食管癌（EC）是一种与治疗抵抗和糟糕预后相关的常见恶性肿瘤。本研究调查了程序性死亡配体-1（PD-L1）在食管癌干细胞（ECSC）形成中的作用。利用多种试验方法富集和鉴定ECSCs。我们发现PD-L1和含溴蛋白结构域4（BRD4）在ECSC中都有上调表达，促进了其干性。抑制BRD4可以抑制ECSC标记物的表达和球形体的形成。此外，BRD4抑制剂下调了膜和核PD-L1水平，并且PD-L1敲除抑制了ECSC的形成。PD-L1降解剂也影响了PD-L1及其下游效应子RelB的表达。此外，抑制RelB通过白细胞介素-6的表达影响了球形体的形成。本研究揭示了BRD4/核PD-L1/RelB轴在ECSC形成中的关键作用，凸显了核PD-L1作为难治性食管癌的潜在免疫治疗靶点。© 2023 Wiley Periodicals LLC.

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.© 2023 Wiley Periodicals LLC.