WD重复蛋白(WDR)家族影响癌生过程，但其在免疫微环境中的作用尚不完全了解。尽管WDR6的功能丧失或获得不会显著改变HCC细胞在体外的增殖和侵袭能力，但其在hepa1-6细胞中的缺陷会严重抑制在免疫竞争性C57BL/6J小鼠中同位移植肿瘤的生长和肺转移。WDR6通过独特的WDxR模式将肿瘤抑制因子UVRAG定位到CUL4A-DDB1-ROC1 E3泛素连接酶复合物中并促进其降解。这会通过阻止p65的自噬降解而提高TNFα位点的染色质可及性，提高肿瘤内髓系衍生抑制性细胞(MDSC)数量，并降低CD8+ T细胞浸润，从而促进HCC进展。这些免疫抑制效应可通过TNFα阻滞得到逆转。TNFα招募NF-κB激活WDR6转录，从而建立WDR6-TNFα环。临床上，WDR6/UVRAG/NF-κB通路在HCC中超活化，预示着不良预后。重要的是，WDxR类肽体破坏了WDR6/UVRAG复合物并增强了反对WDR6失调的抗PD-L1的效率。©2023年作者。根据CC BY 4.0协议发布。

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.© 2023 The Authors. Published under the terms of the CC BY 4.0 license.