A CSF-1R inhibitor, BLZ945, significantly improves survival and reduces glioma progression in a mouse model of proneural glioblastoma (GBM). The study shows that BLZ945 targets tumor-associated macrophages (TAMs) without depleting them, instead altering their function. Despite the absence of TAM depletion, BLZ945 inhibits glioma growth by blocking macrophage survival through CSF-1R inhibition. Glioma-secreted factors, such as GM-CSF and IFN-γ, support TAM survival in the presence of CSF-1R inhibition, leading to a shift in macrophage polarization from alternatively activated (M2) to a more tumor-suppressive state. This change is associated with improved survival in proneural GBM patients. BLZ945 treatment significantly reduces tumor volume and increases survival in both mouse models and patient-derived glioma xenografts. It blocks tumor growth and progression by reducing cell proliferation and increasing apoptosis in glioma cells. The drug also inhibits the paracrine CSF-1/EGF signaling loop, which is involved in glioma invasion. BLZ945 does not affect glioma cell survival directly but disrupts macrophage survival through CSF-1R inhibition. The study identifies a 5-gene signature (minimal gene signature) that is associated with improved survival in proneural GBM patients. This signature includes genes downregulated in TAMs treated with BLZ945, which are linked to M2 macrophage polarization. The results suggest that TAMs in gliomas are protected from CSF-1R inhibitor-induced apoptosis due to glioma-secreted survival factors, leading to a functional re-education of TAMs that enhances anti-tumor responses. The findings highlight the therapeutic potential of targeting TAMs in GBM, particularly in proneural subtypes. CSF-1R inhibition is shown to be effective in multiple preclinical models, including genetically engineered mice and human-derived xenografts. The study also demonstrates that CSF-1R inhibition can block heterotypic signaling between macrophages and glioma cells, which is crucial for tumor progression. These results suggest that targeting TAMs through CSF-1R inhibition could be a promising strategy for GBM treatment.A CSF-1R inhibitor, BLZ945, significantly improves survival and reduces glioma progression in a mouse model of proneural glioblastoma (GBM). The study shows that BLZ945 targets tumor-associated macrophages (TAMs) without depleting them, instead altering their function. Despite the absence of TAM depletion, BLZ945 inhibits glioma growth by blocking macrophage survival through CSF-1R inhibition. Glioma-secreted factors, such as GM-CSF and IFN-γ, support TAM survival in the presence of CSF-1R inhibition, leading to a shift in macrophage polarization from alternatively activated (M2) to a more tumor-suppressive state. This change is associated with improved survival in proneural GBM patients. BLZ945 treatment significantly reduces tumor volume and increases survival in both mouse models and patient-derived glioma xenografts. It blocks tumor growth and progression by reducing cell proliferation and increasing apoptosis in glioma cells. The drug also inhibits the paracrine CSF-1/EGF signaling loop, which is involved in glioma invasion. BLZ945 does not affect glioma cell survival directly but disrupts macrophage survival through CSF-1R inhibition. The study identifies a 5-gene signature (minimal gene signature) that is associated with improved survival in proneural GBM patients. This signature includes genes downregulated in TAMs treated with BLZ945, which are linked to M2 macrophage polarization. The results suggest that TAMs in gliomas are protected from CSF-1R inhibitor-induced apoptosis due to glioma-secreted survival factors, leading to a functional re-education of TAMs that enhances anti-tumor responses. The findings highlight the therapeutic potential of targeting TAMs in GBM, particularly in proneural subtypes. CSF-1R inhibition is shown to be effective in multiple preclinical models, including genetically engineered mice and human-derived xenografts. The study also demonstrates that CSF-1R inhibition can block heterotypic signaling between macrophages and glioma cells, which is crucial for tumor progression. These results suggest that targeting TAMs through CSF-1R inhibition could be a promising strategy for GBM treatment.