缺氧通过升高TNFSF9水平以依赖组蛋白乳酰化的方式促进胶质瘤进展，通过诱导M2巨噬细胞极化

缺氧是导致胶质瘤预后不良和治疗困难的关键因素。既往研究表明，缺氧驱动巨噬细胞的M2极化并促进多种实体瘤的癌症进展。然而，支撑这一过程的更为复杂和多样的机制尚未阐明。在本研究中，我们旨在探讨缺氧在胶质瘤中的作用，并初步研究缺氧引起的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著增强U87和U251细胞的恶性表型。此外，缺氧促使糖酵解产物[乳酸（LA）]的积累，随后被巨噬细胞吸收以诱导其M2极化，这一过程可被糖酵解抑制剂和巨噬细胞中的单羧酸转运蛋白（MCT-1）沉默逆转，表明M2巨噬细胞极化与缺氧促进糖酵解有关。有趣的是，我们还发现，缺氧调控胶质瘤细胞中LA的积累，在被巨噬细胞摄取后，上调H3K18La的表达，并促进肿瘤坏死因子超家族成员9（TNFSF9）的表达，这一过程依赖于组蛋白-乳酰化机制，基于染色质免疫沉淀测序（ChIP-seq）富集分析的结果。后续的体外和体内实验进一步显示，TNFSF9促进胶质瘤的进展。从机制上讲，缺氧引起的胶质瘤细胞中LA的积累被巨噬细胞吸收后，通过MCT-1/H3K18La信号调控TNFSF9表达，诱导其M2巨噬细胞极化，从而促进胶质瘤的恶性进展。本研究新颖且具有重要意义，因为它揭示了能量代谢与表观遗传学在胶质瘤中的潜在联系。

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 macrophage 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 chromatin immunoprecipitation sequencing (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.NEW & NOTEWORTHY Our study revealed that hypoxia induces the production of LA accumulation through glycolysis in glioma cells, which is subsequently absorbed by macrophages and leads to its M2 polarization via the MCT-1/H3K18La/TNFSF9 axis, ultimately significantly promoting the malignant progression of glioma cells. These findings are novel and noteworthy as they provide insights into the connection between energy metabolism and epigenetics in gliomas.