Enhancing Antitumor Nanovaccine Efficacy via Integrated Cholesterol Modulation In Situ

Abstract Antigen presentation is a central component of host immune responses to cancer vaccinations; however, antigen-presenting cells (APCs) often fail to promote sufficient proliferation of specific T cells, thus restricting their efficacy. This study demonstrated that manipulating the dendritic cell (DC) membrane cholesterol levels could enhance antigen-presenting capability. Based on this finding, a membrane cholesterol-depleting nanovaccine designed to deliver antigen to DCs and simultaneously reduce membrane cholesterol was developed. The direct deprivation of membrane cholesterol enhanced the contact frequency between DCs and T cells and reshaped the tumor immune microenvironment to inhibit tumorigenesis and progression in multiple tumor models. Mechanistically, the designed nanovaccines promoted immune synapse formation with CD8+ T cells and augmented T cell activation and proliferation by remodeling the cholesterol microdomains in the DC membrane and blocking efferocytosis pathways that enhance antigen presentation capacity of the DCs. The study proposed a new approach to enhance the effects of vaccines by depleting cholesterol levels in APC cell membranes.