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

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, reprograming pTAMs into sTAMs represents an attractive therapeutic strategy. By screening a collection of small molecule compounds, we find that inhibiting the β-site amyloid precursor protein cleaving enzyme 1 (BACE1) by 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 for maintaining pTAM polarization through trans-IL-6-sIL-6R-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 be potentially streamlined for cancer therapy. Collectively, this study offers a promising therapeutic approach to enhance macrophage-based therapy for malignant tumors.