Tumor-associated macrophages (TAMs) promote metastasis and inhibit cytotoxic T cells. Yet, macrophages can be polarized to kill cancer cells. Macrophage polarization could therefore be a strategy for controlling cancer. Here, we show that macrophages from metastatic pleural effusions of breast cancer patients could be polarized in vitro to kill cancer cells with monophosphoryl lipid A (MPLA, a lipopolysaccharide [LPS] derivative) and IFNγ. Intratumoral injection with MPLA+IFNγ reduced primary tumor growth, greatly suppressed metastasis, and enhanced chemotherapy response in breast and ovarian cancer mouse models. Both macrophages and T cells were critical for the anti-metastatic effects of MPLA+IFNγ. The MPLA+IFNγ treatment stimulated type I interferon signaling, reprogramed CD206+ TAMs to iNOS+ macrophages, and activated cytotoxic T cells through macrophage-secreted interleukin 12 (IL-12) and tumor necrosis factor α (TNFα). MPLA and IFNγ are used individually in clinical practice and together represent a previously unexplored approach to engage a systemic anti-tumor immune response.