Common Pathways Regulating Macrophage Differentiation and Breast Cancer Metastasis

A bstract Breast cancer remains the leading cause of mortality among women worldwide, driven by intricate mechanisms involving genetic alterations and tumor microenvironment (TEM) dynamics. Macrophages, critical components of the innate immune system, exhibit dual roles in breast cancer progression. While their phagocytic activity protects against tumor growth, their polarization into the M2 phenotype, induced by cytokines such as IL-4 and IL-13, drives tumor progression and metastasis. M2 macrophages contribute to breast cancer by activating pathways involving interleukins, TGF-β, and C-C motif chemokine ligand chemokines, which promote angiogenesis, extracellular matrix remodeling, transformation of fibroblasts into cancer-associated fibroblasts, and immune suppression. These processes enhance cancer cell proliferation, invasion, and survival by reshaping the TEM into one that supports tumor growth. Furthermore, tumor cells evade phagocytosis by expressing inhibitory ligands such as CD47 and PD-L1, which further suppress immune responses. Chronic inflammation driven by tumor-associated macrophages exacerbates tumor progression through increased production of inflammatory cytokines like IL-6, IL-1β, and TNF-α, which stimulate angiogenesis and metastasis. The reciprocal interaction between macrophages and tumor cells creates a feedback loop that sustains tumor growth. This study emphasizes the importance of understanding macrophage-driven mechanisms in breast cancer and identifies their polarization and functional plasticity as key therapeutic targets to disrupt tumor progression and metastasis.