The plasma cell malignancy, multiple myeloma (MM), has significantly improved by the application of new drugs and autologous hematopoietic stem cell transplantation. However, MM remains incurable. A number of studies have revealed an anti‐MM effect of natural killer (NK) cells; however, their clinical efficacy is limited. Furthermore, glycogen synthase kinase (GSK)‐3β inhibitors show an antitumor function. In this study, we aimed to evaluate the potential roles of a GSK‐3β inhibitor (TWS119) in the regulation of NK cell cytotoxicity against MM. Our results showed that, in the presence of TWS119, the NK cell line, NK‐92, and in vitro‐expanded primary NK cells exhibited a significantly higher degranulation activity, expression of activating receptors, cellular cytotoxicity, and cytokine secretion when they were exposed to MM cells. Mechanistic studies indicated that TWS119 treatment markedly upregulated RAB27A expression, a key molecule for NK cell degranulation, and induced the colocalization of β‐catenin with NF‐κB in the nucleus of NK cells. More importantly, GSK‐3β inhibition combined with the adoptive transfer of TWS119‐treated NK‐92 cells significantly reduced tumor volume and prolonged the survival time of myeloma‐bearing mice. In summary, our novel findings suggest that targeting GSK‐3β through the activation of β‐catenin/NF‐κB pathway may be an important approach to improve therapeutic efficacy of NK cell transfusion for MM.

Background: Caffeic acid (CA) or 3,4-dihydroxycinnamic acid is a polyphenolic compound primarily found in coffee, herbs, berries, and other fruits. Its antioxidant, anti-inflammatory, and immunomodulatory effects on multiple health conditions have been evaluated and reported. CA’s anti-tumor effect has been reported in solid tumors, but evidence regarding liquid tumors such as multiple myeloma (MM) is limited. The increasing incidence of MM globally provides a justified rationale to explore the potential of CA on human MM cells through caspase-dependent induced apoptosis. Objectives: The study explores CA’s therapeutic effect and mechanism on multiple myeloma. Materials and Methods: We performed flow cytometry at different concentrations and time points after treating human MM cell lines (MM.1R, RPMI8226, and U266) with CA to identify apoptosis and changes in mitochondrial membrane potential. A Western blot was used to assess the expression of an apoptosis-related protein in MM cell lines. Statistical Analysis Used: Student’s t-test was used to evaluate the mean difference between the experimental group and the control group. Results: CA markedly induced the apoptosis of MM cells in a dose- and time-dependent manner. After co-incubation with CA, JC-1 (a cationic lipid fluorescent dye was used as an indicator of mitochondrial transmembrane potential), flow cytometry results showed that the mitochondrial membrane potential of MM cells significantly decreased, and the Western blot showed activation and cleavage of caspase-3, which is the classical marker of the mitochondrial apoptosis pathway. The experimental group was statistically significant compared with the control group ( p < 0.01). Conclusion: Our research demonstrated that CA induced MM cell apoptosis through disturbing mitochondrial membrane integrity, followed by caspase-3 splitting, and suggested that CA might have tremendous therapeutic potential for MM treatment.