S100A8/A9 Drives Emergency Granulopoiesis to Promote Triple‐Negative Breast Cancer Metastasis

Objective Triple‐negative breast cancer (TNBC) is an aggressive subtype of breast cancer characterized by high metastatic potential and limited therapeutic options. Although neutrophils contribute to tumor progression, how tumors systemically regulate neutrophil production remains poorly understood. This study investigated the mechanisms underlying tumor‐induced emergency granulopoiesis (EG) and its contribution to TNBC metastasis. Methods A TNBC mouse model was used to characterize tumor‐induced EG and neutrophil expansion. Proteomic analysis of the bone marrow microenvironment was performed to identify factors associated with tumor‐induced granulopoiesis. The regulation and function of S100A8/A9 were investigated using cellular and pharmacological approaches, and the clinical relevance of this pathway was evaluated in patients with TNBC. Results TNBC induced systemic EG characterized by expansion of granulocyte‐macrophage progenitors (GMPs) and increased neutrophil output. S100A8/A9 was prominently enriched in the bone marrow microenvironment of tumor‐bearing hosts, with neutrophils identified as a major source. G‐CSF induced S100A8/A9 expression through STAT3 activation. S100A8/A9 directly stimulated GMP proliferation, establishing a feed‐forward mechanism that sustained neutrophil production. Pharmacological inhibition of S100A8/A9 suppressed tumor‐associated granulopoiesis, reduced neutrophil expansion, and significantly decreased metastatic burden in vivo. Consistent with these findings, patients with metastatic TNBC exhibited elevated plasma S100A8/A9 levels, increased neutrophil counts, and a higher proportion of immature granulocytes. Conclusion S100A8/A9 is a key mediator linking tumor‐induced systemic hematopoietic reprogramming to metastatic progression in TNBC. Targeting the S100A8/A9 axis may represent a therapeutic strategy to limit tumor‐driven granulopoiesis and metastasis.