Chronic stress reshapes bone marrow microenvironment to facilitate breast cancer bone metastasis

Cancer bone metastasis is associated with poor prognosis and resistance to immune checkpoint inhibitors. Although chronic stress promotes cancer progression, its role in reshaping the bone marrow (BM) immune microenvironment to facilitate metastasis remains poorly understood. We demonstrate that chronic stress promotes breast cancer bone metastasis primarily by reshaping the BM immune microenvironment. Specifically, chronic stress increases BM neutrophils, and inducible, specific clearance of these neutrophils effectively prevented stress-induced bone metastasis. In mice exposed to chronic stress, abundant BM neutrophils excessively consume arginine by upregulating iNOS, creating a low-arginine, pro-metastatic niche that impairs functional CD8⁺ cytotoxic T cells. Mechanistically, chronic stress stimulates norepinephrine (NE) release in the BM, which boosts osteopontin (OPN) expression by monocytes/macrophages. The elevated OPN then interacts with its receptor CD44 on neutrophils to trigger this excessive arginine consumption. This cascade was shut down in mice with a global knockout of the NE receptor ADRβ2. To therapeutically target this process, we developed a bone-targeting conjugate of propranolol (an ADRβ antagonist) and alendronate (AP). Local accumulation of AP in the bone reduced OPN-positive monocytes/macrophages and iNOS-positive neutrophils, restoring BM arginine levels and CD8⁺ T cell populations, and effectively inhibiting chronic stress-induced breast cancer bone metastasis. Our findings reveal a novel neuro-immune-metabolic axis through which chronic stress promotes breast cancer bone metastasis and highlight AP as a potential therapeutic strategy.