P08.03.A DOUBLE-PUNCH STRATEGY: MACROPHAGE MEMBRANE-ENVELOPED IMIPRAMINE AND ACD47 REPROGRAMS TUMOR MICROENVIRONMENT TO ENHANCE GLIOBLASTOMA IMMUNOTHERAPY

Abstract BACKGROUND The immune response rates of patients with glioblastoma (GBM) are relatively low for the complex immunosuppressive tumor microenvironment, which is mainly attributed to the presence of M2-type tumor-associated macrophages (TAMs). Herein, to enhance anti-GBM immune response, we designed a novel biomimetic cascade nanoreactor (Mam@NPs) with “double-punch” strategy for reshaping M2-type TAMs into M1-type. MATERIAL AND METHODS The Mam@NPs were fabricated by a dual pH-responsive CDM-PEG-PDPA diblock copolymer loaded with imipramine (IM) and aCD47 followed by macrophage membrane (Mam) encapsulation. The physio-chemical features of Mam@NPs were analyzed and characterized by dynamic light scattering, transmission electron microscopy and western blot. The BBB transcytosis and GBM targeting capability of Mam@NPs were tested by using BBB model in vitro and bioluminescence/fluorescence in vivo. The antitumor ability of Mam@NPs was evaluated by using CCK8, EdU assay in vitro and bioluminescence in vivo. The immune phenotyping and antitumor immunity were examined by using flow cytometry ELISA and immunohistochemistry. RESULTS This biomimetic cascade-nanoreactor significantly ablated the tumor cells directly by releasing IM and simultaneously bolstering the anti-GBM effects of aCD47. This augmentation arose from the synergistic remodeling effect of IM and aCD47 on the immunosuppressive tumor microenvironment by enhancing CCL3 secretion, reshaping M2-type TAMs into M1-type, promoting the maturation of dendritic cells, stimulating the proliferation/activation of CD8+ T cells, and reducing regulatory T cells. CONCLUSION This work generates a safe and effective “double-punch” biomimetic cascade-nanoreactor, offering an innovative combination treatment strategy for aCD47 together with IM in GBM immunotherapy.