靶向免疫抑制和促癌的胶质母细胞瘤相关巨噬细胞和微胶质细胞（GAMs）具有改善患者预后的巨大潜力。集落刺激因子-1受体（CSF1R）已成为重编程抗炎M2型GAMs的有希望的靶点。然而，关于病人来源的肿瘤感受教育的GAMs的治疗数据以及它们对适应性免疫的影响尚缺乏。将从病人肿瘤中新鲜分离的CD11b+-GAMs用CSF1R靶向药物PLX3397、BLZ945和GW2580进行处理。通过RNA测序、流式细胞术和细胞因子定量评估处理过程中的表型变化。功能分析包括诱生一氧化氮活性、吞噬作用、跨膜迁移和同种肿瘤细胞杀伤实验。在一个复杂的病人来源的三维肿瘤器官样模型中，确认了抗肿瘤效果和GAM激活的变化，该模型作为一个肿瘤化身。观察到GW2580治疗对GAMs的最有效重编程，导致M2相关标记、IL-6和IL-10、ERK1/2和MAPK信号通路的下调，同时M1样标记、启动MHC-II表达富集基因组、吞噬作用和T细胞杀伤明显增加。此外，使用GW2580处理病人来源的胶质母细胞瘤器官样体证实了成功的重编程，导致肿瘤细胞增殖受损。与临床试验失败一致，PLX3397在我们的分析中无效。这项对病人来源的GAMs和人类胶质母细胞瘤化身进行CSF1R靶向药物比较分析确定了GW2580作为最强有力的抑制剂，能够将免疫抑制性GAMs极化为促炎症表型，支持抗肿瘤T细胞反应，同时产生直接的抗肿瘤作用。这些数据表明，GW2580可能成为未来胶质母细胞瘤治疗的重要支柱。

Targeting immunosuppressive and pro-tumorigenic glioblastoma-associated macrophages and microglial cells (GAMs) has great potential to improve patient outcomes. Colony stimulating factor-1 receptor (CSF1R) has emerged as a promising target for reprograming anti-inflammatory M2-like GAMs. However, treatment data on patient-derived, tumor-educated GAMs and their influence on the adaptive immunity are lacking.CD11b+-GAMs freshly isolated from patient tumors were treated with CSF1R-targeting drugs PLX3397, BLZ945, and GW2580. Phenotypical changes upon treatment were assessed using RNAseq, flow cytometry, and cytokine quantification. Functional analyses included iNOS activity, phagocytosis, transmigration, and autologous tumor cell killing assays. Antitumor effects and changes in GAM activation were confirmed in a complex patient-derived 3D tumor organoid model serving as a tumor avatar.The most effective reprogramming of GAMs was observed upon GW2580 treatment, which led to the downregulation of M2-related markers, IL-6, and IL-10, ERK1/2 and MAPK signaling pathways, while M1-like markers, gene set enrichment indicating activated MHC-II presentation, phagocytosis, and T-cell killing were substantially increased. Moreover, treatment of patient-derived glioblastoma organoids with GW2580 confirmed successful reprogramming, resulting in impaired tumor cell proliferation. In line with its failure in clinical trials, PLX3397 was ineffective in our analysis.This comparative analysis of CSF1R-targeting drugs on patient-derived GAMs and human glioblastoma avatars identified GW2580 as the most powerful inhibitor with the ability to polarize immunosuppressive GAMs to a proinflammatory phenotype, supporting antitumor T cell responses while also exerting a direct antitumor effect. These data indicate that GW2580 could be an important pillar in future therapies for glioblastoma.