缺氧是导致预后不良和神经胶质瘤治疗具有挑战性的关键因素。先前的研究表明，缺氧会驱动巨噬细胞的 M2 极化，并促进各种实体瘤的癌症进展。然而，这一过程背后更复杂和多样化的机制仍有待阐明。在此，我们旨在研究缺氧在胶质瘤中的功能，并初步探讨缺氧引起的M2巨噬细胞极化的潜在机制。我们发现缺氧通过调节糖酵解显着增强U87和U251细胞的恶性表型。此外，缺氧介导的糖酵解产物（乳酸，LA）的积累，随后被巨噬细胞吸收以诱导其 M2 极化，并且该过程可被糖酵解抑制剂和沉默的单羧酸转运蛋白（MCT-1）逆转。巨噬细胞，表明 M2 巨噬细胞极化与缺氧促进糖酵解有关。有趣的是，基于 ChIP-seq 富集结果，我们还发现缺氧介导的 LA 在巨噬细胞摄取后在神经胶质瘤细胞中积聚，上调 H3K18La 表达，并以组蛋白乳酰化依赖性方式促进肿瘤坏死因子超家族成员 9 (TNFSF9) 表达分析。随后的体外和体内实验进一步表明TNFSF9促进神经胶质瘤的进展。从机制上讲，缺氧介导的胶质瘤细胞中的LA积累被巨噬细胞吸收，然后通过MCT-1/H3K18La信号传导调节TNFSF9的表达来诱导其M2巨噬细胞极化，从而促进胶质瘤的恶性进展。

Hypoxia is a critical factor contributing to a poor prognosis and challenging glioma therapy. Previous studies have indicated that hypoxia drives M2 polarization of macrophages and promotes cancer progression in various solid tumors. However, the more complex and diverse mechanisms underlying this process remain to be elucidated. Here, we aimed to examine the functions of hypoxia in gliomas and preliminarily investigate the underlying mechanisms of M2 macrophage polarization caused by hypoxia. We found that hypoxia significantly enhances the malignant phenotypes of U87 and U251 cells by regulating glycolysis. In addition, hypoxia-mediated accumulation of the glycolysis product (lactic acid, LA), which is subsequently absorbed by macrophages to induce its M2 polarization, and this process is reverted by both the glycolysis inhibitor and silenced monocarboxylate transporter (MCT-1) in macrophages, indicating that M2 macrophages polarization is associated with the promotion of glycolysis by hypoxia. Interestingly, we also found that hypoxia-mediated LA accumulation in glioma cells upon uptake by macrophages upregulates H3K18La expression and promotes tumor necrosis factor superfamily member 9 (TNFSF9) expression in a histone-lactylation-dependent manner based on the results of ChIP-seq enrichment analysis. Subsequent in vitro and in vivo experiments further indicated that TNFSF9 facilitated glioma progression. Mechanistically, hypoxia-mediated LA accumulation in glioma cells is taken up by macrophages and then induces its M2 macrophage polarization by regulating TNFSF9 expression via MCT-1/H3K18La signaling, thus facilitating the malignant progression of gliomas.