Antibody-dependent cellular cytotoxicity (ADCC) is a key effector mechanism of natural killer (NK) cells mediated by therapeutic monoclonal antibodies (mAbs). This process is facilitated by the Fc receptor CD16a on human NK cells. CD16a appears to be the only activating receptor on NK cells cleaved by the metalloprotease ADAM17 upon stimulation. We previously demonstrated that a point mutation of CD16a prevents this activation-induced surface cleavage. This non-cleavable CD16a variant is now further modified to include the high-affinity variant of CD16a (hnCD16) and engineered into human induced pluripotent stem cells to create a renewable source for the derivation of hiPSC-derived NK cells (hnCD16-iNK cells). Compared to unmodified iNK and peripheral blood-derived NK (PB-NK) cells, hnCD16-iNK cells proved to be highly resistant to activation-induced cleavage of CD16a. We found that hnCD16-iNK cells were functionally mature and exhibited enhanced ADCC against multiple tumor targets. In vivo xenograft studies using a human B cell lymphoma demonstrated that treatment with hnCD16-iNK cells and anti-CD20 mAb led to significantly improved regression of B cell lymphoma compared to treatment utilizing anti-CD20 mAb with either PB-NK cells or unmodified iNK cells. hnCD16-iNK cells combined with anti-Her2 mAb also mediated improved survival in an ovarian cancer xenograft model. Together, these findings show that hnCD16-iNK cells combined with mAbs are highly effective against both hematologic malignancies and solid tumors that are typically resistant to NK cell-mediated killing, demonstrating the feasibility to produce a standardized off-the-shelf engineered NK cell therapy with improved ADCC properties to treat otherwise refractory malignancies.