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It promotes the typical features of epithelial to mesenchymal transition and sustains apoptosis resistance. The present study aimed to assess in vitro and in vivo the efficacy against melanoma of selective small molecules targeting FKBP51, called SAFits. Our findings reveal differing outcomes for SAFits in vitro compared to in vivo. SAFit increased the doxorubicin and dacarbazine cytotoxicity of cultured melanoma cells and was effective in impairing NF-\u03baB activity and related pro-survival genes. Moreover, SAFit affected TGF-\u03b2-signaling and reduced the capability of melanoma cells to migrate through transwell filters and invade the matrigel. Unexpectedly, SAFit was ineffective in reducing tumor growth in a syngeneic melanoma mouse model. A study of the tumor microenvironment revealed an enrichment of M2 macrophages in SAFit-treated mice. Western blot assay showed reduced levels of perforin in protein extracted from SAFit-treated tumor samples. Ex-vivo experiments showed that M1 and M2 macrophages exerted an opposite effect on the cytotoxic capacity of CD8 T cells, supporting the hypothesis that enrichment in M2 macrophages induced by SAFit could accelerate the exhaustion of CD8 lymphocytes. In conclusion, our study shows that selective FKBP51 targeting agents hinder the intrinsic pro-survival pathways of melanoma cells but simultaneously exacerbate immune suppression within the tumor microenvironment, and, therefore, they have not proven to be effective in vivo to counteract melanoma growth.<\/jats:p>","DOI":"10.1038\/s41420-025-02430-y","type":"journal-article","created":{"date-parts":[[2025,4,5]],"date-time":"2025-04-05T02:53:22Z","timestamp":1743821602000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Exploring the potential of selective FKBP51 inhibitors on melanoma: an investigation of their in vitro and in vivo effects"],"prefix":"10.1038","volume":"11","author":[{"given":"Laura","family":"Marrone","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valeria","family":"Di Giacomo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chiara","family":"Malasomma","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marialuisa Alessandra","family":"Vecchione","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Felix","family":"Hausch","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Massimiliano","family":"Cacace","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lucia","family":"D\u2019Esposito","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martina","family":"Tufano","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paolo","family":"D\u2019Arrigo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5557-7307","authenticated-orcid":false,"given":"Maria Fiammetta","family":"Romano","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9401-5814","authenticated-orcid":false,"given":"Simona","family":"Romano","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,4,3]]},"reference":[{"key":"2430_CR1","doi-asserted-by":"publisher","first-page":"4395","DOI":"10.1128\/MCB.15.8.4395","volume":"15","author":"G Baughman","year":"1995","unstructured":"Baughman G, Wiederrecht GJ, Campbell NF, Martin MM, Bourgeois S. 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For animal care, procedures and experiments were approved by the Institutional Animal Care and Use Committee (Autorization n\u00b0 253\/2020-PR). The Federico II University Ethics Committee approved research experiments on human blood (protocol n. 12\/11\/ES19) that were conducted in accordance with the ethical principles of the Declaration of Helsinki. Informed consent was obtained from all blood donor providers of PBMCs.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}}],"article-number":"138"}}