程序性死亡配体 1 (PD-L1) 表达的内在调节仍不清楚。在这里，我们报告锌指蛋白 652 (ZNF652) 是 PD-L1 的有效转录抑制因子。 ZNF652 在各种癌症中经常出现杂合性丢失 (LOH)。较高的 LOH 率和雌激素诱导转录的缺乏导致三阴性乳腺癌 (TNBC) 中 ZNF652 的表达受到抑制。从机制上讲，ZNF652 与 NuRD 转录共阻遏物复合物物理相关，可抑制包括 PD-L1 在内的一组基因。 ZNF652 的过表达会抑制 PD-L1 转录，而 ZNF652 的缺失则会上调 PD-L1。 TNBC 中 ZNF652 的缺失会在体外和体内释放 PD-L1 介导的免疫逃避。值得注意的是，ZNF652 表达在乳腺癌进展过程中逐渐丧失，低 ZNF652 水平与 PD-L1 表达升高、浸润的 CD8 T 细胞较少以及 TNBC 预后不良相关。我们的研究提供了对 PD-L1 调控的见解，并支持将 ZNF652 作为乳腺癌免疫治疗的潜在生物标志物和药物靶标。版权所有 © 2023 作者。由爱思唯尔公司出版。保留所有权利。

The intrinsic regulation of programmed death ligand-1 (PD-L1) expression remains unclear. Here, we report that zinc-finger protein 652 (ZNF652) is a potent transcription repressor of PD-L1. ZNF652 frequently experiences loss of heterozygosity (LOH) in various cancers. Higher LOH rate and lack of estrogen-inducible transcription lead to suppressed expression of ZNF652 in triple-negative breast cancer (TNBC). Mechanistically, ZNF652 is physically associated with the NuRD transcription co-repressor complex to repress a cohort of genes, including PD-L1. Overexpression of ZNF652 inhibits PD-L1 transcription, whereas depletion of ZNF652 upregulates PD-L1. Loss of ZNF652 in TNBC unleashes PD-L1-mediated immune evasion both in vitro and in vivo. Significantly, ZNF652 expression is progressively lost during breast cancer progression, and a low ZNF652 level is correlated with elevated PD-L1 expression, less infiltrated CD8+ T cells, and poor prognosis in TNBC. Our study provides insights into PD-L1 regulation and supports the pursuit of ZNF652 as a potential biomarker and drug target for breast cancer immunotherapy.Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.