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Due to their important role to eradicate tumors, natural killer (NK) cells are increasingly utilized in cancer immunotherapy. While the infusion of NK cells shows clinical benefit in hematological malignancies, NK cell therapy has yet to show therapeutic potential in patients with solid tumors. We recently discovered a unique subset of tumor-infiltrating NK cells that exert immune regulatory functions to inhibit anti-tumor T cell responses in solid tumors. Our preliminary results support that these NK cells also play a critical role to orchestrate changes within the tumor microenvironment and to affect epithelial-to-mesenchymal transition (EMT). In this project, we will use in vitro and in vivo models and ex vivo analysis of patient material to address how these NK cells remodel the tumor microenvironment via the crosstalk with myeloid cells, influence the EMT process to promote metastatic dissemination, and interfere with clinical responses to immune checkpoint therapy. In aggregate, we anticipate these studies will support the role of tumor-infiltrating NK cells to suppress local and systemic immune responses and favor tumor progression, metastatic dissemination, and interfere with therapy. Such findings have direct implications to improve therapies based on activating NK cell as well as to implement predictive and prognostic biomarkers in patients with cancer.