Lymph node-targeted metabolic regulatory nanovaccines to boost cancer immunotherapy by potentiating dendritic cell-mediated antigen presentation

Tumor vaccines represent a promising strategy for the prevention and treatment of cancer. However, suboptimal targeting efficiency to dendritic cells (DCs) and inadequate antigen presentation by metabolically dysfunctional DCs significantly hinder vaccination efficacy. <i>In vitro</i> drug screening reveals that lovastatin (Lov) effectively inhibits antigen degradation in DCs by modulating the mevalonate (MVA) pathway, thereby enhancing antigen presentation. Additionally, tumor-derived water-insoluble neoantigens contain abundant immunogenic mutated components but suffer from limited vaccination efficiency. Based on these findings, a metabolic regulatory nanovaccine (DAL) with excellent lymph node targeting capacity is developed through the self-assembly of dextran derivatives, water-insoluble neoantigens, and Lov to stimulate robust antitumor immunity. DAL effectively targets DCs in lymph nodes, inhibits the MVA pathway to enhance antigen presentation, and promotes cytotoxic T cell infiltration, thereby facilitating long-term immune surveillance. <i>In vivo</i> experiments demonstrate that DAL inhibits tumorigenesis, attenuates tumor progression, and enhances the efficacy of immune checkpoint blockade (ICB) therapy. Collectively, this work provides a metabolic regulatory strategy for tumor vaccination, offering a potential approach to develop personalized vaccines for tumor immunotherapy.