Figures
- 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.
Tables
- TABLE 1
Selected agents targeting metabolism for treatment of various metabolic or inflammatory diseases and cancer
Drug Target Metabolic pathway/consequence Disease model Clinical trials/status Effect on TAMs Glucose metabolism 2-deoxyglucose (2-DG)# Hexokinase 2 (glucose uptake) Inhibition of glucose uptake and therefore aerobic glycolysis Cancer in general, rheumatoid arthritis Stopped due to toxicity (hypoglycaemia) [102] Repolarisation [34] Enasidenib (AG-221), AG-120 (Ivosidenib), AGI-5198, AG-881, Mutant IDH1/2 Inhibition of α-KG reduction to 2-HG by mutant IDH leading to impaired demethylation Acute myeloid leukaemia, bile duct cancer, glioma, haematological malignancies, solid tumours [103, 104] Enasidenib and ivosidenib approved for acute myeloid leukaemia CB-839 Glutaminase 1 Inhibition of glutamin metabolism (increased dependence of glutamine in cancer cells) [105, 106] Colorectal cancer, NSCLC, renal cell carcinoma, melanoma NCT03263429, NCT03831932, NCT02771626 Metformin# AMPK Reduction in glycolytic pathway, reduced glucose blood levels, increased FAO, inhibition of respiration, inhibition of mTOR Type II diabetes, cancer in general, rheumatoid arthritis Approved for type II diabetes,
NCT02019979, NCT02640534, NCT01310231, NCT02312661Repolarisation [97, 98] Nucleotide biosynthesis Methotrexate, Pemetrexed DHFR, GARFT Impaired nucleotide biosynthesis Breast cancer Phase II trial (methodextrate) Amino acid metabolism L-asparaginase (Elspar, Kidrolase), PEG-BCT-100 (ADI-PEG20), AEB-1102 Circulating arginine Breakdown of arginin, targeting cancer cells without ability for arginase de novo synthesis (ASS1 silenced cancer types) Melanoma, hepatocellular carcinoma, acute lymphocytic leukaemia L-asparaginase approved for acute lymphocytic leukaemia Rapamycin, RAD001# mTOR Deregulation of proliferation and protein/lipid/nucleotide production ALS, glioma, NSCLC NCT03359538, NCT01158651, NCT01063478 Repolarisation [95, 96] L-norvaline, CB-1158# Arginase 1 Disruption of de novo arginine synthesis Advanced solid tumours, Alzheimer's disease models [107] Repolarisation [47] PHGDH inhibitors Phosphoglycerate dehydrogenase De novo serine synthesis Breast cancer, lung adenocarcinoma, melanoma [108–110] Lipid metabolism ND-646 ACC Impaired de novo fatty acid synthesis Lung tumour models [82] Pralnacasan, NCX-4016, YVAD, VAD# Caspase-1 Inhibition of inflammasome/lipid accumulation in inflammatory cells Rheumatoid arthritis, osteoarthritis, inflammatory bowel disorders, cancer, autoimmune diseases Pralnacasan studies stopped after phase II Specifically targets and repolarises TAMs [82] Paclitaxel, Methodextrate, Doxorubicin# ABC transporter Impaired efflux leading to accumulation of e.g. xenobiotics or cholesterol in the cell Multidrug resistant cancer [91] Studies ongoing e.g. phase III trial for breast cancer (NCT02488967) Repolarisation [90] Meclofenamate sodium, Zileuton# 5-LOX Conversion of arachidonic acid to 5-HETE and leukotrienes Pain relief, rheumatoid arthritis, osteoarthritis, asthma TME infiltration [79] TAM: tumour-associated macrophages; IDH: isocitrate dehydrogenase; α-KG: α-ketoglutarate; 2-HG: 2-hydroxyglutaric acid; NSCLC: nonsmall cell lung cancer; AMPK: AMP-activated protein kinase; FAO: fatty acid oxidation; mTOR: mammalian target of rapamycin; DHFR: dihydrofolate reductase; GARFT: glycinamide ribonucleotide formyltransferase; ALS: amyotrophic lateral sclerosis; ACC: acetyl-CoA carboxylase; TME: tumour microenvironment; 5-LOX: 5-lipoxygenase; 5-HETE: 5-hydroxyeicosatetraenoic acid. #: potential specific TAM metabolic targets.
