Targeting WDxR motif reprograms immune microenvironment and inhibits hepatocellular carcinoma progression

The WD‐repeat (WDR) family affects carcinogenesis, but its role in the immune microenvironment is poorly characterized. Although functional loss or gain of WDR6 does not markedly change in vitro proliferative and invasive capacity of HCC cells, its deficiency in hepa1‐6 cells drastically inhibits the growth and lung metastasis of orthotopically implanted tumors in immune‐competent C57BL/6J mice. Mechanistically, WDR6 targets tumor suppressor UVRAG to the CUL4A‐DDB1‐ROC1 E3 ubiquitin ligase complex through a unique WDxR motif and promotes its degradation. This upregulates chromatin accessibility at the TNFα locus by blocking autophagic degradation of p65, elevates intratumoral myeloid‐derived suppressor cell (MDSC) number, and reduces CD8(+) T cell infiltration, thereby promoting HCC progression. These immunosuppressive effects are reversed by TNFα blockade. TNFα recruits NF‐κB to activate the transcription of WDR6, establishing a WDR6‐TNFα loop. Clinically, the WDR6/UVRAG/NF‐κB pathway is hyperactivated in HCC, predicting a poor prognosis. Importantly, a WDxR‐like peptide disrupts the WDR6/UVRAG complex and enhances the efficiency of anti‐PD‐L1 against HCC with WDR6 dysregulation.