Dexamethasone drives macrophage repolarization linked to increased triple-negative breast cancer aggressiveness

Glucocorticoids (GCs) are known for their anti-inflammatory potential, which includes macrophage polarization into an anti-inflammatory and tissue remodeling state. GCs are routinely co-administered to cancer patients to alleviate the side effects of chemotherapy. However, it is not well known if GCs can modulate tumor-associated macrophages (TAMs) to promote tumor progression. Here, we show that dexamethasone (DEX) induces dose-dependent differentiation of THP-1 monocyte-derived anti-tumorigenic (M1) macrophages into pro-tumorigenic (M2-like) macrophages, even in the presence of M1 cues, and that DEX can repolarize fully differentiated M1 macrophages into an M2-like state. These macrophages have a cytokine profile similar to the pro-tumorigenic (M2) macrophages and can stimulate the proliferation and invasion of triple-negative breast cancer (TNBC) cells in vitro. DEX treatment of an orthotopic mouse model of TNBC attenuated paclitaxel-mediated tumor growth inhibition, increased M2-like TAMs in primary tumors, and enhanced lung metastasis. Transcriptomic analysis of DEX-treated M1 macrophages revealed not only transcriptomic overlap to M2 macrophages, but to human breast cancer TAM transcriptomic data and further to a specific TAM signature associated with aggressive estrogen receptor-negative breast cancer. Our study illustrates a remarkable macrophage repolarization plasticity upon DEX exposure and warrants care in prescribing high doses of GCs to breast cancer patients, especially to those considered for chemotherapy. Dexamethasone drives macrophage repolarization linked to increased triple-negative breast cancer aggressiveness