Predominant mutated non-canonical tumor-specific antigens identified by proteogenomics demonstrate immunogenicity and tumor suppression in CRC

This study applies an integrative proteogenomic pipeline combining whole-genome sequencing, RNA-seq, and immunopeptidomics in colorectal cancer to systematically discover tumor-specific antigens (TSAs). More than 80% of identified MHC-I neo-epitopes arose from non-coding regions, especially in hypermutated tumors. Functional validation further showed that mutated non-canonical peptides can activate CD8+ T cells and suppress tumor growth, supporting their potential as actionable targets for personalized immunotherapy.