Engineered Nanoparticles for Enhanced Antitumoral Synergy Between Macrophages and T Cells in the Tumor Microenvironment

T cells and macrophages have the potential to collaborate to eliminate tumor cells efficiently. Macrophages can eliminate tumor cells through phagocytosis and subsequently activate T cells by presenting tumor antigens. The activated T cells, in turn, can kill tumor cells and redirect tumor-associated macrophages toward an antitumoral M1 phenotype. However, checkpoint molecules expressed on tumor cells impede the collaborative action of these immune cells. Meanwhile, monotherapy with a single immune checkpoint inhibitor (ICI) for either macrophages or T cells yields suboptimal efficacy in cancer patients. To address this challenge, here a nanoparticle capable of efficiently delivering dual ICIs to tumors for both macrophages and T cells is developed. These programmed cell death protein 1 (PD-1)-transfected macrophage membrane-derived nanoparticles (PMMNPs) can target tumors and provide signal-regulatory protein alpha and PD-1 to block CD47 and programmed cell death-ligand 1 (PD-L1), respectively, on tumor cells. PMMNPs enhance macrophage-mediated cancer cell phagocytosis and antigen presentation, promote T cell activation, and induce the reprogramming of macrophages toward an antitumoral phenotype. In syngeneic tumor-bearing mice, PMMNPs demonstrate superior therapeutic efficacy compared to nanoparticles delivering single ICIs and non-targeted delivery of anti-CD47 and anti-PD-L1 antibodies. PMMNPs capable of augmenting the antitumoral interplay between macrophages and T cells may offer a promising avenue for cancer immunotherapy. Programmed cell death protein 1 (PD-1)-transfected macrophage membrane-derived nanoparticles (PMMNPs) enable tumor-targeted delivery of dual immune checkpoint inhibitors for both T cells and macrophages. Consequently, PMMNPs not only enhance the antitumoral immunity of macrophages and T cells but also foster antitumoral synergy between these cells. This synergy is achieved by promoting tumor antigen presentation and subsequent T cell activation, and inducing the reprogramming of macrophages toward an antitumoral phenotype. image