生物
免疫原性
肝细胞癌
选择性拼接
免疫系统
抗原
免疫学
RNA剪接
癌症研究
人口
免疫疗法
癌症免疫疗法
信使核糖核酸
疫苗效力
癌症
计算生物学
接种疫苗
癌症疫苗
疾病
转录组
基因
病毒学
体细胞
体内
生物信息学
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
出处
期刊:Cell Research
[Springer Nature]
日期:2025-11-28
卷期号:35 (12): 970-986
被引量:4
标识
DOI:10.1038/s41422-025-01199-0
摘要
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.
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