ZIF‐8‐Encapsulated Pexidartinib Delivery via Targeted Peptide‐Modified M1 Macrophages Attenuates MDSC‐Mediated Immunosuppression in Osteosarcoma

Abstract Adoptive cellular therapy is a promising strategy for cancer treatment. However, the effectiveness of this therapy is limited by its intricate and immunosuppressive tumor microenvironment. In this study, a targeted therapeutic strategy for macrophage loading of drugs is presented to enhance anti‐tumor efficacy of macrophages. K7M2‐target peptide (KTP) is used to modify macrophages to enhance their affinity for tumors. Pexidartinib‐loaded ZIF‐8 nanoparticles (P@ZIF‐8) are loaded into macrophages to synergistically alleviate the immunosuppressive tumor microenvironment synergistically. Thus, the M1 macrophages decorated with KTP carried P@ZIF‐8 and are named P@ZIF/M1‐KTP. The tumor volumes in the P@ZIF/M1‐KTP group are significantly smaller than those in the other groups, indicating that P@ZIF/M1‐KTP exhibited enhanced anti‐tumor efficacy. Mechanistically, an increased ratio of CD4+ T cells and a decreased ratio of MDSCs in the tumor tissues after treatment with P@ZIF/M1‐KTP indicated that it can alleviate the immunosuppressive tumor microenvironment. RNA‐seq further confirms the enhanced immune cell function. Consequently, P@ZIF/M1‐KTP has great potential as a novel adoptive cellular therapeutic strategy for tumors.