Tumor-associated macrophages: potential therapeutic strategies and future prospects in cancer

Abstract

Macrophages are the most important phagocytes in vivo. However, the tumor microenvironment can affect the function and polarization of macrophages and form tumor-associated macrophages (TAMs). Usually, the abundance of TAMs in tumors is closely associated with poor prognosis. Preclinical studies have identified important pathways regulating the infiltration and polarization of TAMs during tumor progression. Furthermore, potential therapeutic strategies targeting TAMs in tumors have been studied, including inhibition of macrophage recruitment to tumors, functional repolarization of TAMs toward an antitumor phenotype, and other therapeutic strategies that elicit macrophage-mediated extracellular phagocytosis and intracellular destruction of cancer cells. Therefore, with the increasing impact of tumor immunotherapy, new antitumor strategies to target TAMs are now being discussed.

Keywords: immunotherapy; macrophages; tumor microenvironment.

Figure 1

The distribution of macrophages in different tissues and organs. Macrophages are heterogeneous, showing different names, specific transcription factors and markers. Here, different colors correspond to different items, yellow for names, green for transcription factors and red for markers. IL-6, interleukin 6; MG, mammary gland; PC, peritoneal cavity; TGF-ß, transforming growth factor-β.

Figure 2

History of macrophages in cancer. Advances made over the past decades in the identification of macrophages including checkpoints and stimulatory signals. IFNγ, interferon-γ; IL-10, interleukin 10; PD-1, programmed cell death protein 1; SIRPα, signal regulatory protein α; TAMs, tumor-associated macrophage; TGF-β, transforming growth factor-β.

Figure 3

Macrophages can be polarized into M1 and M2 macrophages with different mechanisms. Macrophages can be polarized into two functional categories: classically activated macrophages (M1) and alternatively activated macrophages (M2) under different stimuli through different transcription factors, and show distinct specific markers on the macrophage subsets, which play important roles in pro-inflammation or anti-inflammation. FcR, Fc receptor; GM-CSF, granulocyte-macrophage colony-stimulating factor; IL10, interleukin 10; LPS, lipopolysaccharide; miRNA, microRNA; NF-κB, nuclear factor-kappa B; STAT1, signal transducer and activator of transcription 1; TGF-ß, transforming growth factor-β; TLR, toll-like receptor; TNFα, tumor necrosis factor-α.

Figure 4

Overview of macrophages involvement in myeloid cell differentiation in cancer through blood circulation. Macrophages development, accumulation, suppressive activity and survival are controlled by a complex network of transcription factors, cytokines and non-cytokine immune regulatory factors. Monocytes and M-MDSCs originate from the common myeloid progenitor (CMP) cell in the bone marrow (also in the spleen of mice) during myelopoiesis (left). They can circulate in the blood and lymph node and home to sites of inflammation and to the solid tumors (right). Under different conditions such as the tumor microenvironment, a variety of factors promote cancer risk, facilitate cancer onset and progression, and polarize TAMs. DCs, dendritic cells; GM-CSF, granulocyte-macrophage colony-stimulating factor; IL-10, interleukin; NF-κB, nuclear factor-kappa B; MDSCs, Myeloid-derived suppressor cells; TAMs, tumor-associated macrophages; TNFα, tumor necrosis factor-α; VEGF, vascular epidermal growth factor.

Figure 5

Immunoregulatory effects of TAMs. TAMs in TME can exert the immune regulatory roles on the different immune cells with different mechanisms by producing a variety of cytokines and effector molecules. On the one hands, TAMs inhibit T cell, B cells, NK cells and DCs. On the other hands, TAMs can promote Tregs, Th17 cells, γδT cells and MDSCs, as well as angiogenesis and metastasis of tumor. DCs, dendritic cells; GM-CSF, granulocyte-macrophage colony-stimulating factor; IL-10, interleukin; MDSCs, Myeloid-derived suppressor cells; NK, nuclear factor-kappa B; PD-1, programmed cell death protein 1; TAMs, tumor-associated macrophages; TGFβ, transforming growth factor-β; TME, tumor microenvironment; TNFα, tumor necrosis factor-α; VEGF, vascular epidermal growth factor.

Figure 6

Main therapeutic strategies targeting TAMs. These therapeutic ways are aimed at either activating the anti-tumoral activity, or inhibiting the recruitment, survival and protumoral functions of macrophages. The process of macrophage-mediated antibody-dependent cellular cytotoxicity (ADCC) involves recognition of the therapeutic antibodies by Fc receptors (FcRs) on TAMs. The ‘don’t eat me’ signal including SIRPα-CD47 pathway and CD24-Siglec 10 pathway. The antibodies against SIRPα-CD47 pathway and CD24-Siglec 10 pathway can activate macrophage-mediated antibody-dependent cellular phagocytosis (ADCP). Here, the main therapeutic strategies targeting TAMs are generally summarized including the ‘don’t eat me’ signal pathways, repolarization, reducing and decreasing the recruitment and survival, and immune-checkpoints blockades with antibodies. IFNR, interferon receptor; TAMs, tumor-associated macrophages; VEGFR, vascular epidermal growth factor R.