Thermosensitive Resiquimod-Loaded Lipid Nanoparticles Promote the Polarization of Tumor-Associated Macrophages to Enhance Bladder Cancer Immunotherapy

Abstract

Bladder cancer is a common malignant tumor of the urinary system and is associated with high morbidity, recurrence, and mortality rates. Immunotherapy with immune checkpoint inhibitors has shown great therapeutic outcomes and safety in bladder cancer. Immune checkpoint inhibitors have also been approved as first- and second-line drugs for the treatment of locally advanced or metastatic bladder cancer. However, immunotherapy has a low response and drug assistance for cancer immunotherapy, which can be ascribed to insufficient antigen presentation, tumor immunosuppressive cell accumulation, and T lymphocyte exhaustion in the tumor microenvironment. To overcome the disadvantages of immunotherapy, we prepared a resiquimod (R848)/photothermal agent (DTPA)-loaded lipid nanoparticle (R848/DTPA@DSPE-PEG NP), which has shown good photothermal conversion efficiency, biosafety, and biocompatibility. R848/DTPA@DSPE-PEG NPs with laser irradiation (635 nm) can damage MB49 cells and induce immunogenic cell death in vitro, which could trigger an immune response. Meanwhile, R848/DTPA@DSPE-PEG NPs can also promote M1-like macrophage polarization and dendritic cell maturation in vitro. Moreover, R848/DTPA@DSPE-PEG NPs with 635 nm laser irradiation can suppress subcutaneous and orthotopic bladder tumor growth and activate the immune response, which can promote dendritic cell maturation and M1-like macrophage polarization, enhance CD8+ T lymphocyte infiltration, and reduce M2-like macrophage polarization in tumors. Bioinformatics analysis found that R848/DTPA@DSPE-PEG NPs can also induce immune-related gene overexpression of immune signaling pathways. Combined R848/DTPA@DSPE-PEG NPs with PD-1 antibody can significantly enhance antitumor therapeutic effects, reprogram tumor immunosuppressive microenvironment, and prolong the survival time.