Figure 1.

Macrophages are key players in cancer. In the premalignant tumor, TAMs find themselves at spots of basement membrane breakdown, infiltrating the stroma and remodeling the surrounding matrix. In the primary tumor, macrophages are found in hypoxic regions where HIF-1α stimulates TAMs to produce various pro-malignant factors such as VEGF, PDGF, ADM, MMPs, and TGF-β, thus inducing angiogenesis, lymphangiogenesis, metastasis, and cancer progression. TAMs also express PD-L1 that binds to PD-1 of Treg cells and determine their apoptosis resistance with further inhibitory effect upon T cells. Production of IL-10 and TGF-β by TAMs are another way of inhibiting the activity of the immune systems: T cell activity and dendritic cells development. TAMs are in close contact with the cancer cells through the blood vessel intravasation and extravasation and also influence each other through feedback mechanisms composed of CSF-1 and EGF and their receptors. Finally, TAMs are contributing to the formation of the premetastatic niche and also to the growth and proliferation of the metastatic tumors.