谷歌浏览器插件
订阅小程序
在清言上使用

Pharmacological Inhibition of BACE1 Suppresses Glioblastoma Growth by Stimulating Macrophage Phagocytosis of Tumor Cells

Nature cancer(2021)

引用 0|浏览1
暂无评分
摘要
Glioblastoma (GBM) contains abundant tumor-associated macrophages (TAMs). The majority of TAMs are tumor-promoting macrophages (pTAMs), while tumor-suppressive macrophages (sTAMs) are the minority. Thus, reprogramming pTAMs into sTAMs represents an attractive therapeutic strategy. By screening a collection of small-molecule compounds, we find that inhibiting β-site amyloid precursor protein-cleaving enzyme 1 (BACE1) with MK-8931 potently reprograms pTAMs into sTAMs and promotes macrophage phagocytosis of glioma cells; moreover, low-dose radiation markedly enhances TAM infiltration and synergizes with MK-8931 treatment to suppress malignant growth. BACE1 is preferentially expressed by pTAMs in human GBMs and is required to maintain pTAM polarization through trans-interleukin 6 (IL-6)–soluble IL-6 receptor (sIL-6R)–signal transducer and activator of transcription 3 (STAT3) signaling. Because MK-8931 and other BACE1 inhibitors have been developed for Alzheimer’s disease and have been shown to be safe for humans in clinical trials, these inhibitors could potentially be streamlined for cancer therapy. Collectively, this study offers a promising therapeutic approach to enhance macrophage-based therapy for malignant tumors. Zhai et al. identify clinical brain-penetrant BACE1 inhibitors as regulators of macrophage-dependent phagocytosis in glioblastoma through IL-6–STAT3 signaling and demonstrate preclinical therapeutic efficacy in orthotopic mouse models and PDXs.
更多
查看译文
关键词
Cancer microenvironment,Cancer therapy,CNS cancer,Life Sciences,general
AI 理解论文
溯源树
样例
生成溯源树,研究论文发展脉络
Chat Paper
正在生成论文摘要