Understanding the impact of metabolism on macrophage function is critical for the development of novel immunotherapeutic strategies. Creative Biolabs describes the impact of metabolic pathways on macrophage function and macrophage polarization and potential strategies to reprogram macrophage metabolism in cancer therapy.

Fig. 1 Metabolic profiling of TAMs and metabolites in the tumor microenvironment regulates TAMs function and polarization.¹

Crosstalk between Macrophage Metabolism and Polarization

M1 and M2 macrophages exhibit different metabolic profiles, but these metabolic pathways are inextricably linked to macrophage polarization.

• Glucose metabolism: activation of M1 macrophages by LPS/IFN-γ, Listeria monocytogenes, thioglycollate, TLR-2, -3, -4, or -9 results in similar patterns of anaerobic glycolytic flux distribution regardless of the pathway of activation.
• Lipid metabolism: lipidomic studies have confirmed that lipid metabolism is associated with macrophage activation. However, abnormal cholesterol metabolism in macrophages leads to a variety of pathologic changes when excess cholesterol is absorbed.
• Amino acid metabolism: SLC7A5 is an important transporter protein that has been shown to mediate amino acid uptake in tumors and T cells, and SLC7A5-mediated metabolic reprogramming has been shown to play a major role in macrophage polarization. SLC7A5 promotes the release of pro-inflammatory cytokines from macrophages by inducing leucine influx through the mTORC1 signaling pathway and by upregulating glycolytic reprogramming.

Metabolites that Regulate Macrophage Polarization

Changes in macrophage metabolism are accompanied by alterations in intermediary metabolism. Specifically, metabolites produced during the TCA cycle play an important role in macrophage regulation.

• Succinate: Succinate is an intermediate product of the TCA cycle that is significantly increased by LPS stimulation. LPS-increased levels of succinate play a critical role in promoting IL-1β production by proinflammatory macrophages. In vitro and in vivo studies have shown that tumor-derived succinic acid in TME can provoke succinate activation of succinate receptor 1 (SUCNR1), leading to macrophage polarization to TAMs.
• Itaconate: Itaconate exerts its anti-inflammatory effects by inhibiting succinate dehydrogenase (SDH) production, leading to increased succinate accumulation and decreased mitochondrial reactive oxygen species (ROS) levels, which inhibits the release of pro-inflammatory cytokines. In addition, itaconate inhibits M2 macrophage polarization as it suppresses JAK1 and STAT6 activation.
• α-Ketoglutarate: Researchers found that glutamine-produced α-ketoglutarate (α-KG) promotes M2 polarization through the Jmjd3 signaling pathway. In addition, α-KG inhibits M1 macrophage function by suppressing the NF-κB pathway in a PHD-dependent manner.
• Citrate: Citrate has been shown to induce pro- or anti-inflammatory macrophage polarization through different mechanisms. Previous studies have shown that mitochondria-derived citrate promotes pro-inflammatory macrophage activation. The mitochondrial citrate carrier (CIC) promotes the export of mitochondrial citrate in LPS-activated macrophages, which leads to increased expression of HIF-1α. HIF-1α, in turn, upregulates IRG1, leading to itaconate production. Inhibition of CIC inhibits citrate accumulation and enhances mitochondrial oxidation by blocking itaconic acid shunting, ultimately leading to a shift in BMDM polarization from M1 to M2 after LPS stimulation.

Possible Strategies to Target TAMs by Reprogramming Metabolism

As a major component of immune cells in TME, TAM plays a key role in tumor progression. Strategies to target TAMs have focused on TAM deletion, inhibition of TAM recruitment, and TAM reprogramming. However, the therapeutic efficacy of these approaches remains suboptimal, and there is an urgent need for new effective therapies targeting TAM in tumor therapy.

Recent studies have highlighted the role of metabolic reprogramming in controlling macrophage function and polarization, and some investigators have summarized feasible strategies to target TAMs by reprogramming metabolism.

• Regulation of TAM function through aerobic glycolysis
• Regulation of TAM function through lipid metabolism
• Regulation of TAM function through tricarboxylic acid cycle metabolism
• Regulation of TAM function by amino acid metabolism
• Regulation of TAM function by phosphatidylinositol metabolism

Metabolic reprogramming leads to functional changes and repolarization of TAM. Increased glycolysis, decreased FAO, and reprogrammed TCA circulation promote TAM repolarization to acquire a pro-inflammatory phenotype. Metabolites produced during metabolic reprogramming also regulate macrophage activation. Therefore, it is crucial to understand the interactions between the factors involved in metabolic alterations and macrophage function.

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Reference

1. Li, Mengyuan, et al. "Metabolism, metabolites, and macrophages in cancer." Journal of Hematology & Oncology 16.1 (2023): 80.