Background <p>Hepatocellular carcinoma (HCC) remains a major global health challenge, characterized by late diagnosis, high recurrence, and limited treatment options for advanced stages. Current therapies face limitations such as toxicity, drug resistance, and an immunosuppressive tumor microenvironment. mRNA vaccines represent a promising therapeutic strategy due to their ability to encode tumor-specific antigens and stimulate robust, targeted immune responses.</p> Methods <p>This review investigates the potential of mRNA vaccines as a therapeutic strategy for HCC. A systematic search was conducted on Web of Science, PubMed, Scopus, and Google Scholar databases from 2005 to 2025 to identify studies on mechanisms, therapeutic strategies, and clinical perspectives of mRNA vaccines in HCC therapy. Keywords, such as “Hepatocellular carcinoma”, “mRNA vaccine”, “Tumor-specific antigen”, “Clinical trials”, were used to search the databases.</p> Results <p>mRNA vaccines for HCC demonstrate potential in preclinical models by inducing antigen-specific T-cell responses and reshaping the immunosuppressive tumor microenvironment. Strategies such as targeting neoantigens from aberrant splicing or non-canonical open reading frames expand the antigen repertoire. Combining mRNA vaccines with immune checkpoint inhibitors shows synergistic efficacy. However, clinical translation faces hurdles, including antigen scarcity due to low tumor mutational burden, suboptimal delivery efficiency, and the complex immunosuppressive landscape of HCC.</p> Conclusion <p>mRNA vaccines offer a transformative modality for HCC treatment. Realizing their full potential requires a multi-faceted approach: expanding the antigen repertoire beyond traditional mutations, developing optimized and targeted delivery systems, and employing rational combination therapies. Future biomarker-driven clinical trials are essential to establish efficacy and integrate these strategies into the HCC treatment paradigm.</p>