Cancer immunotherapy with patients‘ own immune cells engineered to express chimeric antigen receptors (CARs) is a revolutionizing new treatment modality in hematologic oncology. CAR T cell therapy has achieved complete remission rates of 50 - 90% in patients with chemotherapy refractory or relapsed hematologic malignancies like diffuse large B cell lymphoma (DLBCL). By comparison, in DLBCL for example, the complete response rate to conventional therapies in patients with refractory or relapsed disease is below 10%. Still, up to one third of patients treated with CAR T cells relapse within a year after an initial complete response, there is a high burden of therapy associated toxicities and non-hematologic cancers have thus far not been amenable to redirected cellular immunotherapy. Apart from T cells, natural killer (NK) cells are a second cytotoxic lymphocytic lineage that have not been sufficiently explored clinically in the context of CAR therapy. Indeed, NK cells might be a promising alternative to T cells due to an inherent anti-cancer activity and a favorable toxicity profile. With a longstanding interest in human NK cells, our research includes engineering these cells as vehicles for redirected cellular immunotherapy. As a preclinical cancer model, we are using human immune system (HIS) mice carrying EBV-induced lymphomas. This allows the exploration of an autologous human cancer-immune system interface and its manipulation. We are specifically interested in engineering cytotoxic cells beyond redirection to enhance anti-cancer activity of the infused cell product. Another interest in the lab is functional analysis of genes important for human NK cell biology in vivo using HIS mice via genome editing approaches in the context of viral infection and homeostasis. These studies are designed to contribute to novel insights and improvements in the therapeutic potential of engineered immune cells in the fight against cancer.