Macrophage Metabolism As Therapeutic Target for Cancer, Atherosclerosis, and Obesity

Abstract

Macrophages are not only essential components of innate immunity that contribute to host defense against infections, but also tumor growth and the maintenance of tissue homeostasis. An important feature of macrophages is their plasticity and ability to adopt diverse activation states in response to their microenvironment and in line with their functional requirements. Recent immunometabolism studies have shown that alterations in the metabolic profile of macrophages shape their activation state and function. For instance, to fulfill their respective functions lipopolysaccharides-induced pro-inflammatory macrophages and interleukin-4 activated anti-inflammatory macrophages adopt a different metabolism. Thus, metabolic reprogramming of macrophages could become a therapeutic approach to treat diseases that have a high macrophage involvement, such as cancer. In the first part of this review, we will focus on the metabolic pathways altered in differentially activated macrophages and link their metabolic aspects to their pro- and anti-inflammatory phenotype. In the second part, we will discuss how macrophage metabolism is a promising target for therapeutic intervention in inflammatory diseases and cancer.

Keywords: M1–M2 macrophage polarization; cancer; immunometabolism; inflammatory diseases; metabolic reprogramming; metabolic therapy; microenvironment; tumor-associated macrophages.

Figure 1

M1 macrophage metabolism. M1 macrophage metabolism is characterized by enhanced aerobic glycolysis, converting glucose into lactate. M1 macrophages have an increased flux through the pentose phosphate pathway (PPP), generating NADPH, used for the generation of the anti-oxidant glutathione (GSH) and the inflammatory mediators nitric oxide (NO) and reactive oxygen species (ROS). In M1 macrophages, the tricarboxylic acid (TCA) cycle is broken in two places, leading to the accumulation of succinate and citrate. While the accumulation of succinate leads to HIF-1α stabilization and the transcription of pro-inflammatory and glycolytic genes, citrate is used for the generation of fatty acids, NO, ROS, and the synthesis of itaconate. Another aspect of M1 macrophage metabolism is the conversion of l-arginine to NO and l-citrulline. All important metabolic reactions present in M1/M2 macrophages are shown in black, reactions shown in gray are absent or less pronounced. The metabolic pathways strongly upregulated by M1/M2 macrophage polarization are highlighted by a colored shadow, the width of the shadow illustrates the weight of a particular pathway in the macrophage activation state. All metabolic enzymes are indicated in green. Dotted lines represent impaired metabolic reactions. Abbreviations: α-KG: α-ketoglutarate; AASS: aspartate–arginosuccinate shunt pathway; ACLY: ATP-citrate lyase; CAD: cis-aconitate decarboxylase; CIC: mitochondrial citrate carrier; ETC: electron transport chain; FAS: fatty acid synthase; GLUT: glucose transporter; HK: hexokinase; IDH: isocitrate dehydrogenase; iNOS: inducible nitric oxide synthase; LDH: lactate dehydrogenase; MCT: monocarboxylate transporter; ME: malic enzyme; OAA: oxaloacetate; PEP: phosphoenolpyruvate; PDH: pyruvate dehydrogenase; PFK: phosphofructokinase; SDH: succinate dehydrogenase; SLC: solute carrier.

Figure 2

M2 macrophage metabolism. M2 macrophages mainly produce ATP through an oxidative TCA cycle coupled to oxidative phosphorylation (OXPHOS). To fuel the TCA cycle, M2 macrophages rely on fatty acid oxidation (or β-oxidation) and glutamine metabolism. Furthermore, M2 macrophages show a lowered glycolysis and pentose phosphate pathway (PPP). Moreover, M2 macrophages convert l-arginine into urea and l-ornithine, which serves as precursor for l-proline production. All important metabolic reactions present in M1/M2 macrophages are shown in black, reactions shown in gray are absent or less pronounced. The metabolic pathways strongly upregulated by M1/M2 macrophage polarization are highlighted in orange. All metabolic enzymes are indicated in green. Dotted lines represent impaired metabolic reactions. Abbreviations: α-KG: α-ketoglutarate; ARG: arginase; CD: cluster of differentiation; CPT: carnitine palmitoyl transferase; ETC: electron transport chain; LAL: lysosomal acid lipase; PEP: phosphoenolpyruvate; PFK: phosphofructokinase; SLC: solute carrier.

Figure 3

Metabolic reprogramming of tumor-associated macrophages (TAM) toward an antitumoral phenotype might affect tumor growth. Tumors are highly infiltrated by tumor-infiltrating immune cells, with TAM being amongst the most abundant ones. Within the same tumor, the co-existence of two distinct TAM subpopulations has been shown: M2-like protumoral TAM and M1-like antitumoral TAM. The TAM phenotype depends on the stage of tumor development, leading to a majority of M2-like TAM in late stage tumors which stimulate tumor growth, angiogenesis, invasion, metastasis, suppression of antitumor immunity, and mediation of therapy resistance. Strategies that metabolically reprogram protumoral M2 TAM into an antitumoral M1 phenotype, without depleting the full TAM population, could reduce tumor growth and metastasis and allow re-establishment of conventional cancer therapies.