Breast cancer (BRCA) has become the most common cancer worldwide. The tumor microenvironment (TME) in the breast exerts a crucial role in promoting BRCA initiation, progression, and metastasis. Tumor-associated macrophages (TAMs) are the primary component of tumor-infiltrating immune cells through biological mediators which convert TME into malignant tumors. Combinations of these biological mediators can promote tumor growth, metastasis, angiogenesis, immune suppression, and limit the anti-tumor activity of conventional chemotherapy and radiotherapy.The present study aimed to highlight the functions of several biological mediators in the breast which generate TME into malignant tumors. Furthermore, this review offers a rationale for TAM-targeted therapy as a novel treatment strategy for BRCA Results: this review emphasizes TAM-associated biological mediators of TME viz., cancer-associated fibroblasts, endothelial cells, adipocytes, tumor-derived exosomes, extracellular matrix, and other immune cells, which facilitates TME into malignant tumors. Evidence suggests that the increased infiltration of TAMs and elevated expression of TAM-related genes are associated with a poor prognosis of BRCA. Based on these findings, TAM-targeted therapeutic strategies, including inhibitors of CSF-1/CSF-1R, CCL2/CCR2, CCL5-CCR5, bisphosphonate, nanoparticle, and exosomal-targeted delivery have been developed, and are currently being employed in intervention trials.This review concludes the roles of biological mediators of TME interact with TAMs in BRCA that provide a rationale for TAM-targeted therapy as a novel treatment approach for BRCA.Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.