Macrophage-mediated extracellular matrix remodeling awakens dormant breast cancer cells

Breast cancer recurrence remains a major cause of patient mortality. Recurrence arises from disseminated cancer cells that persist in a dormant state and can remain quiescent for extended periods before re-entering proliferation. Despite the clinical importance of this phenomenon, the cellular and molecular mechanisms that govern the awakening of dormant cancer cells remain incompletely understood. Inflammation has been extensively implicated in cancer progression; however, whether and how macrophages contribute to the awakening of dormant breast cancer cells is unclear. Using three-dimensional coculture systems, we show that macrophages promote the awakening of dormant breast cancer cells by remodeling the extracellular matrix (ECM), in vitro. We identify macrophage-derived matrix metalloproteinase-9 (MMP9) and lysyl oxidase (LOX) as key mediators of ECM remodeling, which in turn induces dormant cancer cell awakening. Mechanistically, macrophage-dependent ECM modifications trigger ligand-independent activation of EGFR/HER2 signaling in dormant cancer cells. Together, these findings establish a direct link between inflammation, ECM remodeling, and dormant cell awakening, revealing a previously unrecognized macrophage-cancer cell crosstalk that contributes to breast cancer recurrence.