Macrophage Polarization States in the Tumor Microenvironment

Abstract

The M1/M2 macrophage paradigm plays a key role in tumor progression. M1 macrophages are historically regarded as anti-tumor, while M2-polarized macrophages, commonly deemed tumor-associated macrophages (TAMs), are contributors to many pro-tumorigenic outcomes in cancer through angiogenic and lymphangiogenic regulation, immune suppression, hypoxia induction, tumor cell proliferation, and metastasis. The tumor microenvironment (TME) can influence macrophage recruitment and polarization, giving way to these pro-tumorigenic outcomes. Investigating TME-induced macrophage polarization is critical for further understanding of TAM-related pro-tumor outcomes and potential development of new therapeutic approaches. This review explores the current understanding of TME-induced macrophage polarization and the role of M2-polarized macrophages in promoting tumor progression.

Keywords: cytokine signaling; malignancy; metastasis; polarization; tumor microenvironment; tumor-associated macrophage.

Figure 1

Macrophage polarization gradient. This figure illustrates the heterogeneity of macrophage polarization in place of binary M1/M2 classifications. The pro-inflammatory M1 and anti-inflammatory M2 cells lie on opposite ends of the polarization axis, but many macrophages with mixed pro- and anti-inflammatory characteristics exist in between. Environmental changes may cause macrophages to shift from M1 to M2, vice versa, or to a hybrid of both cells. This highlights the plasticity of macrophages and interdependence on the surrounding environment. This figure was created with Biorender.com (accessed on 1 May 2021).

Figure 2

Signal pathways of macrophage polarization. This figure illustrates several of the various mechanisms that drive extrinsic macrophage polarization. Those pathways include IFN-y and IL-12 secretion by TH1 T-cells, LPS signaling through mTOR/Akt or TLR4, Akt2/NF-κB activation, SHP-1/2 inhibition of Cd11b, SHIP and MyD88 inhibition of M2 genes, PTEN activation, and TNF/TNFR/NF-κB activation to induce M1 gene expression. Induction of M2 genes is directed by the secretion of IL-4 and IL-13 from TH2 T-cells and IL-4Rα receptor activation as well as downstream Stat6-dependent arginase-1 inhibition, PPARγ activation, and TSC1 inhibition of mTOR. This figure was created with Biorender.com (accessed on 1 May 2021).