biostudies-literatureKwok DWNCI NIH HHSNINDS NIH HHSNIH HHSNIGMS NIH HHS463-473https://www.ebi.ac.uk/biostudies/studies/S-EPMC11903331biostudies-literatureUnknown639(8054)T cell-based immunotherapies hold promise in treating cancer by leveraging the immune system's recognition of cancer-specific antigens¹. However, their efficacy is limited in tumours with few somatic mutations and substantial intratumoural heterogeneity^2-4. Here we introduce a previously uncharacterized class of tumour-wide public neoantigens originating from RNA splicing aberrations in diverse cancer types. We identified T cell receptor clones capable of recognizing and targeting neoantigens derived from aberrant splicing in GNAS and RPL22. In cases with multi-site biopsies, we detected the tumour-wide expression of the GNAS neojunction in glioma, mesothelioma, prostate cancer and liver cancer. These neoantigens are endogenously generated and presented by tumour cellNatureTumour-wide RNA splicing aberrations generate actionable public neoantigens.PMC11903331P50 CA097257R01 CA222965R01 CA269733R37 CA259177P30 CA008748T32 GM008568T32 CA151022R50 CA274229R35 NS105068S10 OD028511P01 CA118816R01 CA286507P50 CA217694Diaz ALiu JColton Cove MLakshmanachetty SSaijo ABarpanda AWu SHNejo TYamamichi APhillips JJOgino HKlebanoff CAHervey-Jumper SLChen LHKwok DWWiita APCostello JFWatchmaker PBWoo JChang SMChan GKLGallus MOkada HJung JOkada KHong CStevers NODu AEtxeberria IGrishanina NRRamos EfalseTumour-wide RNA splicing aberrations generate actionable public neoantigens.T cell-based immunotherapies hold promise in treating cancer by leveraging the immune system's recognition of cancer-specific antigens¹. However, their efficacy is limited in tumours with few somatic mutations and substantial intratumoural heterogeneity^2-4. Here we introduce a previously uncharacterized class of tumour-wide public neoantigens originating from RNA splicing aberrations in diverse cancer types. We identified T cell receptor clones capable of recognizing and targeting neoantigens derived from aberrant splicing in GNAS and RPL22. In cases with multi-site biopsies, we detected the tumour-wide expression of the GNAS neojunction in glioma, mesothelioma, prostate cancer and liver cancer. These neoantigens are endogenously generated and presented by tumour cell2025-01-01T00:00:00Z2025 Mar2026-06-02T20:51:50.193Z2025-04-03T23:56:43.295ZS-EPMC119033313997214410.1038/s41586-024-08552-0