Dynamic Interactions Between Tumor-Associated Macrophages and Breast Cancer Cells from a Spatiotemporal Perspective: Mechanisms, Therapeutic Targets, and Prospects for Clinical Translation 
Chun Bai1,2  Yanhua Xu1（corresponding author）

1 Department of Thoracic Oncology Jingzhou Hospital Affiliated to Yangtze University, Jingzhou Hubei Province, 434000;

2 Department of Breast Oncology Huangshi Central Hospital Affiliated Hospital of Hubei Polytechnic University, Huangshi City Hubei Province, 435000;

Abstract: Tumor-associated macrophages (TAMs) are a key immune regulatory hub in the breast cancer (BC) microenvironment. The interaction between TAMs and cancer cells is not static; rather, it evolves over time and across different spatial locations. This dynamic crosstalk strongly affects tumor progression and therapeutic efficacy. Depending on where TAMs are located within the tumor, they exhibit markedly different phenotypes, which in turn influence cancer cells in various ways. At every stage of BC—from initiation and progression to metastasis and treatment response— the function and phenotype of TAMs continue to adapt in concert with disease progression. Building upon these observations, this article provides a comprehensive examination of the multiple communication mechanisms used by TAMs and cancer cells. These include bidirectional signaling pathways, secreted soluble factors, extracellular vesicles, and direct cell–cell contacts. Collectively, these constitute the fundamental framework of their interaction. We also discuss how these interactions contribute to therapy resistance, identify current challenges in clinical translation, and highlight promising avenues for future investigation. This review aims to provide an updated perspective of the BC immune landscape and establishes a conceptual foundation for the development of next-generation immunotherapies.

Key words: TAMs; BC; Spatiotemporal heterogeneity; Therapeutic targets; Clinical translation

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