Melanoma vaccines: current R&D landscape, translational hurdles, and future outlook-a perspective drawn from 442 clinical trials.

[BACKGROUND] Melanoma, a highly malignant skin tumor with high metastatic propensity and poor survival in advanced stages, poses a major global public health challenge, as conventional treatments have notable limitations. Tumor immunotherapy, particularly cancer vaccines, has emerged as a promising approach by activating/regulating immune mechanisms to target cancer cells.

[METHODS] This study systematically searched the Trialtrove database for interventional clinical trials of melanoma and cancer vaccines up to August 5, 2025. After screening via inclusion/exclusion criteria, 442 trials were analyzed, adhering to PRISMA guidelines with independent dual review for data reliability.

[RESULTS] Trials were geographically concentrated in developed regions (69% in the US), with minimal participation from Asia, Africa, and Latin America. A "translational funnel effect" was observed: Phase I/I-II trials accounted for 63.6%, while Phase III trials only 6.1%, with a 22.9% termination rate. Peptide/recombinant protein vaccines (186 trials) and cellular vaccines (151 trials) were mainstream, with nucleic acid vaccines (58 trials) as a promising emerging platform. Combination therapy (227 trials, >50%), especially with immune checkpoint inhibitors (ICIs), dominated; adjuvants (e.g., IL-2, GM-CSF agonists) enhanced efficacy. Most trials focused on Stage III/IV patients (91.1%): key trials showed mRNA-4157 + pembrolizumab reduced recurrence/death risk by 49% in resected melanoma, and herpes simplex virus RP1 + nivolumab achieved 58.3% objective response rate (ORR) in ICI-resistant patients. Primary endpoints favored safety/immunogenicity (215/142 trials), with overall survival (OS, 33 trials) rarely used; academic institutions led funding (52.3%).

[CONCLUSIONS] Melanoma vaccines, especially in combination with ICIs and via personalized platforms, have significant potential. However, challenges include tumor heterogeneity, immunosuppressive tumor microenvironment (TME), inefficient delivery, geographical R&D imbalance, and low Phase III conversion. Interdisciplinary collaboration, international multicenter trials, optimized clinical design (e.g., early-stage patient enrollment), and policy support are needed to advance their clinical translation.