Hepatocellular carcinoma kills roughly 700,000 people annually worldwide, yet it remains stubbornly resistant to the immunotherapy advances that transformed melanoma and lung cancer. Understanding why — and whether mRNA vaccine technology can break through that resistance — has become one of the more consequential questions in oncology. This systematic review synthesizes two decades of evidence to map where the science currently stands.
Covering literature from 2005 to 2025 across four major databases, the review details how mRNA vaccines can encode tumor-specific antigens and drive antigen-specific cytotoxic T-cell responses in HCC preclinical models. A particularly noteworthy focus is the expansion of the antigen repertoire beyond conventional mutations: by targeting neoantigens arising from aberrant RNA splicing events and non-canonical open reading frames, researchers may circumvent one of HCC's most limiting immunological features — its comparatively low tumor mutational burden. The review also identifies combinatorial strategies pairing mRNA vaccines with immune checkpoint inhibitors as showing synergistic efficacy in animal models, though the mechanistic basis for this synergy in the immunosuppressive HCC microenvironment remains incompletely characterized. Key translational barriers identified include suboptimal lipid nanoparticle delivery efficiency to hepatic tumors and antigen heterogeneity between patients.
Placing this in broader context, HCC's immunosuppressive milieu — driven by regulatory T cells, myeloid-derived suppressor cells, and the tolerogenic liver microenvironment — has historically blunted even checkpoint blockade monotherapy. The mRNA platform's rapid customizability makes it theoretically well-suited to a personalized neoantigen approach, but hepatic first-pass metabolism and the liver's innate immune tolerance represent delivery challenges distinct from other tumor types. This review is a thorough synthesis rather than a source of new primary data, which limits its ability to establish efficacy claims. No large Phase II or III trial results are yet available for HCC-specific mRNA vaccines, meaning current optimism rests largely on preclinical and early-phase signals. The field is at an early, potentially pivotal inflection point — incremental today, but worth close monitoring as personalized oncology vaccines mature.