多形性胶质母细胞瘤（GBM）仍然是最致命的中枢神经系统癌症，其生存率很低且靶向治疗很少。 GBM肿瘤微环境复杂且与预后密切相关。在这里，我们分析了微环境内的细胞间通讯，发现 GBM 肿瘤细胞和肿瘤相关巨噬细胞 (TAM) 之间存在高水平的细胞通讯。我们发现淀粉样蛋白前体 (APP)-CD74 轴在 GBM 肿瘤细胞和 TAM 之间显示出最高水平的通讯，并且 APP 和 CD74 表达水平与较差的患者预后显着相关。我们发现GBM表面的APP表达通过APP与CD74/CXCR4细胞表面受体复合物的结合抑制TAM的吞噬作用。我们进一步证明，破坏 APP-CD74 轴可以在体外和体内上调 TAM 的吞噬作用。最后，我们证明APP通过与CD74结合促进SHP-1的磷酸化。总之，我们的研究结果表明 APP-CD74 轴是一种高表达的抗吞噬信号通路，可能是 GBM 的潜在免疫治疗靶点。版权所有 © 2024。由 Elsevier B.V 出版。

Glioblastoma multiforme (GBM) remains the most lethal central nervous system cancer with poor survival and few targeted therapies. The GBM tumor microenvironment is complex and closely associated with outcomes. Here, we analyzed the cell-cell communication within the microenvironment and found the high level of cell communication between GBM tumor cells and tumor-associated macrophages (TAMs). We found that the amyloid protein precursor (APP)-CD74 axis displayed the highest levels of communication between GBM tumor cells and TAMs, and that APP and CD74 expression levels were significantly corelated with poorer patient outcomes. We showed that the expression of APP on the surface of GBM inhibited phagocytosis of TAMs through the binding of APP to the CD74/CXCR4 cell surface receptor complex. We further demonstrated that disrupting the APP-CD74 axis could upregulated the phagocytosis of TAMs in vitro and in vivo. Finally, we demonstrated that APP promotes the phosphorylation of SHP-1 by binding to CD74. Together, our findings revealed that the APP-CD74 axis was a highly expressed anti-phagocytic signaling pathway that may be a potential immunotherapeutic target for GBM.Copyright © 2024. Published by Elsevier B.V.