Natural killer (NK) cell prevention of tumor initiation and metastases requires regulation by both immune receptors and cytokines of the interferon (IFN) family. Recently we first described the ability of the Ig superfamily member CD96 to compete with CD226 (DNAM-1) and to negatively control cytokine responses by NK cells. Now we have evaluated anti-CD96 monoclonal antibody as a novel cancer immunotherapy, alone and in the context of conventional therapies such as surgery, targeted therapies (Her2/neu), doxorubicin, and checkpoint blockade (CTLA-4 or PD-1). Our data demonstrate the general utility of this new immunotherapy in enhancing NK and T cell IFN-g effector function, independently of ADCC, against experimental and spontaneous metastases and established transplanted and de novo primary tumors. We will also describe early studies to compare the activity of co-blockade of CD96 and TIGIT, which both, like CD226 bind CD155.  NK cells also have an intrinsic dependence upon type I IFN priming to execute their effector functions. Type III IFN (IFN-l) shares some common functions with IFN-ab, but a more restricted cellular expression. By using the IL-28Ra gene-targeted strain, we demonstrate for the first time, the ability of IFN-l to directly regulate NK cell effector functions in vivo, alone and in the context of IFN-ab signalling.