PD-L1-mediated immune evasion in triple-negative breast cancer is linked to the loss of ZNF652

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. [Display omitted] •ZNF652 frequently loses heterozygosity in multiple cancers•ZNF652 is a transcription repressor of PD-L1 by recruiting the NuRD complex•Recurrent LOH and lack of E2-induced transcription cause low ZNF652 level in TNBC•Loss of ZNF652 in TNBC unleashes PD-L1-mediated immune evasion in vitro and in vivo Liu et al. identify ZNF652 as an intrinsic transcription repressor of PD-L1. ZNF652 recruits the NuRD complex for the potency of its repressor function. In triple-negative breast cancer, suppressed ZNF652 expression due to loss of heterozygosity and lack of estrogen-stimulated transcription unleashes PD-L1-mediated immune evasion.