Women diagnosed with high grade serous ovarian cancers (HGSOCs) often suffer from disease relapse that is resistant to platinum-based chemotherapy. Effective treatments are needed as patients often die soon after. Chemoresistant tumors are enriched with poorly differentiated stem-like cells (PD-SLCs) that harbor unique traits such as expression of stemness-related genes, enhanced DNA repair, and reduced expression of MHC class I which allows them to escape chemotherapy and cytotoxic T-cells. For successful eradication of chemoresistant HGSOC tumors it is imperative to get rid of both differentiated tumor cells as well as PD-SLCs. Natural killer (NK) cells are innate immune cells that mediate strong cytotoxicity against PD-SLCs particularly those expressing low levels of MHC class I. But endogenous NK cells are few in number and defective in many cancer patients including women diagnosed with HGSOCs. To address this clinical challenge, our group has developed a novel ex vivo platform that can expand and activate NK cells-coined super charged (sNK) cells for allogenic cell therapy. These NK cells can be expanded exponentially and are not only durable but also functionally superior to peripheral blood NK cells. In addition, unlike T cells sNK cells do not mediate GVHD or cause cytokine storm syndrome. Together these qualities make these cells a powerful tool in targeting solid malignancies. Our work demonstrates that ovarian tumors enriched with a poorly differentiated phenotype can be directly targeted by sNK cells. In response to secreted cytokines by the sNK cells any remaining tumor cells become more differentiated and readily targetable with chemotherapy. These findings provide a strong rationale for testing the efficacy of sNK cells, alone and in combination with carboplatin in targeting platinum resistant HGSOCs. We hypothesize that our proposed therapeutic sNK cells in combination with carboplatin will be more effective in targeting platinum resistant HGSOCs enriched with PD-SLCs. To test this hypothesis, we will first test the efficacy of sNK cells, alone and in combination with carboplatin in targeting a large panel of primary chemo resistant HGSOC tumors in vitro and patient-derived xenografts (PDXs) in vivo. This will help us understand the applicability of our proposed therapeutic in a large number of patients with advanced HGSOCs. To investigate the potential biomarkers of response to sNK cells, we will perform single cell profiling of tumor cells at the RNA and protein level using scRNA seq and CyTOF to delineate the expression level of genes and gene sets associated with susceptibility to sNK cells. Top ranking pathways here include MHC class I and stemness associated genes. These findings can help guide selection of patients who may most benefit from this treatment in future clinical trials. We will also explore the underlying mechanism that regulate the antitumor activity of sNK cells and carboplatin combination in targeting the ch...