Clinical translation of mRNA-based cancer vaccines for solid tumors.

Abstract

Vaccines that use messenger RNA (mRNA) have become a promising platform that is transforming cancer immunotherapy. These mRNA vaccines can be generated and manufactured quickly due to their modular design and can also induce CD4⁺ T-cell and CD8⁺ T-cell responses, in contrast to conventional protein or peptide-based vaccines. Additionally, synthetic mRNA can be optimized through various strategies (e.g., codon optimization, chemical modifications, and polyepitopic design) to not only ensure efficient antigen expression and immune activation but also to mitigate excessive innate immune sensing. Technologies that deliver mRNA vaccines (lipid nanoparticles, dendritic cell-based formulations, self-adjuvanted mRNA constructs, and viral vector systems) have all supported the development of mRNA-vaccine clinical applications while providing unique advantages in stability, antigen presentation, or immunogenicity. Clinical trials in the early phases involving a variety of solid tumors, such as pancreatic cancer, glioblastoma, renal cell carcinoma, melanoma, and non-small cell lung cancer, show that mRNA vaccines can elicit durable T-cell responses, expand high-avidity T-cell clones, and, in some cases, prolong recurrence-free survival. However, the clinical benefit has been variable, often limited by tumor heterogeneity, immune evasion, and immunodominance. Combination strategies utilizing immune checkpoint inhibitors, chemotherapy, and adoptive T-cell therapy are under investigation. This review synthesizes evidence from published clinical studies and 65 registered clinical trials on mRNA-based cancer vaccines, summarizing key molecular principles, delivery strategies, clinical translation in solid tumors, and ongoing opportunities for future therapeutic development.