TLR7/8-Agonist-Loaded M1-Macrophage-Derived Nanovesicles Promote the Polarization of Macrophages to Enhance Bladder Cancer Immunotherapy

Abstract

Immune checkpoint inhibitors (ICIs), such as PD-1/PD-L1 antibodies, modulate the cancer killing function of immune cells in the tumor microenvironment (TME). However, immunosuppressive M2-type tumor-associated macrophages (TAMs) are abundant in bladder cancer (BC) and able to release substances such as cytokines to promote tumor growth, evade immune cell attack and lead to tumor ICIs treatment resistance. In the present study, we utilized nanovesicles derived from M1 macrophages, which contained constituents of M1 macrophages (M1 NV), and loaded the vesicles with the TLR7/8 agonist R848, a potent driver of M1 macrophages to construct M1 NV-R848 nanovesicles. Compared with M1 NV or R848 treatment alone, M1 NV-R848 was able to induce polarization of M2 macrophages into M1 macrophages more efficient both in vitro and in vivo. Intravenous injection of M1 NV-R848 improved the immunosuppressive TME and inhibited tumor growth and no significantly toxic or immunogenic in MB-49 tumor-bearing mice. In addition, compared with M1 NV-R848 treatment alone, combined injection of M1 NV-R848 and PD-L1 was able to further inhibit MB-49 tumor growth. Thus, our study demonstrates that M1 NV-R848 has the ability to promote the polarization of M2 TAMs to M1 macrophages and to enhance the efficacy of the ICIs PD-L1 in the treatment of UBC with no significantly toxic or immunogenic.