{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,21]],"date-time":"2026-07-21T14:04:20Z","timestamp":1784642660806,"version":"3.55.0"},"reference-count":59,"publisher":"BMJ","issue":"7","license":[{"start":{"date-parts":[[2026,7,21]],"date-time":"2026-07-21T00:00:00Z","timestamp":1784592000000},"content-version":"unspecified","delay-in-days":20,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100017686","name":"Fujian Provincial Health Technology Project","doi-asserted-by":"publisher","award":["2024ZD01004"],"award-info":[{"award-number":["2024ZD01004"]}],"id":[{"id":"10.13039\/501100017686","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Shanghai Municipality Disruptive Technological Innovation Special Project","award":["26DIPA00400"],"award-info":[{"award-number":["26DIPA00400"]}]},{"name":"National Key Research and Development Project of China","award":["2021YFA1300500"],"award-info":[{"award-number":["2021YFA1300500"]}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82272625"],"award-info":[{"award-number":["82272625"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82573893"],"award-info":[{"award-number":["82573893"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["J Immunother Cancer"],"accepted":{"date-parts":[[2026,7,9]]},"published-print":{"date-parts":[[2026,7]]},"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      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 &gt;75% of tumor cells and identified antigen-presenting cancer-associated fibroblasts that enriched in immunotherapy responders and amplified CD4\n                      <jats:sup>+<\/jats:sup>\n                      T-cell responses. In murine HCC models, neoTST vaccination outperformed neoMuts, inducing dual major histocompatibility complex-I\/II activation and significant tumor growth inhibition.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1136\/jitc-2026-015428","type":"journal-article","created":{"date-parts":[[2026,7,21]],"date-time":"2026-07-21T13:41:14Z","timestamp":1784641274000},"page":"e015428","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":0,"title":["Decoding neoantigen-encoding tumor-specific transcripts unveils a shared target reservoir for immunotherapy in hepatocellular carcinoma"],"prefix":"10.1136","volume":"14","author":[{"given":"Peng","family":"Lin","sequence":"first","affiliation":[{"name":"Department of Integrative Oncology, Fudan University Shanghai Cancer Center, and Shanghai Key Laboratory of Medical Epigenetics, Institutes of Biomedical Sciences, Fudan University, Shanghai, China"},{"name":"Department of Oncology, Fudan University, Shanghai, 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