Metal-organic framework nanoagent induces cuproptosis for effective immunotherapy of malignant glioblastoma

Abstract

Glioblastoma (GBM) is an aggressive brain cancer with an immunosuppressive tumor microenvironment. Here, a copper-based nanoplatform BSO-CAT@MOF-199 @DDM (BCMD) is constructed for mediating cuproptosis and subsequently promoting immunotherapy of glioblastoma. Specifically, BCMD can be degraded in the slightly acidic tumor environment to release Cu2+, which will be further reduced to toxic Cu+ to induce cuproptosis under the regulation of high level of ferredoxin 1 (FDX1). Meanwhile, buthionine-sulfoximine (BSO) and catalase (CAT) released from BCMD can reduce the glutathione (GSH) synthesis and increase O2 content in tumor cells, thereby rendering the tumor cells more sensitive to BCMD-mediated cuproptosis. In vivo experiments show that BCMD mediated cuproptosis can trigger the immunogenic cell death (ICD) to increase the infiltration of cytotoxic T lymphocytes and reverse the immunosuppressive microenvironment of glioblastoma to enhance tumoricidal immunity. Furthermore, anti-tumor therapeutic efficiency of immune checkpoint blockade (ICB) therapy is significantly enhanced by combining BCMD with αPD-L1.