DataVXAdvanced MaterialsPaper
journal article·2024-03

Intracavitary Spraying of Nanoregulator‐Encased Hydrogel Modulates Cholesterol Metabolism of Glioma‐Supportive Macrophage for Postoperative Glioblastoma Immunotherapy

Yuanmin Dong, Jing Zhang, Yan Wang, Yulin Zhang, Daniella Rappaport, Zhenmei Yang, Maosen Han, Ying Liu, Zhipeng Fu, Xiaotian Zhao, Chunwei Tang, Chongdeng Shi, Daizhou Zhang, Dawei Li, Shilei Ni, Anning Li, Jiwei Cui, Tao Li, Peng Sun, Ofra Benny, Cai Zhang, Kun Zhao, Chen Chen, Xinyi Jiang

Advanced Materials· Volume 36· Issue 13
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Source abstract

Abstract

Abstract Glioblastoma multiforme (GBM) is notoriously resistant to immunotherapy due to its intricate immunosuppressive tumor microenvironment (TME). Dysregulated cholesterol metabolism is implicated in the TME and promotes tumor progression. Here, it is found that cholesterol levels in GBM tissues are abnormally high, and glioma‐supportive macrophages (GSMs), an essential “cholesterol factory”, demonstrate aberrantly hyperactive cholesterol metabolism and efflux, providing cholesterol to fuel GBM growth and induce CD8+ T cells exhaustion. Bioinformatics analysis confirms that high 7‐dehydrocholesterol reductase (DHCR7) level in GBM tissues associates with increased cholesterol biosynthesis, suppressed tumoricidal immune response, and poor patient survival, and DHCR7 expression level is significantly elevated in GSMs. Therefore, an intracavitary sprayable nanoregulator (NR)‐encased hydrogel system to modulate cholesterol metabolism of GSMs is reported. The degradable NR‐mediated ablation of DHCR7 in GSMs effectively suppresses cholesterol supply and activates T‐cell immunity. Moreover, the combination of Toll‐like receptor 7/8 (TLR7/8) agonists significantly promotes GSM polarization to antitumor phenotypes and ameliorates the TME. Treatment with the hybrid system exhibits superior antitumor effects in the orthotopic GBM model and postsurgical recurrence model. Altogether, the findings unravel the role of GSMs DHCR7/cholesterol signaling in the regulation of TME, presenting a potential treatment strategy that warrants further clinical trials.
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Research context

PolymersNanomaterials

OpenAlex topics: Cholesterol and Lipid Metabolism · Cancer, Lipids, and Metabolism · Immune cells in cancer

SciVX discovery tags are terminology-based. OpenAlex topics are source-provided classifications.

Affiliations

NMPA Key Laboratory for Technology Research and Evaluation of Drug Products and Key Laboratory of Chemical Biology (Ministry of Education), Department of Pharmaceutics, School of Pharmaceutical Sciences, Cheeloo College of Medicine Shandong University 44 West Culture Road Jinan Shandong Province 250012 China

Department of Neurosurgery, Qilu Hospital and Institute of Brain and Brain‐Inspired Science, Cheeloo College of Medicine Shandong University 44 Cultural West Road Jinan Shandong Province 250012 China

Harry W. and Charlotte Ullman Labov Chair in Cancer Studies, Fraunhofer Innovation Platform (FIP_DD@HUJI), Institute for Drug Research, The School of Pharmacy, Faculty of Medicine | Ein Karem Campus The Hebrew University of Jerusalem Jerusalem 91120 Israel

Shandong Academy of Pharmaceutical Sciences Jinan Shandong Province 250012 China

Department of Radiology, Qilu Hospital, Cheeloo College of Medicine Shandong University 44 Cultural West Road Jinan Shandong Province 250012 China

Key Laboratory of Colloid and Interface Chemistry of the Ministry of Education, School of Chemistry and Chemical Engineering Shandong University Jinan Shandong 250100 China

Department of General Surgery Qilu Hospital, Shandong University 44 Cultural West Road Jinan Shandong Province 250012 China

Shandong University of Traditional Chinese Medicine University Road Jinan Shandong Province 250355 China

Funding

National Natural Science Foundation of China

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