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

Glioblastoma multiforme (GBM) is notoriously resistant to immunotherapy due to its intricate tumor microenvironment (TME). Dysregulated cholesterol metabolism is implicated in the immunosuppressive TME and promotes tumor progression. Here, we found that cholesterol levels in GBM tissues are abnormally high, and glioma-supportive macrophages (GSMs), an essential "cholesterol factory", demonstrated aberrantly hyperactive cholesterol metabolism and efflux, providing cholesterol to fuel GBM growth and induce CD8 + T cells exhaustion. Subsequent bioinformatics analysis confirmed that high 7-dehydrocholesterol reductase (DHCR7) level in GBM tissues was concomitant with increased cholesterol biosynthesis, suppressed tumoricidal immune response, and poor patient survival, and DHCR7 expression level was significantly elevated in GSMs. Therefore, we reported an intracavitary sprayable nanoregulator-encased hydrogel system to modulate cholesterol metabolism of GSMs. The degradable nanoregulator mediated ablation of DHCR7 in GSMs effectively suppressed cholesterol supply and activated T-cell immunity. Moreover, the combination of Toll-like receptor 7/8 (TLR7/8) agonists significantly promoted GSMs polarization to antitumor phenotypes and ameliorated the immunosuppressive TME. Treatment with the hybrid system exhibited superior antitumor effects in orthotopic GBM tumor model and postsurgical recurrence model. Altogether, our findings unravel the role of GSMs DHCR7/cholesterol signaling in the regulation of immunosuppressive TME, presenting a potential GBM treatment strategy that warrants further clinical trials. This article is protected by copyright. All rights reserved.