Targeting WDR12 Unleashes T‐Cell‐Mediated Antitumor Activity in Melanoma by Destabilizing CD276

ABSTRACT Melanoma is the deadliest skin cancer, and despite the success of immune checkpoint blockade, a substantial fraction of patients fail to respond. 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‐cell infiltration and enhances cytotoxic function. Mechanistically, WDR12, in cooperation with the chaperonin subunit CCT7, stabilizes the immune checkpoint CD276 (B7‐H3) on tumor cells, thereby suppressing T‐cell activity and promoting immune escape. To translate these findings, we identify SU14813 as a small‐molecule WDR12 inhibitor that binds WDR12 with high specificity, reduces CD276 stability, and relieves CD276‐mediated T‐cell suppression. In vivo, WDR12 targeting sensitizes tumors to PD‐1 blockade, and combined SU14813 and anti‐PD‐1 therapy produces superior antitumor efficacy. These results define a WDR12‐CCT7‐CD276 axis that sustains immune resistance in melanoma and nominate WDR12 inhibition with PD‐1 blockade as a promising therapeutic strategy.