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.

Stage I–IV Colorectal Cancer Prognosis Can Be Predicted by Type and Number of Intratumoral Macrophages and CLEVER-1+ Vessel Density

“…This finding was expected because of the known interaction between TAMs and vascular cells. TAMs promote angiogenesis and lymphangiogenesis in tumor tissue by several mechanisms, such as the secretion of pro-angiogenic factors including vascular endothelial growth factors [ 15 , 61 ].…”

“…The Cancer Genome Atlas pan-cancer cohort data indicate that high expression of CLEVER-1 is associated with a poor response to immunotherapy and shorter survival [ 23 ]. Other treatment approaches targeting TAMs include reprogramming M2 macrophages to M1 (e.g., using low doses of radiation, targeting toll-like receptors, or use of zoledronic acid) or depleting existing M2 macrophages (e.g., by targeting the CSF-1/CSF-1R pathway), which cause resistance to cancer therapies, preventing TAM recruitment to tumor tissue (e.g., using anti-CCL2 antibodies or CCR2 inhibitors), and preventing TAM-mediated angiogenesis (via anti-VEGF antibody) [ 15 ]. Combination therapies targeting both angiogenesis and TAMs are also being investigated (e.g., Ang-2 and VEGF inhibitors; dual Ang-2/VEGF inhibitors and PD-L1 or CD40 immunotherapy) [ 61 ].…”

“…These two types of macrophages represent the two extremes of the macrophage polarization spectrum. TAMs are plastic cells that can switch phenotype or express both M1 and M2 markers [ 10 , 11 , 12 , 13 , 14 , 15 ]. In the early stage of disease, TAMs are mainly M1 type and polarize to M2 type during disease progression.…”

“…TAMs promote tumor cell proliferation, invasion, and migration; enhance angiogenesis and lymphangiogenesis; suppress T cells; and affect the gut microbiota [ 16 ]. Markers used for M2 macrophage detection include CD163 (macrophage scavenger receptor), CD204 (macrophage scavenger receptor 1), CD206 (macrophage mannose receptor), and CLEVER-1 [ 15 , 17 , 18 , 19 ]. The role and characteristics of M1 and M2 macrophages have been presented in Figure 1 .…”

Macrophage Reprogramming and Cancer Therapeutics: Role of iNOS-Derived NO

“…M1 macrophages exist as pro-inflammatory cells responsible for initiating an immune re-sponse, compromising tissue integrity, and mitigating tumorigenicity overall. This cellular behavior diverges from their M2 analogs, which exist as anti-inflammatory cells that participate in immunosuppressive processes, tissue remodeling, and promoting tumor development in general [20,26]. Although their phenotypical fate depends on signals from the microenvironment, these effector cells exhibit high plasticity and, therefore, may transition between antagonistic conformation in response to peripheral cues.…”