biostudies-literatureVelz JEuropean Research Council1364https://www.ebi.ac.uk/biostudies/studies/S-EPMC11794601biostudies-literatureUnknown16(1)Medulloblastoma is the most frequent malignant primary brain tumor in children. Despite recent advances in integrated genomics, the prognosis in children with high-risk medulloblastoma remains devastating, and new tumor-specific therapeutic approaches are needed. Here, we present an atlas of naturally presented T cell antigens in medulloblastoma. We map the human leukocyte antigen (HLA)-presented peptidomes of 28 tumors and perform comparative immunopeptidome profiling against an in-house benign database. Medulloblastoma is shown to be a rich source of tumor-associated antigens, naturally presented on HLA class I and II molecules. Remarkably, most tumor-associated peptides and proteins are subgroup-specific, whereas shared presentation among all subgroups of medulloblastoma (WNT, SHH, GrouNature communicationsMapping naturally presented T cell antigens in medulloblastoma based on integrative multi-omics.PMC11794601339842Kapolou KWeller MVelz JRohrig ABozinov OCraveiro RBFrey BMGrotzer MReinhard HWeiss TKowalewski DJEyrich MSilginer MKrayenbuhl NNeidert MCWalz JSMedici GMessing-Junger MFreudenmann LKGauder MWestphal MZeitlberger AMRegli LScheid JWirsching HGRammensee HGGhasemi DRPatterson ABSahm FNahnsen SDubbelaar MMohme MLamszus KRushing EJBeccaria KRoth PSill MfalseMapping naturally presented T cell antigens in medulloblastoma based on integrative multi-omics.Medulloblastoma is the most frequent malignant primary brain tumor in children. Despite recent advances in integrated genomics, the prognosis in children with high-risk medulloblastoma remains devastating, and new tumor-specific therapeutic approaches are needed. Here, we present an atlas of naturally presented T cell antigens in medulloblastoma. We map the human leukocyte antigen (HLA)-presented peptidomes of 28 tumors and perform comparative immunopeptidome profiling against an in-house benign database. Medulloblastoma is shown to be a rich source of tumor-associated antigens, naturally presented on HLA class I and II molecules. Remarkably, most tumor-associated peptides and proteins are subgroup-specific, whereas shared presentation among all subgroups of medulloblastoma (WNT, SHH, Grou2025-01-01T00:00:00Z2025 Feb2025-04-04T07:26:39.679Z2025-04-04T07:26:39.679ZS-EPMC117946013990497910.1038/s41467-025-56268-0