Background: PIM2 kinase play a vital role in the generation of plasma cell and bone loss in multiple myeloma(MM), which highly related to the tumor progression and as a potential therapy target in MM. In immune cell,PIM2 kinase involved in the regulation of lymphocyte like T cell and B cell, However, its role in NK cells remains unclear. Methods: Single-cell RNA sequencing data were analysed the expression of PIM2 kinase in NK cells from MM patients and healthy donors.Immune checkpoint expression, cell apoptosis, and NK cell function had been evaluated through flow cytometry.Then, NCBI, UCSC, JASPAR and GEPIA database were used to predict promoter of TIGIT.NK-92 cells with ETS-1 knockdown were established by using sh-RNA. Kinase functional assay (ADP-Glo) were used to confirm PIM2 inhibitor from 160 kinds of natural flavonoids compound.Samples treated with or without drugs were analyzed using mass spectrometry and RNA-seq. The oxygen consumption rate (OCR), and the extracellular acidification rate (ECAR) were measured by assay kit. Result: The PIM2 kinase was highly expressed in the NK cells from MM patients based on single-cell sequencing analysis and confirmed in clinical sample by PCR and flow cytometry.Inhibition of PIM2 kinase can increase the function of NK cells and down regulation TIGIT expression. Mechanism, we confirmed that ETS-1 which was directly binding to the promoter of TIGIT was up-regulated by PIM2 kinase, which can lead the strengthened transcription of TIGIT on NK cells.Furthermore, two novel natural flavonoids compound named Kaempferol and Quercetin dihydrate as PIM2 kinase inhibitors exhibiting higher efficiency at low dose in MM cells,while influence the expression of TIGIT and energy metabolism on NK-92 cells. For in vitro experiment,PIM2 kinase inhibitors can activate NK cell killing function and decrease TIGIT expression,while promoted the apoptosis of MM cells irrespective of adding BMSCs or not in co-culture systems BMSCs. Conclusion: PIM2 kinase involved in the regulation of NK cell.Inhibiting PIM2 kinase could down-regulate the expression of TIGIT and improve energy metabolism to enhance NK cell anti myeloma cell.