Despite advancements in therapeutic cancer vaccines, clinical translation has been hindered by limited efficacy, with Sipuleucel-T remaining the only FDA-approved therapeutic cancer vaccine to date. However, recent advances in personalized mRNA vaccines, such as Moderna's mRNA-4157 and BioNTech's autogene cevumeran, have demonstrated significant reductions in recurrence risk and improved survival across several cancer types, renewing optimism in the field. Personalized cancer vaccines leverage patient-specific tumor antigens to initiate potent and targeted immune responses. This review outlines various classes of personalized vaccines, including DNA-, mRNA-, peptide-, dendritic cell-, and whole-cell-based platforms, and examines the immunological challenges they face, such as tumor heterogeneity, immunosuppressive microenvironments, and inadequate immune memory. To address these limitations, both conventional and nanotechnology-enhanced delivery systems have been developed. Notably, nanovaccines constructed from lipid-polymer hybrids, biomimetic membranes, and stimulus-responsive materials enable codelivery of neoantigens and immunostimulatory agonists, promoting enhanced lymph node targeting, dendritic cell activation, and antigen cross-presentation. Furthermore, biomimetic formulations incorporating autologous tumor membranes preserve native antigenic diversity and allow dynamic adaptation to evolving tumors. When integrated with artificial intelligence for antigen selection and multiomics for patient stratification, these platforms accelerate vaccine design and improve precision. Combination regimens with immune checkpoint inhibitors or other agents further potentiate efficacy and promote durable antitumor immunity. Increasing clinical evidence, especially in melanoma and pancreatic cancer, underscores the potential of these strategies to induce long-term protection and reduce recurrence. Overall, next-generation personalized cancer vaccines are advancing the transition from reactive treatment to proactive, precision-controlled cancer immunotherapy.
