This study investigates the role of lactate dehydrogenase A (LDHA) in regulating tumor-macrophage symbiosis to promote glioblastoma progression. The authors screened a panel of metabolic small-molecule compounds and found that inhibiting glioblastoma cell glycolysis impairs macrophage migration. Stiripentol, an LDHA inhibitor, emerged as the top hit. Further analysis revealed that LDHA activates the extracellular signal-regulated kinase (ERK) pathway, which upregulates yes-associated protein 1 (YAP1) and signal transducer and activator of transcription 3 (STAT3) transcriptional co-activators, leading to increased expression of C-C motif chemokine ligand 2 (CCL2) and CCL7. These chemokines recruit macrophages into the tumor microenvironment. Conversely, infiltrating macrophages produce LDHA-containing extracellular vesicles (EVs) to promote glioblastoma cell glycolysis, proliferation, and survival. Genetic and pharmacological inhibition of LDHA-mediated tumor-macrophage symbiosis significantly suppresses tumor progression and macrophage infiltration in glioblastoma mouse models. Clinical validation using patient tumor and plasma samples confirmed that LDHA and its downstream signals are potential biomarkers correlating positively with macrophage density. The study highlights the therapeutic potential of targeting LDHA-mediated tumor-macrophage symbiosis in glioblastoma.This study investigates the role of lactate dehydrogenase A (LDHA) in regulating tumor-macrophage symbiosis to promote glioblastoma progression. The authors screened a panel of metabolic small-molecule compounds and found that inhibiting glioblastoma cell glycolysis impairs macrophage migration. Stiripentol, an LDHA inhibitor, emerged as the top hit. Further analysis revealed that LDHA activates the extracellular signal-regulated kinase (ERK) pathway, which upregulates yes-associated protein 1 (YAP1) and signal transducer and activator of transcription 3 (STAT3) transcriptional co-activators, leading to increased expression of C-C motif chemokine ligand 2 (CCL2) and CCL7. These chemokines recruit macrophages into the tumor microenvironment. Conversely, infiltrating macrophages produce LDHA-containing extracellular vesicles (EVs) to promote glioblastoma cell glycolysis, proliferation, and survival. Genetic and pharmacological inhibition of LDHA-mediated tumor-macrophage symbiosis significantly suppresses tumor progression and macrophage infiltration in glioblastoma mouse models. Clinical validation using patient tumor and plasma samples confirmed that LDHA and its downstream signals are potential biomarkers correlating positively with macrophage density. The study highlights the therapeutic potential of targeting LDHA-mediated tumor-macrophage symbiosis in glioblastoma.