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This study aimed to verify that tofacitinib can suppress NK cell cytotoxicity, investigate if immune cell profiles can predict responsiveness to tofacitinib, and assess the role of NK cell cytotoxicity in ALS progression.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Primary NK cells were isolated from peripheral blood samples of ALS participants and healthy controls. NK cells were then co\u2010cultured with target cancer cells, with or without tofacitinib, to assess their cytotoxic activity. Flow cytometry was used to generate immune profiles for each participant, based on 154 immune markers, to explore correlations with NK cell cytotoxicity and response to tofacitinib. The potential association between NK cell cytotoxicity and disease severity, as measured by the revised ALS Functional Rating Scale, was also assessed. All analyses were stratified by age and sex.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Tofacitinib effectively reduced the cytotoxicity of primary NK cells isolated from the blood of ALS participants (<jats:italic>n<\/jats:italic>\u2009=\u200980) and healthy controls (<jats:italic>n<\/jats:italic>\u2009=\u200971), with immune cell profiles correlating with the response to tofacitinib. However, NK cell cytotoxicity was lower in ALS participants compared to healthy controls and showed no association with ALS progression.<\/jats:p><\/jats:sec><jats:sec><jats:title>Interpretation<\/jats:title><jats:p>These findings confirm that tofacitinib suppresses NK cell cytotoxicity, and that immune profiling may help identify treatment responder groups. However, further research is needed to fully understand the role and timing of NK cell activity in ALS pathogenesis.<\/jats:p><\/jats:sec>","DOI":"10.1002\/acn3.70127","type":"journal-article","created":{"date-parts":[[2025,7,9]],"date-time":"2025-07-09T13:38:57Z","timestamp":1752068337000},"page":"2036-2044","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["In Vitro Modeling of Natural Killer Cell Cytotoxicity to Inform Personalized <scp>ALS<\/scp> Therapeutics"],"prefix":"10.1002","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3543-4007","authenticated-orcid":false,"given":"Benjamin J.","family":"Murdock","sequence":"first","affiliation":[{"name":"Department of Neurology University of Michigan  Ann Arbor Michigan USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jihyun","family":"Park","sequence":"additional","affiliation":[{"name":"Department of Neurology University of Michigan  Ann Arbor Michigan USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-7966-1322","authenticated-orcid":false,"given":"Dae\u2010Gyu","family":"Jang","sequence":"additional","affiliation":[{"name":"Department of Neurology University of Michigan  Ann Arbor Michigan USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bangyao","family":"Zhao","sequence":"additional","affiliation":[{"name":"Department of Biostatistics School of Public Health University of Michigan  Ann Arbor Michigan USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samuel J.","family":"Teener","sequence":"additional","affiliation":[{"name":"Department of Neurology University of Michigan  Ann Arbor Michigan USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ian F.","family":"Webber\u2010Davis","sequence":"additional","affiliation":[{"name":"Department of Neurology University of Michigan  Ann Arbor Michigan USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lili","family":"Zhao","sequence":"additional","affiliation":[{"name":"Department of Biostatistics School of Public Health University of Michigan  Ann Arbor Michigan USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9162-2694","authenticated-orcid":false,"given":"Eva L.","family":"Feldman","sequence":"additional","affiliation":[{"name":"Department of Neurology University of Michigan  Ann Arbor Michigan USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8780-6637","authenticated-orcid":false,"given":"Stephen A.","family":"Goutman","sequence":"additional","affiliation":[{"name":"Department of Neurology University of Michigan  Ann Arbor Michigan USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,7,8]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.3389\/fneur.2020.00279"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.nbd.2015.02.017"},{"issue":"11","key":"e_1_2_9_4_1","article-title":"NK Cells Associate With ALS in a Sex\u2010 and Age\u2010Dependent Manner","volume":"6","author":"Murdock B. 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