Engineering Dendritic Cell-Targeted Nanoparticles for Dual Enhancement of T Cell Activation and Immune Checkpoint Blockade

Dendritic cells (DCs) within the tumor microenvironment (TME) have insufficient capacity to activate T cells through antigen presentation. Furthermore, the programmed cell-death ligand 1 (PD-L1), abundantly expressed on tumor-associated DCs, binds the programmed cell-death 1 (PD-1)-positive T cells, and suppresses their immune function. Nanomedicines offer a versatile and biocompatible tool to enhance various aspects of cancer immunotherapy - from improving delivery, stability and efficacy of immunotherapeutic agents, to serving as artificial antigen-presenting cells and vaccine carriers. In this lecture I will describe two innovative nanoparticulate systems, with multiple functionalities, designed to enhance anti-tumor immune responses by simultaneously promoting antigen cross-presentation and blocking inhibitory PD-L1 interactions on intratumoral DCs. Mesoporous silica nanoparticles (MSNPs) were loaded with immune-stimulating agents (Clotrimazole (CTL), or tumor cell lysate (TCL)) to boost MHC II-mediated antigen presentation by DCs, and further surface decorated with PD-L1-binding peptide (PDL1bp) to interfere with PD-L1/PD-1 mediated interactions. The MSNPs effectively increased DC activation, promoted T cell stimulation, and enhanced antitumor immune responses in vivo. When tested against B16-F10 melanoma tumors, the CLT-loaded and PDL1bp-functionalized MSNPs significantly inhibited tumor growth compared to anti-PD-L1 therapy, demonstrating the potential of nanomedicine to enhance cancer immunotherapy by simultaneously addressing multiple challenges in the TME, offering a promising alternative to current immunotherapy approaches.