Metabolic regulation of tumor-associated macrophage heterogeneity: insights into the tumor microenvironment and immunotherapeutic opportunities

Abstract

Tumor-associated macrophages (TAMs) are a heterogeneous population that play diverse functions in tumors. Their identity is determined not only by intrinsic factors, such as origins and transcription factors, but also by external signals from the tumor microenvironment (TME), such as inflammatory signals and metabolic reprogramming. Metabolic reprogramming has rendered TAM to exhibit a spectrum of activities ranging from pro-tumorigenic to anti-tumorigenic, closely associated with tumor progression and clinical prognosis. This review implicates the diversity of TAM phenotypes and functions, how this heterogeneity has been re-evaluated with the advent of single-cell technologies, and the impact of TME metabolic reprogramming on TAMs. We also review current therapies targeting TAM metabolism and offer new insights for TAM-dependent anti-tumor immunotherapy by focusing on the critical role of different metabolic programs in TAMs.

Keywords: Immunotherapy; Metabolic reprogramming; Single-cell omics; Tumor microenvironment; Tumor-associated macrophages.

Fig. 1

Heterogeneity of TAMs in tumor microenvironment witnessed in the era of single-cell omics. a,b Single-cell multi-omics underscore TAMs' diverse origins, phenotypes, and functions shaped by the tumor microenvironment, highlighting metabolic reprogramming's influence on TAM heterogeneity. c,d Beyond the traditional polarization dichotomy, Ruo-Yu Ma et al. classified seven TAM subtypes characterized by specific gene signatures and functions using single-cell omics, named: interferon-stimulated (IFN-TAMs), immune-modulated (Reg-TAMs), inflammatory cytokine-enriched (Inflam-TAMs), lipid-associated (LA-TAMs), pro-angiogenic (Angio-TAMs), RTM-like (RTM-TAMs), and proliferative TAMs (Prolif-TAMs). e TAMs' heterogeneity is linked to their varied functions, with emerging research clarifying their roles in tumor progression. MDP Myeloid differentiation primary response protein, RTM Resident tissue macrophages, EMP Erythromyeloid progenitors, Treg Regulatory T cells, MDSC Myeloid-derived suppressor cells, Teff Effector T cells, NK Natural killer cells, ECM Extracellular matrix, CAF Cancer-associated fibroblasts, HGF Hepatocyte growth factor, CCL18 Chemokine (C–C motif) ligand 18, EGF Epidermal growth factor, MMP Matrix metalloproteinase, CXCR4 C-X-C chemokine receptor type 4, SPP1 Secreted phosphoprotein 1, VEGFR Vascular endothelial growth factor receptor, MARCO Macrophage receptor with collagenous structure, Arg1 Arginase 1, iNOS Inducible nitric oxide synthase, IDO Indoleamine 2,3-dioxygenase

Fig. 2

Metabolic reprogramming of TAM in the tumor microenvironment. a TAMs exhibit distinct metabolic characteristics compared to BMDMs, with increased glucose and fatty acid metabolism, supporting their immunosuppressive and tumorigenic activities. They show enhanced glycolysis, TCA cycle, and OXPHOS, along with FAO and cholesterol efflux. Further, as they respond to microenvironmental cues, the unique metabolic pathways in TAMs, particularly those involving specific amino acids, underpin their functional heterogeneity. b The interconnected metabolic pathways of TAMs, driven by tumor environment cues, contribute to their functional and phenotypic diversity. Key components include GLUT1, LDHA, and enzymes and transporters involved in lipid and amino acid metabolism. BCKAs Branched-chain keto acids, MCT1 Monocarboxylate transporter 1, KIC Ketoisocaproic acid, KMV Ketomethylvaleric acid, PKM2 Pyruvate kinase M2, GLUT1 Glucose transporter 1, LCFAs Long-chain fatty acids, SR-BI Scavenger receptor class B type 1, MCAD Medium-chain acyl-CoA dehydrogenase, MGLL Monoglyceride lipase, FASN Fatty acid synthase, SREBP1 Sterol regulatory element-binding protein 1, FABP Fatty acid-binding protein, LPL Lipoprotein lipase, ABCA1 ATP-binding cassette transporter A1, HA Hyaluronic acid, AHR Aryl hydrocarbon receptor, PERK Protein kinase R, ATF-4 Activating transcription factor 4, PSAT1 Phosphoserine aminotransferase 1, G6P Glucose-6-phosphate, DHAP Dihydroxyacetone phosphate, PFK1 Phosphofructokinase-1, F2,6BP Fructose 2,6-bisphosphate, PFKFB3 6-Phosphofructo-2-kinase/fructose-2,6-biphosphatase 3, UDP-GlcNAc Uridine diphosphate N-acetylglucosamine, F6P Fructose 6-phosphate, F1,6BP Fructose 1,6-bisphosphate, G3P Glyceraldehyde 3-phosphate, 1,3BPG 1,3-Bisphosphoglyceric acid, 3PG 3-Phosphoglyceric acid, PEP Phosphoenolpyruvate, GAPDH Glyceraldehyde 3-phosphate dehydrogenase, PKM Pyruvate kinase M, LDHA Lactate dehydrogenase A, TAGs Triacylglycerols, FA Fatty acid, Acetyl-CoA Acetyl coenzyme A, CPT1 Carnitine Palmitoyltransferase1, FA-FABPs Fatty acid-Fatty acid-binding proteins, CAT2B Cationic amino acid transporter 2B, GLS Glutaminase, GS Glutamine synthetase, GDH Glutamate dehydrogenase, SLC1A5 Solute carrier family 1 member 5, SLC38A1/2 Solute carrier family 38 members 1 and 2, OAAs Oxaloacetates

Fig. 3

Macrophage metabolic targets and associated Agents. Targeting the metabolic reprogramming of TAMs has the potential to reshape their phenotype and function, thereby offering a promising therapeutic strategy for macrophage repolarization in cancer. The fundamental approach in treating tumors via TAM metabolic reprogramming involves stimulating TAMs towards an M1-like pro-inflammatory phenotype. This strategy includes regulating intracellular ATP levels and redox state, which in turn impacts their phagocytic and digestive abilities and the generation of various signaling molecules, while simultaneously inhibiting M2-like anti-inflammatory polarization. Despite the growing interest in targeting TAM metabolism, our current understanding of TAM metabolic reprogramming is still incomplete, and there remains a dearth of specific targeted therapeutics. Future investigations should focus on exploring the metabolic mechanisms of reprogramming within specific subgroups, in the context of single-cell multi-omics studies, to identify unique therapeutic targets. ETC Electron Transport Chain, IDO Indoleamine 2,3-dioxygenase, GS Glutamine Synthetase, LXR Liver X receptor, ABCA1 ATP-binding cassette transporter A1, IRG1 Immune Responsive Gene 1, ACOD1 Aconitate Decarboxylase 1, TLR9 Toll-Like Receptor 9, Arg1 Arginase 1, HADCs Histone Deacetylases