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. 2021 Jan 13;22(2):746. doi: 10.3390/ijms22020746

Figure 2.

Figure 2

Macrophage polarization in the TME is influenced by local factors towards an M1 proinflammatory, antitumor or towards an M2 protumor, anti-inflammatory state. Cancer and TME cells directly influence the macrophage phenotypic dynamics by modifying the composition of secreted exosomes, which circulate the noncoding RNAs (ncRNAs), microRNAs (miRNAs) and other molecules between cells. (A) The upregulation of miR-130a, miR-1207-5p and miR-125b direct the macrophage polarization towards an M1 phenotype in non-small cell lung cancer (NSCLC), which will express M1 proinflammatory markers such as interleukin (IL)-12, IL-23, TNF-α and interferon gamma (IFN-γ), which further increase the reactive oxygen species (ROS), leading to efficient tumor suppression. The local TME is a hypoxic environment that stimulates the upregulation of hypoxia-inducible factor 1 (HIF-1) genes. Hypoxia-inducible factor 1-alpha (HIF-1α) is upregulated by local hypoxia and by an upregulation of miR-31-5p and downregulation of miR-214. HIF-1α is a known modulator of M2 macrophage polarization. (B) Polarization towards the M2 phenotype is acquired by the direct influence of HIF-1α and various dysregulated miRNAs from the local TME, including the upregulation of miR-103a, miR-21-5p and miR-320a and downregulation of miR-4319, miR-130a and miR-155. M2-polarized macrophages express specific markers, such as IL-4, IL-10, IL-13, TGF-β and PGE2, which further support the pro-neoplastic processes. HIF-1α and M2 macrophages support the tumor progression by enhancing the epithelial-to-mesenchymal transition (EMT), angiogenesis and metastasis.