MIF mediates monocyte-dependent inhibition of natural killer cell cytotoxicity in triple-negative breast cancer.

Immunotherapies remain ineffective in triple-negative breast cancer (TNBC), underscoring the need to define drivers of immune suppression. Natural killer (NK) cells are crucial for eliminating disseminated tumor cells (DTCs) through NK cell cytotoxicity (NKCC), but this is impaired in metastasis. While tumor cell-intrinsic mechanisms of NK cell evasion are known, the role of other cells in the tumor microenvironment remains unclear. Using the Cherry-niche labeling system, we profiled early TNBC lung micrometastases and identified bone marrow-derived monocytes to be highly enriched and capable of suppressing NK cells within metastatic niches. Functional studies revealed that monocyte-derived macrophage migration inhibitory factor (MIF) suppresses NKCC against TNBC cells via CXCR4. MIF inhibition restored NK cell activatory receptors, cytotoxic mediators, and tumor cell killing in vitro, while reducing metastatic outgrowth and increasing NK cell activatory receptors in vivo. These findings reveal MIF as a potential target to enhance NK cell function in TNBC metastasis.