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Tumors can evade cytotoxic lymphocytes by upregulating multiple inhibitory checkpoints. Here we identify WDR12 as a determinant of immunotherapy resistance: WDR12 expression is elevated in nonresponders, and its genetic inhibition increases intratumoral CD8+ T\u2010cell infiltration and enhances cytotoxic function. Mechanistically, WDR12, in cooperation with the chaperonin subunit CCT7, stabilizes the immune checkpoint CD276 (B7\u2010H3) on tumor cells, thereby suppressing T\u2010cell activity and promoting immune escape. To translate these findings, we identify SU14813 as a small\u2010molecule WDR12 inhibitor that binds WDR12 with high specificity, reduces CD276 stability, and relieves CD276\u2010mediated T\u2010cell suppression. In vivo, WDR12 targeting sensitizes tumors to PD\u20101 blockade, and combined SU14813 and anti\u2010PD\u20101 therapy produces superior antitumor efficacy. These results define a WDR12\u2010CCT7\u2010CD276 axis that sustains immune resistance in melanoma and nominate WDR12 inhibition with PD\u20101 blockade as a promising therapeutic strategy.<\/jats:p>","DOI":"10.1002\/advs.76255","type":"journal-article","created":{"date-parts":[[2026,6,27]],"date-time":"2026-06-27T11:20:12Z","timestamp":1782559212000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Targeting WDR12 Unleashes T\u2010Cell\u2010Mediated Antitumor Activity in Melanoma by Destabilizing CD276"],"prefix":"10.1002","volume":"13","author":[{"given":"Jie","family":"Pan","sequence":"first","affiliation":[{"name":"The Department of Dermatology Xiangya Hospital Central South University  Changsha China"},{"name":"National Engineering Research Center of Personalized Diagnostic and Therapeutic Technology  Changsha China"},{"name":"Furong Labratory  Changsha Hunan China"},{"name":"National Clinical Research Center 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