Among the various type of cancers, breast cancer is one of the most life-threatening disorders and the dominant reason for cancer-related death in women worldwide. Breast cancer mortality is decreasing but still accounts for 15% of the cancer death ratio in females particularly due to metastatic and chemoresistance. Recently involvement of the tumor microenvironment (TME) in distant metastasis and therapeutic resistance has been recognized. Tumor-associated macrophages (TAMs) are also part of TME. TAMs can change their phenotypes, depending on the signals from the surrounding microenvironment, and can either kill tumor cells or promote tumor development and metastasis. Therefore, Target-TAMs have become increasingly interested as a potential therapeutic strategy in breast cancer.

M2-TAMs in Breast Cancer

TAMs in breast cancer are influenced by signals from myeloid-derived suppressor cells (MDSCs), tumor cells, B lymphocytes, and T lymphocytes. Downregulation of signal transducer and activator of transcription 3 (STAT3) transcription factor plays a vital role in the differentiation of monocytes and monocyte myeloid-derived suppressor cells (Mo-MDSC) into mature TAMs. Interleukin-4 (IL-4) and IL-13 derived from T-helper 2 cells, eosinophils or basophils, elicit changes in the M2 activation of TAMs. Sustained phosphoinositide 3-kinase (PI3K) activity-induced macrophages to polarize from M0 to M2. Breast cancer M2 cells have poor antigen presentation ability and express immunosuppressive factors, such as IL-10 and transforming growth factor β (TGFβ). Amino acid metabolism in TAMs results in the metabolic starving of T cells and the production of immunosuppressive metabolites by the indoleamine 2,3 dioxygenase (IDO) pathway. Lastly, TAMs express PD-L1 and PD-L2, which contribute to the checkpoint blockade in T cells. TAMs also express proteases, such as matrix metalloproteinase 9 (MMP9), in breast cancer that downregulate the extracellular matrix and play significant roles in the progression of angiogenesis and tumors. In those ways, TAMs can promote the recruitment and polarization of monocytes toward M2 cells, leading to angiogenesis, cancer cell migration, invasion, tumor growth, and immunosuppression.

Fig.1 TAM-associated mechanisms that promote the development of breast cancer.^1,2

Clinical Implications of TAMs in Breast Cancer

In general, high infiltration of TAMs is correlated with unfavorable clinicopathological features and survival in patients with primary invasive breast cancer. Their polarization, localization, and the relative amount related to other immune-type fractions in a tumor lesion may be more important than their mere presence. For instance, it is credible that M1/M2 ratio affects results in breast cancer.

Therapies of Targeting TAMs in Breast Cancer

Accumulated evidence has suggested that a high density of TAMs in tissue is correlated with resistance to anticancer therapy. TAMs decreased the sensitivity of several anticancer therapies. Based on these findings, TAMs are emerging as attractive targets in the field of tumor therapy. Different anti-tumor therapies to target TAMs in breast cancer are being extensively studied based on the following strategies:

• Inhibition of macrophages recruitment into the tumor. Targeting the chemokine ligand 2 (CCL2)/chemokine receptor 2 (CCR2) and colony-stimulating factor (CSF)/CSF receptor (CSFR) signaling pathways causes the downregulation of monocyte mobilization from the bone marrow, which then decreases the infiltration of macrophages into breast cancer tumors.
• Suppression or depletion of TAMs survival. Chemical drugs that promote apoptosis in macrophages and the monoclonal antibodies (MAbs) that activate immune cells are two methods being used against TAMs.
• Reprogramming TAMs to antitumor M1-like phenotype. Increasing the impression of tumor necrosis factor (TNFα), IL12, and interferons have revealed that M2 cells are repolarized toward M1 cells.
• Blocking the tumor-promoting activity of TAMs M2-like polarized. STAT3 and STAT6 play important roles in the activation of cytokine and growth factor signaling in M2 cells. Inhibition of STAT3 and STAT6 pathways is regarded as a strategy for treating breast cancer.

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References

1. Huang, Xinqun, Jingsong Cao, and Xuyu Zu. "Tumor-associated macrophages: An important player in breast cancer progression." Thoracic Cancer 13.3 (2022): 269-276.
2. Under Open Access license CC BY 4.0, without modification.