Metabolism, metabolites, and macrophages in cancer

Abstract

Tumour-associated macrophages (TAMs) are crucial components of the tumour microenvironment and play a significant role in tumour development and drug resistance by creating an immunosuppressive microenvironment. Macrophages are essential components of both the innate and adaptive immune systems and contribute to pathogen resistance and the regulation of organism homeostasis. Macrophage function and polarization are closely linked to altered metabolism. Generally, M1 macrophages rely primarily on aerobic glycolysis, whereas M2 macrophages depend on oxidative metabolism. Metabolic studies have revealed that the metabolic signature of TAMs and metabolites in the tumour microenvironment regulate the function and polarization of TAMs. However, the precise effects of metabolic reprogramming on tumours and TAMs remain incompletely understood. In this review, we discuss the impact of metabolic pathways on macrophage function and polarization as well as potential strategies for reprogramming macrophage metabolism in cancer treatment.

Keywords: Cancer; Metabolism; Metabolism reprogramming; Tumour microenvironment; Tumour-associated macrophages.

Fig. 1

Macrophage polarization and its function in cancer progression. After differentiation into macrophages from monocytes, macrophages can be further polarized into M1 and M2 subsets under different stimuli or microenvironments. M1 macrophages inhibit tumourigenesis by secreting IL-1β, IL-18, IFN-γ, and TNF-α, whereas M2 macrophages promote cancer development through several biological molecules, such as Arg1, IL-4, and TGF-β

Fig. 2

Part of metabolic adaptations of macrophages. Macrophage activation through LPS/IFN-γ results in similar flux distribution patterns towards glycolysis regardless of the pathway activated. HIF-1α activation can increase fructose-2,6-bisphosphate concentration and the glycolytic flux. CARKL could antagonize LPS-induced cytokines production. The decrease of OXPHOS induced by LPS leads to the accumulation of intermediate metabolites in the tricarboxylic acid cycle, especially succinic acid. Succinic acid can transfer from mitochondria to intracellular, inhibit the activity of prolyl hydroxylase (PHD) enzyme, and increase HIF-1α by promoting its stability. Notably, mTOR-HIF-1α axis involves in glycolysis in M1-polarized macrophages. In hypoxia state, HIF-1α can promote glycolysis by inducing expression of the related enzymes and transcriptional effectors. Meanwhile, HIF-1α can promote the expression of proinflammatory genes in macrophages

Fig. 3

Metabolic reprogramming in macrophages. M1-polarized macrophages primarily depend on glucose and the flux of glucose into lactate, reactive oxygen species (ROS) production, and nitric oxide (NO) generation for tumour killing after stimulation with the cytokines IFN-γ, TNF and LPS, which involves a cell-intrinsic shift towards aerobic glycolysis, generation of ROS, disruption of the TCA cycle, and inhibition of OXPHOS. M2-polarized macrophages primarily depend on β-oxidation of fatty acids and the tricarboxylic acid cycle (TCA cycle) after stimulation of cytokines IL-4, IL-13, and IL-10. During these processes, some key molecules participate in the metabolic mechanisms including mTOR, HIF-1α, SIRT1, and AKT