Heterotypic interactions across diverse cell types can enable tumor progression and hold the potential to expand therapeutic interventions. Here, combined profiling and functional studies of glioma cells in glioblastoma multiforme (GBM) models establish that PTEN deficiency activates YAP1, which directly upregulates lysyl oxidase (LOX) expression. Mechanistically, secreted LOX functions as a potent macrophage chemoattractant via activation of the β1 integrin-PYK2 pathway in macrophages. These infiltrating macrophages secrete SPP1, which sustains glioma cell survival and stimulates angiogenesis. In PTEN-null GBM models, LOX inhibition markedly suppresses macrophage infiltration and tumor progression. Correspondingly, YAP1-LOX and β1 integrin-SPP1 signaling correlates positively with higher macrophage density and lower overall survival in GBM patients. This symbiotic glioma-macrophage interplay provides therapeutic targets specifically for PTEN-deficient GBM. Display omitted •PTEN deficiency in GBM drives macrophage infiltration via upregulation of LOX•LOX is directly regulated by YAP1 in PTEN-deficient GBM•LOX recruits macrophages into GBM via the β1 integrin-PYK2 pathway•LOX inhibition impairs PTEN-deficient GBM progression by decreasing TAM-derived SPP1 Chen et al. find that PTEN deficiency in glioblastoma (GBM) increases macrophage infiltration via a YAP1-LOX-β1 integrin-PYK2 axis, the infiltrated macrophages in turn secrete SPP1 to support GBM survival. In PTEN-null GBM xenograft mouse models, inhibition of LOX reduces macrophage infiltration and tumor growth.