The HyperTargIPS-NK project aims to combine novel technologies from three research laboratories and a stem cell company to develop a revolutionary therapeutic modality for patients with devastating refractory malignancies. The treatment we propose is based on allogenic transplantation of induced pluripotent stem (iPS) cell-derived natural killer (NK) cells, genetically modified to a hyperactive state to ensure high potency NK cell targeting and destruction of tumor cells. CAR NK-based cancer treatment is an extremely promising new therapeutic avenue. However, the full potential of CAR NK therapies will only be achieved when an off-the-shelf product is rapidly accessible to patients in need. IPS with its unlimited expansion potential is the ideal cell source for NK-based products, however, improved efficiencies of NK cell production, suitably activated status, and resistance to immune suppression would need to be achieved. We have several breakthrough technologies to address these issues with 1) a novel iPS cell differentiation system based on our newly identified metabolic regulators that can be easily scaled to generate billions of functional NK cells, 2) identified and validated several novel and state-of-the-art CAR, non-CAR and TRUCK based regulators of NK activation to elicit the hyper activated NK cell state and prolonging NK survival, and 3) improved NK response to tumors via tumor microenvironment remodeling. We will target the NK cells towards three life-threatening cancers for which novel treatment options are urgently needed as they are considered among the most lethal cancers; i.e. Pancreatic cancer, Glioblastoma, and Acute Myeloid leukemia (AML). Our iPS culture system, NK activation systems, and gene editing systems, have already been designed towards GMP compatibility. Taken together, these advances ensure that once this study is successful, our Hyper-Targ-IPS-NK cells are poised for rapid translation towards the clinic with our industrial partner.