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Although the involvement of natural killer (NK) cells in the antitumor effects of IMiDs has been reported, it is unclear whether IMiDs inhibit cancer cell metastasis by regulating the antitumor function of NK cells. In this study, we examined the protective effects of thalidomide against cancer metastasis by focusing on its immunomodulatory effects through NK cells. Using experimental lung metastasis models, we found that pharmacological effects of thalidomide on host cells, but not its direct anticancer tumor effects, are responsible for the inhibition of lung metastases. To exert the antimetastatic effects of thalidomide, both \u03b3\u2010interferon (IFN\u2010\u03b3) production and direct cytotoxicity of NK cells were essential, without notable contribution from T cells. In thalidomide\u2010treated mice, there was a significant increase in the terminally differentiated mature CD27<jats:sup>lo<\/jats:sup> NK cells in the peripheral tissues and NK cells in thalidomide\u2010treated mice showed significantly higher cytotoxicity and IFN\u2010\u03b3 production. The NK cell expression of T\u2010bet was upregulated by thalidomide treatment and the downregulation of glycogen synthase kinase\u20103\u03b2 expression was observed in thalidomide\u2010treated NK cells. Collectively, our study suggests that thalidomide induces the functional maturation of peripheral NK cells through alteration of T\u2010bet expression to inhibit lung metastasis of cancer cells.<\/jats:p>","DOI":"10.1111\/cas.14538","type":"journal-article","created":{"date-parts":[[2020,6,23]],"date-time":"2020-06-23T08:44:20Z","timestamp":1592901860000},"page":"2770-2778","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Antimetastatic effects of thalidomide by inducing the functional maturation of peripheral natural killer cells"],"prefix":"10.1111","volume":"111","author":[{"given":"Kiho","family":"Miyazato","sequence":"first","affiliation":[{"name":"Institute of Natural Medicine University of Toyama Toyama 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