Tumor-Associated Macrophage Subsets: Shaping Polarization and Targeting

Abstract

The tumor microenvironment (TME) is a critical regulator of tumor growth, progression, and metastasis. Among the innate immune cells recruited to the tumor site, macrophages are the most abundant cell population and are present at all stages of tumor progression. They undergo M1/M2 polarization in response to signals derived from TME. M1 macrophages suppress tumor growth, while their M2 counterparts exert pro-tumoral effects by promoting tumor growth, angiogenesis, metastasis, and resistance to current therapies. Several subsets of the M2 phenotype have been observed, often denoted as M2a, M2b, M2c, and M2d. These are induced by different stimuli and differ in phenotypes as well as functions. In this review, we discuss the key features of each M2 subset, their implications in cancers, and highlight the strategies that are being developed to harness TAMs for cancer treatment.

Keywords: cell signaling; polarization; solid cancers; targeted therapy; tumor microenvironment; tumor-associated macrophages.

Figure 1

M1 and M2a polarization. (A) M1 macrophages polarize through signaling pathways mediated by STAT1, PI3K/Akt, NFκB, and IRFs. Binding of IFN-γ to its receptor leads to the recruitment of JAK1 and JAK2, inducing the phosphorylation of STAT1, which then dimerizes and translocates into the nucleus. In response to the LPS-TLR4 engagement, PI3K/Akt-, NFκB-, and IRFs-mediated signaling are triggered. (B) M2a macrophages polarize through the PI3K/Akt- and STAT6-mediated signaling pathways. Macrophages express both type I and type II IL-4 receptors. The engagement of the type I/II IL-4 receptor results in the phosphorylation and subsequent dimerization of STAT3. Once activated, STAT3 dimers translocate into the nucleus and trigger corresponding gene expression. In contrast, IRSs can only be activated by the type I IL-4 receptor and do not translocate to the nucleus. Instead, activated IRSs can induce signaling pathways such as PI3K/Akt-mediated signaling.

Figure 2

M2b polarization. The macrophage polarization toward the M2b phenotype needs two classical stimuli (ICs and LPS/IL-1). The crosslinking of FcγR by ICs triggers the activation of PI3K-, MAPK/ERK-, and NF-κB-mediated signaling pathways. To fully polarize, the binding of LPS or IL-1 to their respective receptors is also required, which then induces the activation of NFκB, PI3K/Akt, IRFs, and MAPKs. In addition, stimuli (e.g., irradiation, microRNA 122) other than the classical inducers have been described. The presence of long non-coding RNA GAS5 negatively correlates with M2b polarization. In response to irradiation exposure, the induced miRNA-122 expression leads to the degradation of GAS5, thereby favoring M2b polarization.

Figure 3

M2c polarization. M2c macrophages polarize through signaling pathways mediated by STAT3, MAPK/ERK, and PI3K/Akt. Engagement of GAS6 produced by M2c with MerTK induces IL-10 production, which in turn activates M2c, resulting in a positive loop that favors M2c polarization.

Figure 4

M2d polarization. The binding of IL-6 to the IL-6R/gp130 receptor complex leads to the recruitment of JAK1/2, which in turn phosphorylates STAT3, leading to STAT3 dimerization and translocation into the nucleus, where it activates gene transcription. LIF belongs to the IL-6 family and binding of LIF to its receptor results in IL-6 production. Thus, M2d macrophages can consume IL-6 in an autocrine manner.

Figure 5

A graphic overview of macrophage polarization and their characteristics. Macrophages are first differentiated from their precursor monocytes to uncommitted M0 macrophages. In response to different stimuli, M0 macrophages can further polarize into distinct subsets with characteristic phenotypic markers and cytokine production profiles.

Figure 6

Relationship between the different macrophage subsets. For details see the text.