How Deeply Can mRNA Vaccines Affect the Responsiveness to Immune Checkpoint Inhibitors Through Changes in the Tumor Microenvironment? Evidence from Melanoma.

Messenger RNA (mRNA) vaccines are emerging as promising tools capable of reshaping how cancer interacts with the immune system and responds to immunotherapy. These vaccines not only act as platforms for antigen delivery but can also influence the tumor microenvironment (TME), fostering a shift from immunologically "cold'' conditions toward "hotter'' and treatment-responsive states. In melanoma, this capability has been found to enhance the efficacy of the immune checkpoint inhibitors (ICIs), as mRNA-based priming can provide the robust antitumor activation needed for more effective checkpoint blockade. Early clinical studies with personalized or off-the-shelf vaccines showed benefits in patients with high-risk resected melanoma or refractory to PD-1 inhibition. Combining mRNA vaccines with ICIs, along with other immunomodulatory strategies, may be helpful to overcome resistance arising from the TME and achieve more durable clinical benefits. Besides these advances, computational and in silico modeling are providing new insights into how mRNA vaccines modulate the TME, helping to identify factors such as antigen-presenting cell (APC) density, CD8+ T-cell infiltration, and macrophage polarization that may predict treatment success and guide personalized strategies. Together, these developments indicate that combining mRNA vaccination with ICIs, supported by computational tools, may improve clinical outcomes in melanoma and, potentially, in selected tumor types with favorable immunological features, although important biological constraints limit direct extrapolation to less immunogenic malignancies.