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

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.