A 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. In this work, a hydrogen-bonded organic framework (HOF) specifically designed for GBM immunotherapy is developed, 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, tumor microenvironment (TME)-initiated chemiexcited photodynamic therapy (PDT) is enhanced during the regulation of cholesterol metabolism, and the biotuner can effectively trigger immunogenic cell death (ICD) and increase the infiltration of cytotoxic T lymphocytes (CTLs) in GBM. By reversing the immunosuppressive microenvironment and bolstering chemiexcited-PDT, this 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. A versatile nanocarrier, hydrogen-bonded organic framework (HOF)-based biotuner, regulates extra/intracellular cholesterol metabolism for bidirectionally blocking immune checkpoints to metabolically dismantle the immunosuppressive microenvironment. It synergizes with chemiexcited-PDT to enable effective immunotherapy and significantly inhibit glioblastoma growth. The biotuner is tailored to address the immunotherapeutic dilemma and metabolic characteristics of glioblastomas, providing new insights into the metabolically regulated immunosuppressive microenvironment of glioblastomas.image