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Simple Summary  Glycogen synthase kinase-3 (GSK-3) is a serine/threonine protein kinase that has gained considerable interest as a therapeutic target for cancer due to its key involvement in growth arrest and apoptosis of tumor cells. Moreover, GSK-3, especially GSK-3β, limits the activation of NK cells, key innate effectors in cancer immunosurveillance, triggered by diverse activating receptors. However, the role of GSK-3 in the regulation of activating ligands on target cells that confer susceptibility to NK cells remains unclear and is the aim of this study. Here, we provide evidence that GSK-3α primarily restrains the expression of ligands for activating receptors such as NKG2D, NKp30 but not DNAM-1, thereby reducing target susceptibility to NK cells. Thus, our results suggest a distinct role of GSK-3 isoforms in target cells vs NK cells for regulating NK cell reactivity and GSK-3α inhibition as a relevant strategy to enhance target susceptibility to NK cells.    Abstract  Natural killer (NK) cells are innate cytotoxic lymphocytes that provide early protection against cancer. NK cell cytotoxicity against cancer cells is triggered by multiple activating receptors that recognize specific ligands expressed on target cells. We previously demonstrated that glycogen synthase kinase (GSK)-3β, but not GSK-3α, is a negative regulator of NK cell functions via diverse activating receptors, including NKG2D and NKp30. However, the role of GSK-3 isoforms in the regulation of specific ligands on target cells is poorly understood, which remains a challenge limiting GSK-3 targeting for NK cell-based therapy. Here, we demonstrate that GSK-3α rather than GSK-3β is the primary isoform restraining the expression of NKG2D ligands, particularly ULBP2/5/6, on tumor cells, thereby regulating their susceptibility to NK cells. GSK-3α also regulated the expression of the NKp30 ligand B7-H6, but not the DNAM-1 ligands PVR or nectin-2. This regulation occurred independently of BCR-ABL1 mutation that confers tyrosine kinase inhibitor (TKI) resistance. Mechanistically, an increase in PI3K/Akt signaling in concert with c-Myc was required for ligand upregulation in response to GSK-3α inhibition. Importantly, GSK-3α inhibition improved cancer surveillance by human NK cells in vivo. Collectively, our results highlight the distinct role of GSK-3 isoforms in the regulation of NK cell reactivity against target cells and suggest that GSK-3α modulation could be used to enhance tumor cell susceptibility to NK cells in an NKG2D- and NKp30-dependent manner.

GSK-3α Inhibition in Drug-Resistant CML Cells Promotes Susceptibility to NK Cell-Mediated Lysis in an NKG2D- and NKp30-Dependent Manner