Combining PIM‐2 and PARP1 Inhibitors Induces MICA Expression on Multiple Myeloma Cells to Activate NK Cells through NKG2D Binding

Abstract While immunogenic death in tumor cells activates specific anti‐tumor T cells, the activation of non‐specific natural killer (NK) cells through tumor interactions remains underexplored. This study investigates how inducing DNA damage in multiple myeloma (MM) cells leads to MICA overexpression, facilitating NKG2D binding on NK cells.We analyzed the relationship between PIM‐2, PARP1, and MM prognosis using public data and clinical samples. An in vitro co‐culture of MM and NK cells assessed the effects of SMI‐16a (PIM‐2 inhibitor) and ABT888 (PARP1 inhibitor) on tumor proliferation and apoptosis, focusing on DNA damage, MICA expression, and NK cell functionality. An NSG mouse model evaluated the combined effects on tumor growth and NK cell activity.The combination significantly increased DNA damage, marked by elevated pH2AX, and enhanced NK cell functional markers, including perforin and granzyme B. Increased DNA damage correlated with heightened MICA expression, activating NK cells via the NKG2D/MICA signaling pathway. PIM‐2 and PARP1 inhibitors synergistically induce MICA expression on MM cells, enhancing NK cell activation through NKG2D binding, offering a promising therapeutic strategy for MM patients.