mRNA-Based Therapy in Melanoma, Personalized Neoantigen Vaccines and the Future of Precision Immunotherapy

Abstract

Melanoma is one of the most immunogenic solid malignancies and has become a major model for the development of precision immunotherapy. Although immune checkpoint inhibitors and molecularly targeted therapies have substantially improved outcomes, primary and acquired resistance, disease recurrence and metastatic progression remain important clinical challenges. Messenger RNA (mRNA) technology has emerged as a highly adaptable therapeutic platform capable of converting tumor-specific genomic information into individualized anticancer treatment. In melanoma, the most advanced application is the development of personalized mRNA vaccines encoding patient-specific tumor neoantigens. These vaccines exploit the high mutational burden of melanoma to generate broad CD4+ and CD8+ T-cell responses directed against tumor-specific epitopes while minimizing recognition of normal tissues. The clinical development of mRNA-based individualized neoantigen therapy has progressed rapidly. In the phase IIb KEYNOTE-942 study, mRNA-4157/V940 combined with pembrolizumab improved recurrence-related outcomes compared with pembrolizumab alone in patients with resected high-risk melanoma. In August 2026, the phase III INTerpath-001 trial reported statistically significant and clinically meaningful improvements in both recurrence-free survival and distant metastasis-free survival for the combination of intismeran autogene (V940) and pembrolizumab compared with pembrolizumab alone. This represents an important milestone for mRNA-based cancer therapy. Future directions include optimization of neoantigen prediction, incorporation of multi-omic tumor profiling, improved lipid nanoparticle delivery, combination with immune checkpoint blockade and cellular therapies, and development of mRNA constructs capable of modifying the tumor microenvironment. The integration of genomic, transcriptomic, epigenetic and immunological information may ultimately enable dynamic, continuously personalized mRNA therapy for melanoma.