{"id":"doi:10.1136/jitc-2026-015428","kind":"article","title":"Decoding neoantigen-encoding tumor-specific transcripts unveils a shared target reservoir for immunotherapy in hepatocellular carcinoma","authors":["Lin P","Wen Y","Zhao J","Zhang F","Su Y","He H","Yu H","Li Q","Liu C","Hu Z","Li Y","Fang Z","Liang L","Huang S"],"author_count":14,"year":2026,"published":"2026-07-21","venue":"Journal for immunotherapy of cancer","cited_by":0,"doi":"10.1136/jitc-2026-015428","arxiv_id":null,"nct_id":null,"source_url":"https://doi.org/10.1136/jitc-2026-015428","archive_url":"https://space-kitty.com/papers/doi:10.1136/jitc-2026-015428","updated":null,"pmid":"42481156","pmcid":"PMC13405042","openalex_id":null,"pdf_url":"https://europepmc.org/articles/PMC13405042/pdf","abstract":"Background Primary liver cancer, predominantly hepatocellular carcinoma (HCC), has limited therapeutic options. While mutation-derived neoantigen vaccine holds promise, its success is hindered by low antigen availability. This study explores transcriptome-derived neoantigens (neoantigen-encoding tumor-specific transcripts, neoTSTs) in HCC, characterizing their features, generation mechanisms, and therapeutic potential. Methods We developed a computational pipeline integrating STAR/StringTie-based transcript assembly with multiexon/single-exon reference datasets (23,972 human control samples) for tumor-specific transcripts (TSTs) identification. A custom sliding-window algorithm compared TST-encoded peptides against UniProt, with neoTSTs predicted using netMHCPan. This framework was applied to 1,013 patients with liver cancer. NeoTSTs were validated through proteomics, immunopeptidomics, and HLA-transgenic models. Multiomics analyses characterized splicing patterns, transposable elements, and transcription factor regulation. Single-cell RNA-seq and Hep53.4 murine models assessed tumor coverage and immunotherapeutic efficacy. Results We analyzed RNA-seq data from 1,013 patients with liver cancer and constructed a multilayered reference dataset. Using a customized pipeline, we identified an average of 60 neoTSTs per patient, significantly surpassing mutation-derived neoantigens (neoMuts). NeoTSTs exhibited higher population frequencies, with 73.1% providing multiple epitopes, and were validated through mass spectrometry and HLA transgenic mouse models. Mechanistically, neoTSTs were generated via retained introns, transposable element activation, HNF4A-regulated alternative promoters, and de novo transmembrane domain generation. Single-cell analysis revealed neoTSTs cover >75% of tumor cells and identified antigen-presenting cancer-associated fibroblasts that enriched in immunotherapy responders and amplified CD4 + T-cell responses. In murine HCC models, neoTST vaccination outperformed neoMuts, inducing dual major histocompatibility complex-I/II activation and significant tumor growth inhibition. Conclusions NeoTSTs represent a superior neoantigen source in HCC, compensating for the limitations of mutation-derived targets. The remarkable abundance and patient-to-patient sharedness of neoTSTs underscore their dual potential: (1) as personalized immunotherapeutic targets, and (2) as broadly applicable antigens for low-TMB tumors. These findings provide a transformative framework for expanding treatment options in HCC immunotherapy.","abstract_license":"CC-BY (article license as recorded by Europe PMC; abstract reproduced unmodified apart from markup removal)","license":"CC-BY","is_open_access":true,"retracted":false,"peer_reviewed":null,"categories":[],"details":null,"provenance":"europepmc","attribution":"Abstract of \"Decoding neoantigen-encoding tumor-specific transcripts unveils a shared target reservoir for immunotherapy in hepatocellular carcinoma\" by Lin P, Wen Y, Zhao J et al., https://doi.org/10.1136/jitc-2026-015428, used under its Creative Commons Attribution license (CC-BY); markup removed, otherwise unmodified.","topics":[{"slug":"mrna-cancer-vaccines","name":"mRNA Therapeutics & Cancer Vaccines","domain_slug":"medicine"}],"cited_in_dossiers":[{"slug":"mrna-cancer-vaccines","title":"mRNA Therapeutics & Cancer Vaccines: State of the Field (October 2026)","url":"https://space-kitty.com/dossiers/mrna-cancer-vaccines"}]}