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

Abstract

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. In vitro 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. In vivo 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.