Abstract Glioblastoma (GBM) is a lethal brain tumor containing a subpopulation of glioblastoma stem cells (GSCs) that interaction with surrounding cells, including infiltrating tumor-associated macrophages and microglia (TAMs). While GSCs and TAMs are in close proximity and likely interact to coordinate tumor growth, there are limited mechanisms identified that support their communication. Here, we identified glycoprotein NMB (GPNMB) as a key factor mediating a unique bi-directional interaction between GSCs and TAMs in GBM. Specifically, GSCs educate macrophages and microglia to preferentially express GPNMB in the GBM tumor microenvironment. As a result, TAM-secreted GPNMB interacts with its receptor CD44 on GSCs to promote their glycolytic and self-renewal abilities via activating the PYK2-RSK2 signaling axis. Disrupting GPNMB-mediated GSC-TAM interplay suppresses tumor progression and self-renewal in GBM mouse models. Our study uncovers a pro-tumor function of GPNMB-mediated GSC-TAM bi-directional communication and supports GPNMB as a promising therapeutic target for GBM.
Yang et al. (2025) studied this question.