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Harnessing innate immunity is emerging as a promising therapeutic approach in cancer. We report here the design of tetraspecific molecules engaging natural killer (NK) cell-activating receptors NKp46 and CD16a, the β-chain of the interleukin-2 receptor (IL-2R), and a tumor-associated antigen (TAA). In vitro, these tetraspecific antibody-based natural killer cell engager therapeutics (ANKETs) induce a preferential activation and proliferation of NK cells, and the binding to the targeted TAA triggers NK cell cytotoxicity and cytokine and chemokine production. In vivo, tetraspecific ANKETs induce NK cell proliferation and their accumulation at the tumor bed, as well as the control of local and disseminated tumors. Treatment of non-human primates with CD20-directed tetraspecific ANKET leads to CD20 + circulating B cell depletion, with minimal systemic cytokine release and no sign of toxicity. Tetraspecific ANKETs, thus, constitute a technological platform for harnessing NK cells as next-generation cancer immunotherapies., Competing Interests: Declaration of interests Innate Pharma has filed patent applications relating to ANKETs and its use of ANKETs in the treatment of tumors (US patent no. 10,113,003, together with other patents and patent applications), as well as applications for use of ANKETs as a trademark. With the exception of E.L., N.F., S.S., J.-L.D., and R.L.G., all the authors are employees of Innate Pharma., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)