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Immune rejection is one of the most serious challenges in allogeneic transplantation, including allogeneic induced pluripotent stem cell (allo-iPSC)-derived cell therapy. Beta-2-Microglobulin gene-knockout, human leukocyte antigen (HLA) class I-deficient iPSCs can evade immune rejection by host T cells, which occurs due to HLA mismatches. However, natural killer (NK) cells recognize HLA class Ⅰ-deficient cells and reject them, which is known as the missing-self response. Introducing chimeric HLA-E protein to HLA class Ⅰ-deficient iPSCs suppresses the missing-self response of NK cells expressing the inhibitory receptor NKG2A; however, technology to suppress NKG2A-negative NK cells is still required. Here, we developed novel agonists for the other inhibitory receptor, killer immunoglobulin receptor (KIR), on NK cells. We found that antibodies that bind to activating KIR enhance NK cell activation and developed selective agonists for inhibitory KIRs (KIR2DL1, KIR2DL2/3, and KIR3DL1). Introducing these selective inhibitory KIR agonists on T cells and HLA class Ⅰ-deficient iPSCs allowed them to evade immune rejection by NK cells. Additionally, we identified an NKG2A-selective agonist as an alternative to chimeric HLA-E, which stimulates the activating receptor NKG2C. This technology enhances immune tolerance in allo-iPSCs and facilitates the development of various iPSC-derived regenerative medicines. The online version contains supplementary material available at 10.1038/s41598-025-18394-z. Subject terms: Allotransplantation, NK cells

Natural killer (NK) cells are an important innate defense against malignancies, and exogenous sources of NK cells have been developed as anti-cancer agents. Nevertheless, the apparent limitations of NK cells in clearing cancers have suggested that their efficacy might be augmented by combination with other treatments. We have developed cell-penetrating peptides that target the transcription factors ATF5, CEBPB, and CEBPD and that promote apoptotic cancer cell death both in vitro and in vivo without apparent toxicity to non-transformed cells. We report here that one such peptide, Dpep, significantly sensitizes a variety of tumor cell types to the cytotoxic activity of the NK cell line, NK-92MI. Such sensitization requires pre-exposure of tumor cells to Dpep and does not appear due to effects of Dpep on NK cells themselves. Our findings suggest that Dpep acts in this context to lower the apoptotic threshold of tumor cells to NK cell toxicity. Additionally, while Dpep pre-treatment does not prevent tumor cells from causing NK cell “inactivation”, it sensitizes cancer cells to repeated rounds of exposure to fresh NK cells. These findings thus indicate that Dpep pre-treatment is an effective strategy to sensitize cancer cells to the cytotoxic actions of NK cells.

The lack of curative therapies for acute myeloid leukaemia (AML) remains an ongoing challenge despite recent advances in the understanding of the molecular basis of the disease. Here we identify the WNK1-OXSR1/STK39 pathway as a previously uncharacterised dependency in AML. We show that genetic depletion and pharmacological inhibition of WNK1 or its downstream phosphorylation targets OXSR1 and STK39 strongly reduce cell proliferation and induce apoptosis in leukaemia cells in vitro and in vivo. Furthermore, we show that the WNK1-OXSR1/STK39 pathway controls mTORC1 signalling via regulating amino acid uptake through a mechanism involving the phosphorylation of amino acid transporters, such as SLC38A2. Our findings underscore an important role of the WNK1-OXSR1/STK39 pathway in regulating amino acid uptake and driving AML progression. With-No-lysine (K) kinase 1 (WNK1) is an atypical serine-threonine kinase that has been implicated in ion transport. Here, the authors show that WNK1 regulates amino acid transport and mTORC1 activity, and that the axis is a vulnerability for acute myeloid leukemia