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The unique capacity of natural killer (NK) cells to attack cancer cells without antigen specificity makes them an optimal immunotherapeutic tool for targeting tumors. Several approaches are currently being pursued to maximize the anti-tumor properties of NK cells in the clinic, including the development of NK cell expansion protocols for adoptive transfer, the establishment of a favorable microenvironment for NK cell activity, the redirection of NK cell activity against tumor cells, and the blockage of inhibitory mechanisms that constrain NK cell function. We here summarize the recent strategies in NK cell-based immunotherapies and discuss the requirement to further optimize these approaches for enhancement of the clinical outcome of NK cell-based immunotherapy targeting tumors.<\/jats:p>","DOI":"10.3390\/cells11193147","type":"journal-article","created":{"date-parts":[[2022,10,8]],"date-time":"2022-10-08T01:52:21Z","timestamp":1665193941000},"page":"3147","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Next Generation Immuno-Oncology Strategies: Unleashing NK Cells Activity"],"prefix":"10.3390","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4849-1593","authenticated-orcid":false,"given":"Alberto","family":"Mendoza-Valderrey","sequence":"first","affiliation":[{"name":"Rosalie and Harold Rae Brown Cancer Immunotherapy Research Program, Borstein Family Melanoma Program, Translational Immunology Department, Saint John\u2019s Cancer Institute, Santa Monica, CA 90404, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5969-9181","authenticated-orcid":false,"given":"Maite","family":"Alvarez","sequence":"additional","affiliation":[{"name":"Program for Immunology and Immunotherapy, CIMA, Universidad de Navarra, 31008 Pamplona, Spain"},{"name":"Navarra Institute for Health Research (IdiSNA), 31008 Pamplona, Spain"},{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red de C\u00e1ncer (CIBERONC), 28029 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5782-333X","authenticated-orcid":false,"given":"Andrea","family":"De Maria","sequence":"additional","affiliation":[{"name":"Department of Health Sciences, University of Genoa, 16126 Genova, Italy"},{"name":"IRCCS Ospedale Policlinico San Martino, 16132 Genova, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5248-4356","authenticated-orcid":false,"given":"Kim","family":"Margolin","sequence":"additional","affiliation":[{"name":"Borstein Family Melanoma Program, Saint John\u2019s Cancer Institute, Santa Monica, CA 90404, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ignacio","family":"Melero","sequence":"additional","affiliation":[{"name":"Program for Immunology and Immunotherapy, CIMA, Universidad de Navarra, 31008 Pamplona, Spain"},{"name":"Navarra Institute for Health Research (IdiSNA), 31008 Pamplona, Spain"},{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red de C\u00e1ncer (CIBERONC), 28029 Madrid, Spain"},{"name":"Department of Immunology and Immunotherapy, Cl\u00ednica Universidad de Navarra, 31008 Pamplona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria Libera","family":"Ascierto","sequence":"additional","affiliation":[{"name":"Rosalie and Harold Rae Brown Cancer Immunotherapy Research Program, Borstein Family Melanoma Program, Translational Immunology Department, Saint John\u2019s Cancer Institute, Santa Monica, CA 90404, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,10,6]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"772","DOI":"10.1084\/jem.143.4.772","article-title":"Killer cells: A functional comparison between natural, immune T-cell and antibody-dependent in vitro systems","volume":"143","author":"Kiessling","year":"1976","journal-title":"J. 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