Engineering TGF-β Inhibitor-Encapsulated Macrophage-Inspired Multi-Functional Nanoparticles for Combination Cancer Immunotherapy.

The emergence of cancer immunotherapies, notably immune checkpoint inhibitors, has revolutionized anti-cancer treatments. These treatments, however, have been reported to be effective in a limited range of cancers and cause immune-related adverse effects. Thus, for a broader applicability and enhanced responsiveness to solid tumor immunotherapy, immunomodulation of the tumor microenvironment is crucial. Transforming growth factor-β (TGF-β) has been implicated in reducing immunotherapy responsiveness by promoting M2-type differentiation of macrophages and facilitating cancer cell metastasis. In this study, we developed macrophage membrane-coated nanoparticles loaded with a TGF-βR1 kinase inhibitor, SD-208 (M ϕ -SDNP). Inhibitions of M2 macrophage polarization and epithelial-to-mesenchymal transition (EMT) of cancer cells were comprehensively evaluated through in vitro and in vivo experiments. Bio-distribution study and in vivo therapeutic effects of M ϕ -SDNP were investigated in orthotopic breast cancer model and intraveneously injected metastasis model. M ϕ -SDNPs effectively inhibited cancer metastasis and converted the immunosuppressive tumor microenvironment (cold tumor) into an immunostimulatory tumor microenvironment (hot tumor), through specific tumor targeting and blockade of M2-type macrophage differentiation. Administration of M ϕ -SDNPs considerably augmented the population of cytotoxic T lymphocytes (CTLs) in the tumor tissue, thereby significantly enhancing responsiveness to immune checkpoint inhibitors, which demonstrates a robust anti-cancer effect in conjunction with anti-PD-1 antibodies. Collectively, responsiveness to immune checkpoint inhibitors was considerably enhanced and a robust anti-cancer effect was demonstrated with the combination treatment of M ϕ -SDNPs and anti-PD-1 antibody. This suggests a promising direction for future therapeutic strategies, utilizing bio-inspired nanotechnology to improve the efficacy of cancer immunotherapy.