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.
Adv Mater. 2024 Mar;36(13):e2311109. doi: 10.1002/adma.202311109. Epub 2023 Dec 28.
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.
多形性胶质母细胞瘤（GBM）由于其复杂的免疫抑制肿瘤微环境（TME）而对免疫疗法具有很强的抵抗力。胆固醇代谢失调与 TME 有关，并促进肿瘤进展。研究发现，GBM 组织中的胆固醇水平异常升高，而支持神经胶质瘤的巨噬细胞（GSM）是一个重要的“胆固醇工厂”，表现出异常活跃的胆固醇代谢和外排，为 GBM 生长提供胆固醇，并诱导 CD8 T 细胞耗竭。生物信息学分析证实，GBM 组织中高 7-脱氢胆固醇还原酶（DHCR7）水平与胆固醇生物合成增加、肿瘤杀伤免疫反应受抑制和患者预后不良有关，而 DHCR7 在 GSM 中的表达水平显著升高。因此，报道了一种腔内可喷涂纳米调节剂（NR）包裹水凝胶系统来调节 GSM 的胆固醇代谢。可降解 NR 介导的 DHCR7 在 GSM 中的消融有效地抑制了胆固醇的供应并激活了 T 细胞免疫。此外，Toll 样受体 7/8（TLR7/8）激动剂的联合使用显著促进了 GSM 向抗肿瘤表型的极化，并改善了 TME。该混合系统在原位 GBM 模型和手术后复发模型中的治疗效果优于单纯治疗。总之，这些发现揭示了 GSMs DHCR7/胆固醇信号在调节 TME 中的作用，为进一步的临床试验提供了一种有潜力的治疗策略。
