The hypoxia-driven crosstalk between tumor and tumor-associated macrophages: mechanisms and clinical treatment strategies

Abstract

Given that hypoxia is a persistent physiological feature of many different solid tumors and a key driver for cancer malignancy, it is thought to be a major target in cancer treatment recently. Tumor-associated macrophages (TAMs) are the most abundant immune cells in the tumor microenvironment (TME), which have a large impact on tumor development and immunotherapy. TAMs massively accumulate within hypoxic tumor regions. TAMs and hypoxia represent a deadly combination because hypoxia has been suggested to induce a pro-tumorigenic macrophage phenotype. Hypoxia not only directly affects macrophage polarization, but it also has an indirect effect by altering the communication between tumor cells and macrophages. For example, hypoxia can influence the expression of chemokines and exosomes, both of which have profound impacts on the recipient cells. Recently, it has been demonstrated that the intricate interaction between cancer cells and TAMs in the hypoxic TME is relevant to poor prognosis and increased tumor malignancy. However, there are no comprehensive literature reviews on the molecular mechanisms underlying the hypoxia-mediated communication between tumor cells and TAMs. Therefore, this review has the aim to collect all recently available data on this topic and provide insights for developing novel therapeutic strategies for reducing the effects of hypoxia.

Keywords: Hypoxia-inducible factor; Inhibitor; Intercellular communication; Oxygen sensor.

Fig. 1

Overview of the effects of hypoxia on tumor cells. Hypoxia contributes to many critical aspects of cancer, including genome instability, autophagy, metabolic reprogramming, angiogenesis, migration, invasion, extracellular matrix remodeling, epithelial mesenchymal transition (EMT), stem cell maintenance, immune evasion and therapy resistance

Fig. 2

Oxygen sensing mechanisms. In presence of oxygen, HIF α is hydroxylated by prolyl hydroxylase (PHD) and FIH (factor inhibiting HIF), leading to rapid proteosomal degradation mediated by von Hippel–Lindau (VHL) protein and failure of recruiting transcriptional coactivators. The absence of oxygen leads to the stabilization and translocation of HIF-α to the nucleus where it heterodimerizes with HIF-1β to form the HIF–α/1β complex. Then, this complex recruits transcriptional coactivator and regulates target gene expression. Histone lysine demethylases (KDMs) can directly sense oxygen to control cell fate by regulating the chromatin structure in a HIF-independent manner. For example, KDM6A and KDM5A are inactivated during hypoxia, causing hypermethylation of H3K27 (KDM6A target) and H3K4 (KDM5A target)

Fig. 3

Hypoxia-driven crosstalk between tumor cells and tumor-associated macrophages (TAMs). The complex interplay between tumor cells and TAMs under hypoxia conditions may have tumor-promoting and tumor-suppressive consequences. The mediators that are responsible for tumor cell-to-TAM communication under hypoxia include exosomes, cytokines, growth factors, cellular debris, and oncometabolites. In addition, hypoxia can regulate the expression of cell surface ligands and receptors mediating cell signaling transduction

Fig. 4

Mechanisms of action of the HIF inhibitors currently on the market or under clinical trials. HIF inhibitors target HIF on different levels, ranking from transcription, translation, protein stabilization, transcriptional coactivators recruitment, and dimerization. The clearance of ROS leads to decreased HIF-α stabilization and accumulation