In this study, we identify that the first-in-class XPO1 inhibitor selinexor potentiates NK cell activity against CLL cells alone and in combination with acalabrutinib and anti-CD20 mAb via downregulation of HLA-E and upregulation of TRAIL death receptors DR4 and DR5. Here, XPO1 is linked to B-cell chronic lymphocytic leukemia.