Macrophage-Regulatory T Cell Reprogramming in the Pre-metastatic Niche: Mechanisms and Therapeutic Implications

The pre-metastatic niche (PMN) is a tumor-conditioned immunosuppressive microenvironment that forms in distant organs prior to metastatic colonization. Macrophages and regulatory T cells (Tregs) play central roles in its formation and function. Tumor-derived exosomes and soluble factors reprogram macrophages into M2-like states, leading to extracellular matrix (ECM) remodeling, increased angiogenesis, vascular leakiness, and fibrotic niche formation. Simultaneously, Tregs are recruited and amplified through pathways involving myeloid-derived suppressor cells (MDSCs), S100 calcium-binding protein A8/A9 ( S100A8/A9 ), receptor for advanced glycation end products (RAGE), and Toll-like receptor 4 ( TLR4 ), as well as fibroblast-derived exosomal C-C motif chemokine ligand 1 ( CCL1 )-C-C chemokine receptor type 8 ( CCR8 ) signaling. Cytokines from macrophages suppress natural killer (NK) and cluster of differentiation 8-positive (CD8 + ) T-cell cytotoxicity, facilitating immune evasion. The interaction between macrophages and Tregs creates self-reinforcing suppressive circuits that influence metastatic boundaries and condition tumor cells for dormancy or growth. This review summarizes the core mechanisms by which macrophages and Tregs mediate PMN formation, highlights the critical role of exosomes in macrophage reprogramming and niche boundary establishment, and discusses targeted therapeutic strategies and translational challenges. • Pre-metastatic niche (PMN) biomarkers can enhance the stratification of metastasis risk in cancer patients. • Tumor-derived exosomes (TDEs) reprogram macrophage phenotypes to construct the PMN. • Macrophage-regulatory T cell (Treg) crosstalk drives extracellular matrix (ECM) remodeling within the PMN.

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