Abstract
mRNA has emerged as a transformative platform in vaccine oncology, offering rapid design, non-acquired security and powerful activation of adaptive immune. Despite encouraging preclinical and clinical results, challenges such as efficient distribution, tumor immune evasion, and patient-specific antigen selection limits their widespread clinical translations. We systematically reviewed preclinical studies and clinical trials examining mRNA vaccines in various cancer, including glioblastoma, melanoma, lungs, breasts, digestive systems, ovarian, prostate, kidney and hematological malignancies. Comparative analysis were carried out between mRNA, DNA and peptide vaccine platforms. Additionally, we critically examined the tumor resistance mechanism and proposed the next generation strategies, including the nanometer-based delivery system, self-ampliming mRNA (saRNA), and bioinformatics-operated antigen discovery, which are using single-cell sequencing. Clinical trials continuously display the safety and immunity of mRNA vaccines, with a strong induction of CD8+ T cell reactions and cancer types. However, efficacy outcomes remain variable, with strongest responses in high-mutation-burden tumors such as melanoma and NSCLC, and limited benefit in low-mutation-burden tumors such as prostate and ovarian cancers. Our ideological structure introduces the integration of mRNA vaccines with car-T cells and monoclonal antibodies to remove tumor immune resistance. In addition, we present an accurate algorithm, taking advantage of scRNA-seq for patient-specific neostagen selection, and highlight the benefits of saRNA in increasing antigen expression with low dosage requirements. mRNA vaccine represents a rapidly growing frontier in cancer immunotherapy, yet their success will depend on addressing biological and translation obstacles. This review synthesizes not only current clinical evidence, but also provides innovative conceptual models and future instructions that may redefine the design of the next generation cancer vaccines. By bridging advances in nanotechnology, computational biology and adaptive clinical trial designs, the task offers a roadmap to achieve sustainable, individual and widely accessible cancer immunotherapy.