Highly plastic macrophage niches orchestrate acquired quiescence and reactivation in breast-cancer bone metastasis

Breast cancer recurrence and metastasis are leading causes of cancer-related deaths, driven by therapy-resistant cells. The bone serves as a common site for breast cancer recurrence, but the factors that reawaken these cells remain unclear. Researchers have now identified a unique, adaptable population of CXCL16 macrophages that link distant metastatic sites, such as the lung and brain, with the bone marrow's disease-associated traits.

These CXCL16 macrophages create a short-lived niche that inhibits the proliferation of circulating cancer cells.

Through single-cell transcriptomics, researchers have observed how myeloid niches within the bone metastatic environment adapt: a transient CXCL16 macrophage niche limits metastatic growth, while G-CSF macrophage and neutrophil niches rekindle tumor growth. In primary tumors, cancer-associated fibroblasts (CAFs) secrete excessive amounts of G-CSF, a response triggered by cancer-cell signals.

This leads to an expansion of a G-CSF-receptor-positive subset of cancer cells with a high metastatic potential. In advanced human bone metastases, CXCL16 macrophages primarily localize in areas rich with CAFs but avoid cancer-cell clusters, suggesting immune evasion.

These findings reveal a connection between CAF-bone-marrow interactions, stromal inflammation, immune remodeling, and metastatic progression, potentially making CAFs a promising therapeutic target.