Personalized immunotherapy in HCC: synthesis, delivery, and clinical progress of mRNA-based vaccines.

Messenger RNA (mRNA)-based vaccines have quickly developed as a unique approach to cancer immunotherapy with specific antigen expression, flexible design, and safety. They are broadly categorized into self-amplifying mRNA (SAM) vaccines and non-replicating mRNA vaccines. SAM vaccines contain viral replicase elements enabling intracellular RNA amplification and strong antigen expression, whereas non-replicating mRNA vaccines encode only the target antigen and rely on direct translation for immunogenicity. Hepatocellular carcinoma (HCC) is a highly aggressive cancer that often exhibits resistance to standard-of-care therapy and appears to benefit from being targeted with mRNA vaccines to produce an anti-tumor immune response. Herein, we review the stepwise approach of vaccine construction of mRNA vaccines, including building a DNA template, in vitro transcription, capping, polyadenylation, and purification of the mRNA, and their delivery as lipid nanoparticles (LNPs), dendritic cells, or naked RNA. In addition, we present a synthesis of progress made through the identification of HCC-specific neoantigens and high-affinity neoantigens (HANs) that activate cytotoxic T cells, correlating with better patient outcomes. Recent preclinical and clinical studies demonstrate the safety and efficacy of mRNA vaccines that encode either tumor-associated or patient-specific neoantigens, often in combination with local therapeutics or immune checkpoint inhibitors. We offer further considerations regarding combinations of mRNA vaccines with strategies including but not limited to adoptive cell therapy, tumor suppressor gene restoration, anti-angiogenesis drugs, and metabolic reprogramming. In many ways, a key consideration is the strategies being developed to overcome the immunosuppressive tumor microenvironment in the liver, and mRNA-induced co-stimulation (e.g., OX40L), TP53 gene editing, and targeting of myeloid-derived suppressor cells. Overall, our review has offered perspectives on the many types of opportunistic strategies being investigated, combining mRNA vaccines to not only prime for anti-tumor immunity or alternate human sources of anti-tumor immunity but also remodel the immunologic landscape that permeates HCC. With numerous ongoing studies and rapid technology advances, mRNA-based immunotherapies are sure to transform how we manage liver cancer.