Scant understanding of the glioblastoma microenvironment and molecular bases hampers development of efficient treatment strategies. Analyses of gene signatures of human gliomas demonstrate that the SETD2 mutation is correlated with poor prognosis of IDH1/2 wild-type (IDH-WT) adult glioblastoma patients. To better understand the crosstalk between SETD2 mutant (SETD2-mut) glioblastoma cells and the tumor microenvironment, we leverage single-cell transcriptomics to comprehensively map cellular populations in glioblastoma. In this study, we identify a specific subtype of high-grade glioma-associated microglia (HGG-AM). Further analysis shows that transforming growth factor (TGF)-β1 derived from SETD2-mut/IDH-WT tumor cells activates HGG-AM, exhibiting pro-inflammation and proliferation signatures. Particularly, HGG-AM secretes interleukin (IL)-1β via the apolipoprotein E (ApoE)-mediated NLRP1 inflammasome, thereby promoting tumor progression. HGG-AM present extensive proliferation and infiltration to supplement the activated microglia pool. Notably, TGF-β1/TβRI depletion dramatically reduces HGG-AM density and suppresses tumor growth. Altogether, our studies identify a specific microglia subpopulation and establish the cellular basis of interactions between HGG-AM and glioblastoma cells.

对胶质母细胞瘤微环境和分子基础的了解不足阻碍了有效治疗策略的发展。对人类胶质瘤基因特征的分析表明，SETD2突变与IDH1/2野生型 (IDH-WT) 成人胶质母细胞瘤患者的不良预后相关。为了更好地理解SETD2之间的串扰突变（SETD2-mut）胶质母细胞瘤细胞和肿瘤微环境，我们利用单细胞转录组学全面绘制胶质母细胞瘤中的细胞群。在这项研究中，我们确定了高级别胶质瘤相关小胶质细胞 (HGG-AM) 的特定亚型。进一步分析表明，源自 SETD2-mut/IDH-WT 肿瘤细胞的转化生长因子 (TGF)-β1 可激活 HGG-AM，表现出促炎和增殖特征。特别是，HGG-AM 通过载脂蛋白 E (ApoE) 介导的 NLRP1 炎性体分泌白细胞介素 (IL)-1β，从而促进肿瘤进展。HGG-AM 呈现广泛的增殖和浸润，以补充活化的小胶质细胞池。值得注意的是，TGF-β1/TβRI 耗竭会显着降低 HGG-AM 密度并抑制肿瘤生长。共，