The potential efficacy of NK cell-based immunotherapy in melanoma patients will rely on melanoma phenotype (expression of ligands for activating receptors and low expression of MHC class I molecules for the use of autologous NK cells), NK cell status (no exhausted, no senescent), NK cell phenotype (high level of NKG2D, NCRs and DNAM-1; CD16 expression for ADCC), microenvironment (proinflammatory versus inhibitory), NK cell crosstalk with other cell types (e.g., DCs, macrophages, MDSCs). The gene discussed is CD226; the disease is melanoma.