ABSTRACT: The landscape of cancer treatment has been transformed by immune checkpoint inhibitors; however, the failure to benefit a large number of patients with cancer has underlined the need to identify promising targets for more effective interventions. In this study, we leverage 23andMe, Inc.’s large-scale human germline genetic and health database to uncover the previously unknown role of UL16-binding protein 6 (ULBP6), a high-affinity NK group 2D (NKG2D) ligand, in cancer and its promise as an immuno-oncology therapeutic target. We confirm ULBP6 expression in human tumors and demonstrate that soluble ULBP6 shed from tumors circumvents NKG2D activation provided by membrane-anchored NKG2D ligands to inhibit immune cell activation and tumor cell killing. Based on these findings, we developed 23ME-01473, a humanized Fc effector–enhanced antibody that binds to ULBP6 and its closely related family members, ULBP2 and ULBP5. 23ME-01473 effectively blocks soluble ULBP6-mediated immunosuppression to restore the NKG2D axis on NK and T cells to elicit tumor growth control. Moreover, the Fc effector–enhanced design of 23ME-01473 increases its binding affinity to fragment crystallizable gamma receptor IIIa, which, together with 23ME-01473’s binding to membrane-anchored ULBP6/2/5 on cancer cells, allows for augmented antibody-dependent cellular cytotoxicity induction, providing a second activation node for NK cells. Our studies demonstrate the therapeutic potential of an Fc effector–enhanced anti-ULBP6/2/5 antibody to reinvigorate NK cell and T-cell activation and cytotoxicity for the treatment of cancer. SIGNIFICANCE: This study emphasizes the utility of population-based genome-wide assessments for discovering naturally occurring genetic variants associated with lifetime risks for cancer or immune diseases as novel drug targets. We identify ULBP6 as a potential keystone member of the NKG2D pathway, which is important for antitumor immunity. Targeting ULBP6 may hold therapeutic promise for patients with cancer.