To explore a therapeutic approach with dual functions of activating cytotoxic CD8⁺ T cells and remodeling immunosuppressive tumor-associated macrophages (TAMs), the engineered macrophage-derived nanovesicles (MAC-PNV) were developed in this study. The MAC-PNV were derived from activated DC-like M1 macrophages after reprogramming macrophages by transcription factors PIB (PU.1, IRF8, and BATF3) and further stimulated with antigenic peptide, lipopolysaccharide (LPS), and interferon-γ (IFN-γ). In vitro results demonstrated that the enriched antigen-presenting complexes and co-stimulatory molecules were displayed on the surface of pro-inflammatory cargo-contained MAC-PNV, which enabled significant activation of CD8⁺ T cells and repolarization of M2 macrophages towards the M1 phenotype. After peritumoral administration, MAC-PNV alone significantly inhibited tumor growth by promoting the activation and intra-tumoral infiltration of CD8⁺ T cells, and remodeling the immunosuppressive tumor microenvironment (TME) in B16-OVA-bearing mouse models. More importantly, MAC-PNV remarkably enhanced the anti-tumor efficacy of low-dose liposomal doxorubicin (DOX-Lipo, 1 mg/kg), along with reducing its dose-limiting toxicities in B16-F10-bearing mouse models. This study highlights that the MAC-PNV would be a potential and effective immunomodulatory enhancer for providing a promising combination strategy with clinical chemotherapeutics.

Nanovesicles  /  PIB transcription factors  /  Cell reprogramming  /  Dendritic cells  /  CD8⁺ T cell activation  /  Tumor-associated macrophages  /  Tumor immunotherapy  /  Immunomodulatory enhancer