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

Article · 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

- Archive id: doi:10.1038/s41422-025-01199-0
- Published: 2025-11-28
- Venue: Cell Research
- DOI: https://doi.org/10.1038/s41422-025-01199-0
- PMID: 41315871
- Citations: 10
- Source URL: https://doi.org/10.1038/s41422-025-01199-0
- Provenance: openalex

## 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 reproduced under CC-BY (publisher license, via OpenAlex)._

Topics: [mRNA Therapeutics & Cancer Vaccines](https://space-kitty.com/topics/mrna-cancer-vaccines)

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