Advances in Therapeutic Melanoma Vaccines (2010–2025)

Background/Objectives: Immune checkpoint inhibitors (ICIs) and other systemic therapies can extend the survival of many patients with advanced melanoma, renewing interest in complementary strategies for unresectable or metastatic disease. Therapeutic cancer vaccines represent a possible approach. Recent evidence suggests commercially available mRNA vaccines can sensitize tumors to ICIs, challenging prior assumptions about neoantigen presentation. Despite renewed public interest in personalized cancer vaccine development, the proliferation of narrative and scoping reviews has not been matched by systematic mechanistic synthesis—platforms investigated across the 2010s and 2020s have not been rigorously compared within a single article. Accordingly, this review focuses on major vaccine platforms and proposes a comparative framework for understanding therapeutic melanoma vaccine development and immunologic rationale. Methods: Melanoma vaccine clinical trials listed on ClinicalTrials.gov were identified from 2010 to 2025. Eligible studies were screened and included in a qualitative review evaluating trial characteristics, vaccine platforms, study design, and reported outcomes. Results: There is one active Phase III clinical trial for melanoma vaccines in the US. Key principles of melanoma vaccinology include adjuvant, antigen, and delivery platform selection. From 2010 to 2025, four vaccine candidates advanced to Phase III trials, two provided Phase III results for peer review, one trial is ongoing, and no vaccines have been FDA-approved. Inconsistent reporting of outcomes and a lack of published results limited comparability across studies, precluding formal meta-analysis. Conclusions: Therapeutic melanoma vaccine options remain limited by translational challenges in study design and reporting gaps. This review synthesizes contemporary clinical trial activity and immunologic principles to inform future research.