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Objective: In this report, we extended the studies to melanoma tumors to observe whether there were differences in response to sNK cells. Methods: We investigated the safety and tissue biodistribution profile of sNK cells in hu-BLT mice. This included the effect of sNK cell therapy on the peripheral blood-derived PBMCs, bone marrow, and spleen of hu-BLT mice. Results: Our investigation showed promising outcomes, as sNK cell infusions effectively inhibited melanoma tumor growth in hu-BLT mice. These potent cells not only traversed through the peripheral blood, spleen, and bone marrow but also infiltrated the tumor site, triggering in vivo differentiation of melanoma tumors. Moreover, the infusion of sNK cells increased the percentages of NK cells in the peripheral blood of hu-BLT mice, restoring cytotoxicity and IFN-\u03b3 secretion within the peripheral blood, spleen, and bone marrow of melanoma-bearing mice. Conclusions: This therapeutic approach not only reversed tumor progression but also revitalized the functionality of endogenous NK cells, potentially reversing the immunosuppressive effects induced by tumor cells in cancer patients.<\/jats:p>","DOI":"10.3390\/cancers17152430","type":"journal-article","created":{"date-parts":[[2025,7,23]],"date-time":"2025-07-23T08:02:06Z","timestamp":1753257726000},"page":"2430","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Supercharged Natural Killer (sNK) Cells Inhibit Melanoma Tumor Progression and Restore Endogenous NK Cell Function in Humanized BLT Mice"],"prefix":"10.3390","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1936-5985","authenticated-orcid":false,"given":"Kawaljit","family":"Kaur","sequence":"first","affiliation":[{"name":"Division of Oral Biology and Oral Medicine, The Jane and Jerry Weintraub Center for Reconstructive Biotechnology, UCLA School of Dentistry and Medicine, 10833 Le Conte Ave, Los Angeles, CA 90095, USA"},{"name":"The Jonsson Comprehensive Cancer Center, University of California, Los Angeles, CA 90024, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3902-7652","authenticated-orcid":false,"given":"Paytsar","family":"Topchyan","sequence":"additional","affiliation":[{"name":"Division of Oral Biology and Oral Medicine, The Jane and Jerry Weintraub Center for Reconstructive Biotechnology, UCLA School of Dentistry and Medicine, 10833 Le Conte Ave, Los Angeles, CA 90095, USA"},{"name":"The Jonsson Comprehensive Cancer Center, University of California, Los Angeles, CA 90024, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anahid","family":"Jewett","sequence":"additional","affiliation":[{"name":"Division of Oral Biology and Oral Medicine, The Jane and Jerry Weintraub Center for Reconstructive Biotechnology, UCLA School of Dentistry and Medicine, 10833 Le Conte Ave, Los Angeles, CA 90095, USA"},{"name":"The Jonsson Comprehensive Cancer Center, University of California, Los Angeles, CA 90024, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,7,23]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1007\/978-3-319-22539-5_4","article-title":"Melanoma: Clinical Presentations","volume":"167","author":"Kibbi","year":"2016","journal-title":"Cancer Treat. 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