The puppet master in the breast cancer “microecological community”: spatial and metabolic regulation of macrophage heterogeneity

Tumor-associated macrophages (TAMs) are among the most abundant immune components within the breast cancer (BRCA) microenvironment and exert multifaceted roles in tumor progression, immune evasion, and therapy resistance. While traditionally classified along the M1/M2 polarization axis, emerging evidence from single-cell and spatial transcriptomic studies has revealed a spectrum of phenotypically diverse, functionally distinct TAM subsets. These subsets are shaped by BRCA molecular subtype, tumor stage, and microenvironmental factors such as cytokines, hypoxia, and metabolic cues, challenging the conventional dichotomy. This review summarizes current understanding of TAM origin, polarization, and subtypes-specific functions across different breast cancers subtypes. Functionally, heterogeneous spatial-metabolic TAMs contribute to angiogenesis, metastasis, and immunosuppression—particularly their crosstalk with T cells and immune checkpoints. Emerging therapeutic strategies are discussed, including TAMs depletion and reprogramming. Altogether, to examine major challenges in TAM research, such as the lack of standardized classification systems and actionable biomarkers, proposes future directions for integrating TAM-targeted therapies into personalized immuno-oncology.