{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,27]],"date-time":"2026-08-27T14:30:52Z","timestamp":1787841052194,"version":"build-2784847793"},"reference-count":125,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,8,27]],"date-time":"2026-08-27T00:00:00Z","timestamp":1787788800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>\n                    Aberrant pre-mRNA splicing in cancer generates protein sequences that are rare or absent in normal tissues, creating a rich source of tumor-specific neoantigens for immunotherapy. These splicing-derived neoantigens arise through diverse mechanisms, including recurrent somatic mutations in core spliceosome components (\n                    <jats:italic>SF3B1<\/jats:italic>\n                    ,\n                    <jats:italic>SRSF2<\/jats:italic>\n                    ,\n                    <jats:italic>U2AF1<\/jats:italic>\n                    , and\n                    <jats:italic>ZRSR2<\/jats:italic>\n                    ), epigenetic derepression of transposable elements that give rise to chimeric exon-TE junctions, and coordinated dysregulation of splicing regulatory networks in cancers lacking spliceosome coding mutations. These processes produce two major classes of immunotherapeutic targets: 1) MHC class I-restricted neopeptides that can be recognized by T-cell-based therapies, and 2) extracellular neoepitopes (ExNeoEpitopes) within transmembrane proteins that are accessible to HLA-independent antibody-based modalities, including monoclonal antibodies (mAbs), bispecific engagers (BiTEs), antibody-drug conjugates (ADCs), and chimeric antigen receptor (CAR)-T or CAR-NK cells. Despite their strong immunogenic potential, effective therapeutic exploitation requires overcoming key immunological barriers, including T-cell exhaustion, impaired antigen presentation through MHC-I downregulation, and suppression within the tumor microenvironment. Recent advances in computational neoantigen prediction, immunopeptidomics, surface proteomics, long-read and single-cell isoform sequencing, and AI-guided therapeutic design are enabling more systematic discovery and validation of splicing-derived targets. This review integrates current understanding of the biological origins, immunological barriers, target classes of splicing neoantigens, and the technologies that enable their advancement in cancer immunotherapy.\n                  <\/jats:p>","DOI":"10.3389\/fimmu.2026.1900283","type":"journal-article","created":{"date-parts":[[2026,8,27]],"date-time":"2026-08-27T13:37:21Z","timestamp":1787837841000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Targeting splicing-derived neoantigens for precision cancer immunotherapy"],"prefix":"10.3389","volume":"17","author":[{"given":"Mutian","family":"Tang","sequence":"first","affiliation":[{"name":"Division of Immunobiology, Cincinnati Children\u2019s Hospital Medical Center","place":["Cincinnati, OH, United States"]},{"name":"Division of Biomedical Informatics, Cincinnati Children\u2019s Hospital Medical Center","place":["Cincinnati, OH, United States"]},{"name":"Immunology Graduate Program, University of Cincinnati College of Medicine","place":["Cincinnati, OH, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"H. Leighton","family":"Grimes","sequence":"additional","affiliation":[{"name":"Division of Immunobiology, Cincinnati Children\u2019s Hospital Medical Center","place":["Cincinnati, OH, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nathan","family":"Salomonis","sequence":"additional","affiliation":[{"name":"Division of Biomedical Informatics, Cincinnati Children\u2019s Hospital Medical Center","place":["Cincinnati, OH, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,8,27]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1038\/nature07509","article-title":"Alternative isoform regulation in human tissue transcriptomes","volume":"456","author":"Wang","year":"2008","journal-title":"Nature"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1038\/nature10496","article-title":"Frequent pathway mutations of splicing machinery in 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