Abstract
The advancement of mRNA-based cancer immunotherapies has gained significant momentum, particularly after the success of mRNA vaccines during the COVID-19 pandemic and the recognition of mRNA vaccine development with the 2023 Nobel Prize. mRNA encoding cytokines, antibodies, and chimeric antigen receptor T cells has demonstrated substantial therapeutic potential in both preclinical models and clinical trials. Previous study identified vascular endothelial growth factor B (VEGF-B) as a metabolic regulator that controls lipid synthesis and maintains mitochondrial membrane integrity, essential for the survival of activated T cells. In this study, we demonstrate that mRNA encoding VEGF-B, delivered to tumors via lipid nanoparticles, effectively controls tumor growth in both subcutaneous and lung metastasis tumor models. Combination with programmed death-1 blockade significantly amplified therapeutic efficacy, leading to complete tumor regression in the lung metastasis model. Immune profiling revealed that nanoparticle delivery of VEGF-B mRNA reprograms the tumor microenvironment by increasing CD8+ T cell infiltration and enhancing the expression of effector molecules, including interferon-γ, tumor necrosis factor alpha, and granzyme B, while downregulating the exhaustion molecule programmed death-1. These findings highlight the considerable promise of mRNA-based therapies in reshaping the tumor microenvironment and enhancing cancer immunotherapy outcomes.