of viral, bacterial, and parasitic infections and cross reactive HLA class I epitopes.• Bioinformatics tools for data analysis, visualization, and community standards for reproducibility.We welcome Original Research, Reviews, Mini Reviews, Methods, Perspectives, Brief Research Reports, FAIR2, and Hypothesis and Theory articles from across the immunology, proteomics, and computational biology communities.FAIR2 articles are highly encouraged on this topic. Topic editors: Rex Devasahayam Arokia Balaya, Saptami Kanekar, Saketh Kapoor Source: https://www.frontiersin.org/research-topics/81327/immunopeptidomics-advances-in-antigen-discovery-and-therapy