Cholesterol Metabolic Regulated Hydrogen-Bonded Organic Framework (HOF)-based Biotuner for Antibody Non-dependent Immunotherapy Tailored for Glioblastoma.

The metabolic reprogramming of glioblastoma (GBM) poses a tremendous obstacle to effective immunotherapy due to its impact on the immunosuppressive microenvironment. Here, we develop a hydrogen-bonded organic frameworks (HOF) specifically designed for GBM immunotherapy, taking advantage of the relatively isolated cholesterol metabolism microenvironment in the central nervous system (CNS). The HOF-based biotuner regulates extra/intracellular cholesterol metabolism, effectively blocking the programmed cell death protein 1/programmed death-ligand 1 (PD-1/PD-L1) pathway and reducing 2B4 expression. This metabolically disrupts the immunosuppressive microenvironment of GBM and rejuvenates CD8 T cells. Moreover, cholesterol metabolism regulation offers additional benefits in treating GBM invasion. Furthermore, in response to the tumor microenvironment (TEM)-initiated chemiexcited photodynamic therapy (PDT), which was enhanced during the regulation of cholesterol metabolism, the biotuner could effectively trigger immunogenic cell death (ICD) and increase the infiltration of cytotoxic T lymphocytes (CTLs) in GBM. By reversing immunosuppressive microenvironment and bolstering chemiexcited-PDT, our approach invigorates efficient antibody non-dependent immunotherapy for GBM. This study provides a model for enhancing immunotherapy through cholesterol metabolism regulation and explores the feasibility of a "metabolic checkpoint" strategy in GBM treatment. This article is protected by copyright. All rights reserved.