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 BennyCai Zhang*, Kun Zhao*, Chen Chen*, Xinyi Jiang*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

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.

Original languageAmerican English
JournalAdvanced Materials
Early online date21 Dec 2023
DOIs
StateE-pub ahead of print - 21 Dec 2023

Bibliographical note

Publisher Copyright:
© 2023 Wiley-VCH GmbH.

Keywords

  • CD8+ T cells exhaustion
  • TLR7/8 agonists
  • cholesterol metabolism
  • glioma-supportive macrophage polarization
  • sprayable hydrogel

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