Effect of repurposed metabolic drugs on human macrophage polarization and antitumoral activity

AIM: This study aimed to investigate whether the polarization of monocyte-derived macrophages towards an anti-inflammatory phenotype could be hindered by modulating cellular metabolism. Several metabolic drugs were selected: Perhexiline (PerHx) and Nitazoxanide (NTZ) targeting fatty acid oxidation, CB839 (Telaglenastat) targeting glutaminolysis and Metformin (Metf) targeting the mitochondrial electron transport chain. RESULTS: Our findings demonstrate that the presence of PerHx, NTZ, and CB839 during IL-4-mediated macrophages polarization impaired the acquisition of full anti-inflammatory phenotype, as evidenced by reduced expression of CD163 and CD209 and decreased secretion of CCL17 chemokine. Besides, CB839 induced tumoricidal activity in macrophages, comparable to that observed in macrophages activated by LPS and IFNγ. CONCLUSION: This study reveals that targeting glutamine metabolism with CB839 effectively blocks the IL-4-induced anti-inflammatory phenotype in macrophages and enhances their tumor-killing capability. Our results provide a compelling rationale for repurposing metabolic drugs to create a pro-inflammatory tumor microenvironment, thereby potentially enhancing the efficacy of current immunotherapies.