Bi-Target Nanomodulator for Glioma-Associated Myeloid Cells Polarization by Inducing Pyroptosis and Regulating Tryptophan Metabolism to Reshape Immunosuppressive Microenvironment of IDH-Mutant Gliomas.

Abstract

Since 2-hydroxyglutarate (2-HG) released from isocitrate dehydrogenase (IDH)-mutant gliomas results in the strong immunosuppressive tumor microenvironment (TME), the immunotherapy effect is unsatisfactory. In this work, we develop a hybridized cell membrane of glioma-macrophage cells (GMM) camouflaged bi-target nanomodulator (LNO@CH/Ca₃(PO₄)₂, LCC) comprised of LaNiO₃ (LNO) core and Ca₃(PO₄)₂ shell loaded with the aryl hydrocarbon receptor (AhR) antagonist (CH223191, CH), which can synergistically modulate glioma-associated myeloid cells (GAM) polarization by inducing pyroptosis and regulating tryptophan metabolism to enhance the efficacy of IDH-mutant gliomas immunotherapy. The hybrid cell membrane endows LCC@GMM with good blood brain barrier (BBB) penetration as well as dual homing ability to tumor cells and GAM. LCC@GMM not only induces pyroptosis in tumor cells by the production of cytotoxic reactive oxygen species (ROS) and the released La³ ⁺ but also regulates tryptophan metabolism in GAM via the released CH, effectively overcoming the immunosuppressive effects of IDH-mutant gliomas. The bi-target synergistic regulation of GAM reshapes the immunosuppressive TME of IDH-mutant gliomas and offers a novel idea for immunotherapy of IDH-mutant gliomas.