The most common metastasis of breast cancer is to the brain. Current therapies are not meaningfully improving survival. Tumor-associated macrophages (TAMs) in breast cancer usually display an alternatively activated (M2-like) phenotype, which suppresses antitumor immunity and aids in metastasis, including brain metastasis. Therefore, reprogramming TAMs from M2-to M1-like phenotype could be a promising therapeutic approach for metastatic breast cancer. However, the molecular basis governing macrophage reprogramming during breast cancer brain metastasis remains elusive and there is no effective approach to reprogram TAMs in the tumor microenvironment. We propose to employ integrated strategies to reveal whether and how TAM reprogramming contributes to breast cancer brain metastasis. We also plan to determine how TAM reprogramming can work with immune checkpoint inhibitors to suppress brain metastasis of breast cancer.