{"id":"doi:10.1038/s41422-025-01199-0","kind":"article","title":"Harnessing alternative splicing for off-the-shelf mRNA neoantigen vaccines in hepatocellular carcinoma","authors":["Haoliang Zhao","Yifei Cheng","Tiancheng Zhang","Qianxi Wang","Yanan Xu","Ganggang Wang","Yuanli Song","Hang Chen","Yingcheng Wu","Mao Zhang","Youpei Lin","Changyou Zhan","Jia Fan","Qiang Gao"],"author_count":14,"year":2025,"published":"2025-11-28","venue":"Cell Research","cited_by":10,"doi":"10.1038/s41422-025-01199-0","arxiv_id":null,"nct_id":null,"source_url":"https://doi.org/10.1038/s41422-025-01199-0","archive_url":"https://space-kitty.com/papers/doi:10.1038/s41422-025-01199-0","updated":null,"pmid":"41315871","pmcid":null,"openalex_id":"W4416776692","pdf_url":null,"abstract":"Hepatocellular carcinoma (HCC) remains a major therapeutic challenge. Although targeting tumor-specific antigens represents a cornerstone of cancer immunotherapy, current approaches focus predominantly on mutation-derived neoantigens, which offer limited population coverage. Through an integrative analysis of multi-omics data from 279 HCC patients, we demonstrate that aberrant splicing (AS) events occur at a > 59-fold higher frequency than somatic mutations and generate substantially more immunogenic peptides with broader patient applicability (50.94% vs 4.40% population coverage). Focusing on AS transcripts, our stringent selection pipeline identified 34 neoantigens, prioritizing strong immunogenicity for effective vaccine development. Proof-of-concept in vivo experiments demonstrated the efficacy of mRNA vaccines encoding these neoantigens, resulting in significant tumor regression and enhanced intra-tumor infiltration of neoantigen-reactive T cells. We also address the challenge of transporter-associated antigen processing (TAP) deficiency in HCC by proposing the use of TAP-independent AS-derived neoantigens to circumvent immune evasion. Our findings establish AS as a promising source of neoantigens for off-the-shelf mRNA vaccines in HCC and underscore the need to overcome antigen-presentation barriers for effective immunotherapy.","abstract_license":"CC-BY (publisher license, via OpenAlex)","license":"cc-by","is_open_access":true,"retracted":false,"peer_reviewed":null,"categories":["Immunotherapy and Immune Responses"],"details":null,"provenance":"openalex","attribution":"Abstract of \"Harnessing alternative splicing for off-the-shelf mRNA neoantigen vaccines in hepatocellular carcinoma\" by Haoliang Zhao, Yifei Cheng, Tiancheng Zhang et al., https://doi.org/10.1038/s41422-025-01199-0, 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":[]}