Next-Generation mRNA Vaccines in Melanoma: Advances in Delivery and Combination Strategies

Messenger RNA (mRNA) vaccines have redefined cancer immunotherapy, offering unparalleled flexibility to encode tumor-specific antigens and to be adapted to individual mutational landscapes. Melanoma, with its high mutational burden and responsiveness to immune checkpoint blockade, has become the leading model for translating these advances into clinical benefit. Recent innovations in delivery—ranging from lipid nanoparticles and polymeric carriers to biomimetic hybrids and intratumoral administration—are dismantling long-standing barriers of stability, targeting, and immunogenicity. Clinical milestones, including the randomized phase IIb KEYNOTE-942, show that adding the personalized neoantigen vaccine mRNA-4157 (V940) to pembrolizumab prolonged recurrence-free survival versus pembrolizumab alone (HR 0.561, 95% CI 0.309–1.017; 18-month RFS 79% vs. 62%), with the ASCO 3-year update reporting 2.5-year RFS 74.8% vs. 55.6% and sustained distant metastasis-free survival benefit in resected high-risk melanoma. Parallel preclinical studies highlight the potential of multifunctional platforms co-delivering cytokines or innate agonists to reshape the tumor microenvironment and achieve durable systemic immunity. As artificial intelligence drives epitope selection and modular manufacturing accelerates personalization, mRNA vaccines may have the potential to transition from adjuncts to main therapies in melanoma and beyond.