Targeting splicing-derived neoantigens for precision cancer immunotherapy

Résumé fourni par la source

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 ( SF3B1 , SRSF2 , U2AF1 , and ZRSR2 ), 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.

Ce résumé expose les affirmations des auteurs. BNTIC ne l’interprète pas comme une validation indépendante des résultats.