Slimming and Reinvigorating Tumor-Associated Dendritic Cells with Hierarchical Lipid Rewiring Nanoparticles.

Dendritic cells (DCs) are crucial mediators of innate and adaptive anti-tumor immunity, whereas exogenously- and endogenously-driven lipid accumulation causes immune tolerance of tumor-associated DCs (TADCs) and thereby diminishes tumor responsiveness to various therapies. Herein, we design a type of multilevel lipid rewiring nanoparticles (NPs) for TADC revitalization. These self-assembled NPs specifically bind to the lipid transport receptor Msr1 on the TADC surface and orchestrate the restriction of extracellular lipid uptake, cytoplasmic de novo lipid biosynthesis and nuclear lipogenic gene transcription. We find that the slimming of TADCs via the three-in-one lipid metabolic reprogramming substantially promotes their maturation and rehabilitate their functions in inflammatory cytokine production, cytotoxic T cell recruitment and tumor inhibition. Significantly, it further overcomes tumor resistance to immune checkpoint blockade therapy. Our study presents a non-canonical strategy to remodel tumor-infiltrating immune cells and paves a new path for improving the efficacy of cancer immunotherapy. This article is protected by copyright. All rights reserved.