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While cytotoxic T\u00a0cell (CTL)\u2010based immunotherapies have made remarkable progress in recent years, the therapeutic potential of natural killer\u2010(NK) cells is increasingly recognized. However, resistance mechanisms to both CTL\u2010 and NK\u2010cell\u2010mediated immunotherapies hinder effective treatment. To evaluate the exclusive role of NK\u2010cells in anti\u2010melanoma immunity, we performed\n                    <jats:italic>2D<\/jats:italic>\n                    and\n                    <jats:italic>3D<\/jats:italic>\n                    co\u2010culture\u2010based cytotoxicity assays under varying conditions. Our findings revealed a protective phenotype in melanoma cells following prolonged exposure to primary NK\u2010cells. By combining experimental data with bioinformatic analyses, we identified key genes and pathways involved in melanoma cell adaptation to NK\u2010cell\u2010mediated killing (NKmK). We found that cytokines such as IFN\u03b3 play a major role in suppressing NKmK with MHC II surface expression being a critical factor. Targeting the master regulator CIITA, which governs MHC II expression and is affected by IFN\u03b3, significantly reduced melanoma cell resistance to NKmK. This study provides potential strategies to overcome resistance to NK\u2010cell\u2010based immunotherapies and offers novel insights into melanoma immune escape mechanisms.\n                  <\/jats:p>","DOI":"10.1002\/1878-0261.70133","type":"journal-article","created":{"date-parts":[[2025,10,13]],"date-time":"2025-10-13T07:40:24Z","timestamp":1760341224000},"page":"3096-3119","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["The\n                    <scp>IFN\u03b3<\/scp>\n                    \u2010\n                    <scp>CIITA<\/scp>\n                    \u2010\n                    <scp>MHC II<\/scp>\n                    axis modulates melanoma cell susceptibility to\n                    <scp>NK<\/scp>\n                    \u2010cell\u2010mediated cytotoxicity"],"prefix":"10.1002","volume":"19","author":[{"given":"Lena C. 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