Macrophages Promote Pre-Metastatic Niche Formation of Breast Cancer through AHR Activity

Macrophages that acquire an immunosuppressive phenotype are crucial for creating the pre-metastatic niche (PMN), which is essential for facilitating breast cancer metastasis to the distant organ. Our study showed that increased aryl hydrocarbon receptor (AHR) activity in lung macrophages is vital for establishing the immunosuppressive PMN in breast cancer. AHR activation led to higher PD-L1 expression on macrophages through directly binding to the promoter of Pdl1, subsequently, promoting Treg cell differentiation in the PMN. Mice with Ahr conditional deletion in macrophages had reduced lung metastasis of breast cancer. The elevated AHR level in PMN macrophages was induced by GM-CSF released from breast cancer cells, which activated STAT5 and prevented AHR ubiquitination in macrophages. In breast cancer patients, the expression of AHR and PD-L1 correlated with Treg cell infiltration, and high AHR expression was associated with a poor prognosis. Our findings uncover a previously unknown cellular and molecular mechanism through which macrophages establish the lung PMN in breast cancer.