Tamoxifen promotes metastasis of breast cancer via reshaping lipid-driven fibrotic microenvironments in the lung

Patients with estrogen receptor (ER)-positive breast cancer (BC) remain at risk of distant recurrence for up to 20 years after diagnosis, with an overall recurrence rate of approximately 30%. Although tamoxifen is a cornerstone of endocrine therapy, its long-term effects on metastatic niche formation remain poorly defined. Here, we investigated the impact of long-term tamoxifen treatment on metastatic niche formation. Using PyMT and 4T1 allograft mouse models, we found that tamoxifen increased lung metastasis, despite reduced or unchanged primary tumor size. Lungs from tamoxifen-treated mice exhibited fibrotic features, such as collagen deposition, increased airway wall thickness, and altered expression levels of fibrosis-associated proteins. These changes were accompanied by elevated neutral lipid levels and upregulation of lipid metabolism-related genes. Single-cell RNA sequencing (scRNA-seq) revealed an expansion of a macrophage subpopulation enriched for lipid metabolic gene signatures and exhibiting strong interaction with fibroblasts via TGFβ signaling. Immunofluorescence and flow cytometry further demonstrated an increased number of PRG4+ macrophages in the lungs of tamoxifen-treated mice. Importantly, inhibition of lipid accumulation with the fatty acid synthase inhibitor C75 reduced PRG4+ macrophage numbers, attenuated fibrosis, and suppressed lung metastasis. Together, these findings implicate long-term tamoxifen treatment as a potential risk factor for lung metastasis in ER-positive BC by disrupting the lung microenvironment, and suggest that targeting lipid metabolism may represent a therapeutic strategy to limit metastatic progression, particularly in the lung.