Enhancing antitumour nanovaccine efficacy via integrated cholesterol modulation in situ

Antigen presentation is a central component of host immune responses to cancer vaccinations; however, antigen-presenting cells often fail to promote sufficient proliferation of specific T cells, thereby restricting their efficacy. This study shows that manipulating the cholesterol levels in dendritic cell (DC) membranes could enhance the antigen-presenting capability. On the basis of this finding, we developed a membrane-cholesterol-depleting nanovaccine designed to deliver antigens to DCs and simultaneously reduce the membrane cholesterol. The direct deprivation of membrane cholesterol enhanced the contact frequency between DCs and T cells and reshaped the tumour immune microenvironment to inhibit tumourigenesis and progression in multiple tumour models. Mechanistically, the designed nanovaccines promoted immune synapse formation with CD8⁺ T cells and augmented T cell activation and proliferation by remodelling the cholesterol microdomains in the DC membrane and blocking efferocytosis pathways, boosting the antigen presentation capacity. The study proposes an approach to enhance the effects of vaccines by depleting cholesterol levels in antigen-presenting cell membranes.