Solid tumors are refractory to cellular immunotherapies in part because they contain suppressive immune effectors such as myeloidderived suppressor cells (MDSCs) that inhibit cytotoxic lymphocytes. Strategies to reverse the suppressive tumor microenvironment (TME) should also attract and activate immune effectors with antitumor activity. To address this need, we developed genemodified natural killer (NK) cells bearing a chimeric receptor in which the activating receptor NKG2D is fused to the cytotoxic z-chain of the T-cell receptor (NKG2D.z). NKG2D.z-NK cells target MDSCs, which overexpress NKG2D ligands within the TME. We examined the ability of NKG2D.z-NK cells to eliminate MDSCs in a xenograft TME model and improve the antitumor function of tumordirected chimeric antigen receptor (CAR)-modified T cells. We show that NKG2D.z-NK cells are cytotoxic against MDSCs, but spare NKG2D ligandexpressing normal tissues. NKG2D.z-NK cells, but not unmodified NK cells, secrete proinflammatory cytokines and chemokines in response to MDSCs at the tumor site and improve infiltration and antitumor activity of subsequently infused CAR-T cells, even in tumors for which an immunosuppressive TME is an impediment to treatment. Unlike endogenous NKG2D, NKG2D.z is not susceptible to TME-mediated downmodulation and thus maintains its function even within suppressive microenvironments. As clinical confirmation, NKG2D.z-NK cells generated from patients with neuroblastoma killed autologous intra-tumoral MDSCs capable of suppressing CAR-T function. A combination therapy for solid tumors that includes both NKG2D.z-NK cells and CART cells may improve responses over therapies based on CART cells alone.