胶质母细胞瘤（GBM）肿瘤富集有免疫抑制的髓系细胞，并且对免疫检查点治疗（ICT）具有耐药性。针对表观遗传途径以重新编程免疫抑制的髓系细胞的功能表型，以克服ICT的耐药性尚未被探索。对人类GBM肿瘤的单细胞和空间转录组分析显示，在肿瘤内具有表观遗传酶-组蛋白3赖氨酸27去甲基酶（KDM6B）的免疫抑制髓系细胞亚群中表达较高。重要的是，髓系细胞特异性的Kdm6b基因删除增强了GBM肿瘤携带小鼠的促炎途径并改善了生存率。机制研究表明，Kdm6b的缺失通过抑制免疫抑制因子包括Mafb，Socs3和Sirpa，增强髓系细胞的抗原呈递、干扰素反应和吞噬作用。此外，KDM6B的药物抑制模拟了Kdm6b缺失的髓系细胞的功能表型，并增强了抗PD1的疗效。因此，本研究确定了KDM6B作为髓系细胞亚群功能表型的表观遗传调节因子，并为增强ICT反应的潜在治疗靶点。© 2023. 作者（签署许可）独家授权给 Springer Nature America, Inc.

Glioblastoma (GBM) tumors are enriched in immune-suppressive myeloid cells and are refractory to immune checkpoint therapy (ICT). Targeting epigenetic pathways to reprogram the functional phenotype of immune-suppressive myeloid cells to overcome resistance to ICT remains unexplored. Single-cell and spatial transcriptomic analyses of human GBM tumors demonstrated high expression of an epigenetic enzyme-histone 3 lysine 27 demethylase (KDM6B)-in intratumoral immune-suppressive myeloid cell subsets. Importantly, myeloid cell-specific Kdm6b deletion enhanced proinflammatory pathways and improved survival in GBM tumor-bearing mice. Mechanistic studies showed that the absence of Kdm6b enhances antigen presentation, interferon response and phagocytosis in myeloid cells by inhibition of mediators of immune suppression including Mafb, Socs3 and Sirpa. Further, pharmacological inhibition of KDM6B mirrored the functional phenotype of Kdm6b-deleted myeloid cells and enhanced anti-PD1 efficacy. This study thus identified KDM6B as an epigenetic regulator of the functional phenotype of myeloid cell subsets and a potential therapeutic target for enhanced response to ICT.© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.