Metabolism in tumour-associated macrophages: a quid pro quo with the tumour microenvironment

Abstract

Lung cancer is the leading cause of death from cancer worldwide. Recent studies demonstrated that the tumour microenvironment (TME) is pivotal for tumour progression, providing multiple targeting opportunities for therapeutic strategies. As one of the most abundant stromal cell types in the TME, tumour-associated macrophages (TAMs) exhibit high plasticity. Malignant cells alter their metabolic profiles to adapt to the limited availability of oxygen and nutrients in the TME, resulting in functional alteration of TAMs. The metabolic features of TAMs are strongly associated with their functional plasticity, which further impacts metabolic profiling in the TME and contributes to tumourigenesis and progression. Here, we review the functional determination of the TME by TAM metabolic alterations, including glycolysis as well as fatty acid and amino acid metabolism, which in turn are influenced by environmental changes. Additionally, we discuss metabolic reprogramming of TAMs to a tumouricidal phenotype as a potential antitumoural therapeutic strategy.

FIGURE 1

Tumour microenvironment (TME) metabolites activate tumour-associated macrophages (TAMs). In TME, glucose, lipid, tryptophan and arginine metabolites activate TAMs. These activated TAMs consume glucose, tryptophan and arginine leading to depletion of these metabolites, which in turn impact TME and its immune status. Moreover, TAM-derived metabolites (e.g. lactic acid, kynurenine, glutamine and 15-hydroxyeicosatetraenoic acid (15-HETE)) regulate angiogenesis, T-cell activation and tumour progression. Transporters and/or metabolites of glucose metabolism are indicated as orange, amino acid metabolism as blue and lipid metabolism as green. LDHA: lactate dehydrogenase A; EV: extracellular vesicle; IDO: indolamin-2,3-dioxygenase; ARG: arginase; GS: glutamine synthase; TXB₂: thromboxane B2; FAS: fatty acid synthase; FAs: fatty acids.

FIGURE 2

Metabolic architecture of tumour associated macrophages. Upward arrows indicate upregulation, downward arrows indicate downregulation and question marks illustrate the potential but inexplicit transporters. Transporters and/or metabolites of glucose metabolism are indicated as orange, amino acid metabolism as blue and lipid metabolism as green. IDO: indolamin-2,3-dioxygenase; GLUT: glucose transporter; HK: hexokinase; ENO: enolase; LDH: lactate dehydrogenase; MCTs: monocarboxylate transporters; ARG: arginase; NOS: nitric oxide synthase; NO: nitric oxide; mTOR: mammalian target of rapamycin; PI3K: phosphoinositide 3-kinases; HIF: hypoxia inducible factor; VEGF: vascular endothelial growth factor; KDM: histone lysine demethylase; TET: ten-eleven translocation; ORNT1: ornithine translocase; OAA: oxaloacetic acid; TCA cycle: tricarboxylic acid cycle; α-KG: α-ketoglutarate; COA: coenzyme A; PGE₂: prostaglandin E₂; EP2: prostaglandin E2 receptor 2; PD-L1: programmed death-ligand 1; FA: fatty acid; COX-2, cyclooxygenase-2; 5-LOX: 5-lipoxygenase; HETE: hydroxyeicosatetraenoic acid; MMP: matrix metalloproteinase; IL: interleukin; E-FABP: epidermal fatty acid binding proteins; 15-LOX-2: 15-lipoxygenase-2; IFN: interferon; GRP: G-protein-coupled receptor.