Tumor-associated macrophages promote glucose metabolism by driving histone H3 lysine 18 lactylation in glioma progression

The tumor-associated macrophages (TAMs) play multiple roles in the progression of glioma. However, whether and how TAMs are involved in regulating glucose metabolism in glioma remains unclear. Using conditioned medium (CM) co-culturing, this study revealed that pro-tumor (M2-like) TAMs enhanced tumor glycolysis and progression by elevating lactate production and driving histone H3 lysine 18 lactylation (H3K18la) in glioma cells through secreting the cytokine vascular endothelial growth factor A (VEGFA). Patients with gliomas who exhibited elevated H3K18la levels had significantly reduced overall survival. Moreover, specific inhibition of H3K18la levels also significantly inhibited aerobic glycolysis and malignant behaviour in glioma cells. Mechanistically, combining CUT&Tag and mRNA-sequencing analysis with ChIP-qPCR, we observed that the lactate-dependent H3K18la upregulation reduced its enrichment at the promoter of the downstream carbohydrate metabolism-related gene ADP-Dependent Glucokinase (ADPGK) and activated ADPGK expression, thereby enhancing glycolysis and lactate production in glioma cells. Ultimately, this lactate/H3K18la/ADPGK/glycolysis/lactate positive feedback loop exacerbated tumor malignant behaviour. Moreover, depleting M2-like TAMs with BLZ945 in vivo reduced H3K18la and ADPGK expression, which in turn suppressed tumor glucose metabolism and growth, leading to prolonged survival in the glioma mouse model. Our cumulative findings suggest that the TAMs/H3K18la/ADPGK axis represents a potential therapeutic target for glioma.