A Cholesterol Metabolic Regulated Hydrogen‐Bonded Organic Framework (HOF)‐Based Biotuner for Antibody Non‐Dependent Immunotherapy Tailored for Glioblastoma

Abstract

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

Magnetic Metal–Organic Framework-Based Nanoplatform with Platelet Membrane Coating as a Synergistic Programmed Cell Death Protein 1 Inhibitor against Hepatocellular Carcinoma

“…Furthermore, combination therapy decreased the volume of ascites and improved the quality of life (QOL) of mice. Based on a single mechanism, many existing strategies, including turning the "cold" tumor into a "hot" tumor, 42 improving tumor immunogenicity, 43 and reversing TIL exhaustion, 44 have been formulated to improve the efficacy of PD-1 inhibitors. However, these strategies exhibit limited effectiveness owing to the intricate nature of the tumor microenvironment.…”

Metal–Organic Framework-Based Nanovaccine for Relieving Immunosuppressive Tumors via Hindering Efferocytosis of Macrophages and Promoting Pyroptosis and Cuproptosis of Cancer Cells

“…Moreover, an obvious enhancement in the secretion of proinflammatory cytokines (TNF-α) and interleukin 12p70 (IL-12p70) was observed (Figure g,h), suggesting that Cu-THBQ/AX can reprogram the immunosuppressive TME and transform the “cold” tumor into a “hot” one. In addition, the formation of pores in cellular membranes, characterized by pyroptosis, will cause the release of DAMPs, such as CRT and HMGB1 (Figure i as well as Figures S40 and S41), which can stimulate DCs to engulf the debris of dying cells and subsequently mature. , As measured by flow cytometry, the maturation of DCs was enhanced in Cu-THBQ, Cu-THBQ/A, and Cu-THBQ/AX preincubated group (Figures j and S42), and the loading of XMD8-92 did not result in further enhancement of maturation of DCs. Meanwhile, the secretion of proinflammatory cytokines, including TNF-α and IL-12p70, was also increased in the supernatant of DCs (Figure k–m), indicating that Cu-THBQ/AX could induce immunogenic pyroptosis by breaking the cellular redox balance.…”

Recent advances in nanomedicine for metabolism-targeted cancer therapy

“…Furthermore, the nanocomposite could regulate both extracellular and intracellular cholesterol metabolism, which effectively blocked the PD-1/PD-L1 pathway and reduced the expression of 2B4, eventually eliciting positive immune responses to inhibit tumour regression. 170 Additionally, cholesterol consumption can regulate the processes of cancer metastasis. Lamellipodia, a marker of cell invasion, is highly dependent on the integrity of lipid rafts.…”