Macrophages that acquire an immunosuppressive phenotype play a crucial role in establishing the pre-metastatic niche (PMN), which is essential for facilitating breast cancer metastasis to distant organs. Our study showed that increased activity of the aryl hydrocarbon receptor (AHR) in lung macrophages plays a crucial role in establishing the immunosuppressive PMN in breast cancer. Specifically, AHR activation led to high expression of PD-L1 on macrophages by directly binding to the promoter of Pdl1. This upregulation of PD-L1 promoted the differentiation of regulatory T cells (Tregs) within the PMN, further enhancing immunosuppressive conditions. Mice with Ahr conditional deletion in macrophages had reduced lung metastasis of breast cancer. The elevated AHR levels in PMN macrophages were induced by GM-CSF, which was secreted by breast cancer cells. Mechanistically, the activated STAT5 signaling pathway induced by GM-CSF prevented AHR from being ubiquitinated, thereby sustaining its activity in macrophages. In breast cancer patients, the expression of AHR and PD-L1 was correlated with increased Treg cell infiltration, and higher levels of AHR were associated with a poor prognosis. These findings reveal that the crosstalk of breast cancer cells, lung macrophages, and Treg cells via the GM-CSF-STAT5-AHR-PD-L1 cascade modulates the lung pre-metastatic niche during breast cancer progression.

获得免疫抑制表型的巨噬细胞在建立转移前生态位 （PMN） 中起着至关重要的作用，这对于促进乳腺癌向远处器官的转移至关重要。我们的研究表明，肺巨噬细胞中芳烃受体 （AHR） 活性的增加在乳腺癌中建立免疫抑制性 PMN 起着至关重要的作用。具体而言，AHR 激活通过直接结合 Pdl1 的启动子导致 PD-L1 在巨噬细胞上高表达。PD-L1 的这种上调促进了 PMN 内调节性 T 细胞 （Tregs） 的分化，进一步增强了免疫抑制条件。巨噬细胞中 Ahr 条件性缺失的小鼠减少了乳腺癌的肺转移。PMN 巨噬细胞中 AHR 水平升高是由乳腺癌细胞分泌的 GM-CSF 诱导的。从机制上讲，GM-CSF 诱导的激活的 STAT5 信号通路阻止了 AHR 泛素化，从而维持了其在巨噬细胞中的活性。在乳腺癌患者中，AHR 和 PD-L1 的表达与 Treg 细胞浸润增加相关，高水平的 AHR 与不良预后相关。这些发现揭示了乳腺癌细胞、肺巨噬细胞和 Treg 细胞通过 GM-CSF-STAT5-AHR-PD-L1 级联反应调节乳腺癌进展过程中肺转移前生态位。