Natural killer (NK) cells are highly effective cells of our immune system that are capable of clearing cancer cells. Within cancer patients, including MDS patients, NK cells have decreased function and are unable to kill MDS cells. To render NK cells as an effective therapy for MDS, we derive NK cells from healthy human donors, and activate them with a triple cocktail of three proteins that potently activate the NK cells in only 12 hours to acquire memory. Following this activation, the NK cells can be infused directly into patients with excellent safety profile in leukemia and in MDS patients, or used in the lab. Our laboratory research demonstrates that these memory NK cells have significantly improved activity against MDS compared to conventional NK cells; however, many of these memory NK cells do not respond to MDS cells; therefore, not mounting an effective response necessary to generate clinically meaningful outcomes in patients. Here, we apply several new approaches that allow us to comprehensively define what is different between the NK cells that respond to MDS and are an effective therapy, and the NK cells that do not respond to MDS. These findings will allow us to identify what makes an effective NK cell therapy which we will apply towards future clinical trials to enrich for the best NK cells. Conversely, the results will also identify inhibitors of NK cell function. We will block and modify the NK cells to release these brakes that are stopping the NK cell from responding to MDS. This will design a custom therapy for MDS that unleashes more NK cells to effectively eliminate MDS cells, thereby improving patient quality of life and clinical outcomes.