Transcriptional factor BRD4 promotes the stemness of esophageal cancer by activating the nuclear PD‐L1/RelB axis

Abstract

Esophageal cancer (EC) is a prevalent malignancy associated with therapeutic resistance and poor prognosis. This study investigates the role of programmed death‐ligand 1 (PD‐L1) in esophageal cancer stem cell (ECSC) formation. ECSCs were enriched and characterized using various assays. We found that both PD‐L1 and bromodomain‐containing protein 4 (BRD4) were upregulated in ECSCs, promoting their stemness. Inhibiting BRD4 suppressed ECSC markers expression and sphere formation. Furthermore, BRD4 inhibitors downregulated membrane and nuclear PD‐L1 levels, with knockdown of PD‐L1 inhibiting ECSC formation. PD‐L1 degraders also affected PD‐L1 and its downstream effector RelB expression. Moreover, inhibiting RelB influenced sphere formation through interleukin‐6 expression. This study reveals the critical role of the BRD4/nuclear PD‐L1/RelB axis in ECSC formation, highlighting nuclear PD‐L1 as a potential immunotherapeutic target for refractory EC.