Cancer remains a leading global health burden. mRNA cancer vaccines, which are propelled by their rapid development, manufacturing flexibility, and proven efficacy against infectious diseases, have emerged as a transformative approach in cancer immunotherapy. While offering significant advantages over traditional methods, challenges related to mRNA instability and in vivo delivery efficiency persist. However, technological advancements, particularly in nanoparticle formulations such as lipid nanoparticles (LNPs), have substantially mitigated these concerns. This review comprehensively examines the mechanism of action of mRNA vaccines, focusing on their ability to encode tumor-specific antigens (TSAs), particularly neoantigens, and tumor-associated antigens (TAAs) to elicit potent anti-tumor immune responses. We critically analyzed the promising application of mRNA vaccines as monotherapies and, more significantly, in combination with immune checkpoint inhibitors, chemotherapy, adoptive cell therapies (e.g., CAR-T), and radiation to overcome the immunosuppressive tumor microenvironment. The core of this review synthesizes compelling results from key clinical trials across various cancers (e.g., melanoma, non-small cell lung cancer, and prostate cancer), highlighting significant outcomes such as induced neoantigen-specific T-cell responses, improved recurrence-free survival, and objective tumor regression. We also discuss the groundbreaking potential of personalized neoantigen mRNA vaccines. Current challenges, including tumor heterogeneity, optimal delivery strategies, biomarker identification, and enhancing therapeutic efficacy/safety profiles, are thoroughly evaluated alongside potential solutions. Finally, we explore future directions emphasizing next-generation approaches such as advanced nanovaccines and refined personalized platforms. This review aims to provide a timely and critical analysis of the rapidly evolving landscape of mRNA cancer vaccines, underscoring their immense potential to revolutionize cancer treatment paradigms.
