A variety of immune cell therapies proposed for use in the treatment of cancer, including both autologous cells (Lymphokine Activated Killer, Cytokine Induced Killer) or cell lines (TALL-104, NK-92), rely on recognition of NKG2D ligands on malignant cells for targeting. These ligands, such as MICA and MICB in humans are stress response ligands and are commonly, but not ubiquitously expressed within tumors. Several tumor escape mechanisms have been reported, including ligand downregulation and internalization, or proteolytic cleavage and shedding of their exposed portions (releasing soluble MICA and MICB; sMICA, sMICB). Therefore, an ability to prescreen patients for the level of tumor cell surface expression and shedding of these ligands would prevent needless treatment of patients that are unable to respond, whereas targeted pretreatment of patients to increase surface expression and/or block shedding would enhance the subsequent effectiveness of these therapies. Here, we report that serum tests of sMICA and sMICB in conjunction with tumor measurements might be used to determine rates of shedding from a tumor and that treatment with a selected combination of histone deacetylase inhibitors (to upregulate cell surface MICA/B in some tumors), and metalloproteinase inhibitors (to block MICA/B shedding in others) can be incorporated to regulate cell surface MICA/B levels before immune cell therapy, significantly enhancing their effectiveness (either used alone or as carrier vehicles for oncolytic viruses). Ultimately prescreening patients undergoing such immune cell therapies might be used to personalize cancer treatment regimens based on the NKG2D-ligand status of the tumor.