Harnessing alternative splicing for off-the-shelf mRNA neoantigen vaccines in hepatocellular carcinoma

作者：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 · 发表于：Cell Research · 年份：2025 · DOI：10.1038/s41422-025-01199-0 · 被引用次数：6 · 研究领域：Cancer Immunotherapy and Biomarkers、Immunotherapy and Immune Responses、Single-cell and spatial transcriptomics

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.