Tumor-associated macrophages: an effective player of the tumor microenvironment

Abstract

Cancer progression is primarily caused by interactions between transformed cells and the components of the tumor microenvironment (TME). TAMs (tumor-associated macrophages) make up the majority of the invading immune components, which are further categorized as anti-tumor M1 and pro-tumor M2 subtypes. While M1 is known to have anti-cancer properties, M2 is recognized to extend a protective role to the tumor. As a result, the tumor manipulates the TME in such a way that it induces macrophage infiltration and M1 to M2 switching bias to secure its survival. This M2-TAM bias in the TME promotes cancer cell proliferation, neoangiogenesis, lymphangiogenesis, epithelial-to-mesenchymal transition, matrix remodeling for metastatic support, and TME manipulation to an immunosuppressive state. TAMs additionally promote the emergence of cancer stem cells (CSCs), which are known for their ability to originate, metastasize, and relapse into tumors. CSCs also help M2-TAM by revealing immune escape and survival strategies during the initiation and relapse phases. This review describes the reasons for immunotherapy failure and, thereby, devises better strategies to impair the tumor-TAM crosstalk. This study will shed light on the understudied TAM-mediated tumor progression and address the much-needed holistic approach to anti-cancer therapy, which encompasses targeting cancer cells, CSCs, and TAMs all at the same time.

Keywords: anticancer therapy; cancer stem cells; immunosuppression; immunotherapy; macrophage reprogramming; pro-tumor immunity; tumor microenvironment; tumor-associated macrophages.

Figure 1

The components of the TME: TME consists of an intricate interplay among various cellular components, including tumor cells, CSCs, tumor-associated macrophages (M1 and M2), CD4⁺ and CD8⁺ T cells, B cells, dendritic cells, immune-suppressive Treg cells, as well as other cells, and a complex network of dysregulated vasculature. In addition to several mechanisms, cancer cells along with CSCs play an active role in the polarization of pro-inflammatory M1 macrophages towards anti-inflammatory M2 macrophages. Created with BioRender.com.

Figure 2

M2-TAM promoting different aspects of tumor development: TAMs encourage increased tumor cell proliferation by secreting tumor cell proliferating growth factors such as EGF and FGF. TAMs cause neoangiogenesis and lymphangiogenesis by releasing various pro-angiogenic factors such as VEGF, PDGF, TGFβ, MMPs, and CXCL8. TAMs also lead to increased EMT and extracellular matrix remodeling by releasing factors such as CCL18, TGFβ, MMPs, and TNFα, which ultimately causes metastasis and secondary tumor formation. TAMs negatively affect the functions of NK cells, DCs, and cytotoxic T cells and promote immunosuppression by actively playing a role in the recruitment of Treg cells in the TME. Created with BioRender.com.

Figure 3

The CSC–TAM crosstalk: CSCs employ various modalities to recruit M2-TAMs, such as CCL2, CCL5, CCL8, and CSF1. M2-TAMs are also polarized in the tumor site by CCL2, CCL5, IL6, IL10, and CSF1 by CSCs. Reciprocally, TAMs promote CSC function by releasing CSF1, TGFβ, IL6, IL10, IL35, EGF, and FGF among others, thereby, maintaining a vicious loop for sustenance of one another. Created with BioRender.com.

Figure 4

Therapeutic intervention to curb the tumor–TAM interplay: Mechanisms to inhibit the cancer-TAM crosstalk include depletion and blocking M2-TAM recruitment, re-programming of M2-TAMs, engaging phagocytic activity, and dysregulating CSC–TAM crosstalk. Created with BioRender.com.