Abstract：
Evidence recently showed that pleiotropic cytokine interferon-gamma (IFN-γ) in the tumor microenvironment (TME) plays a positive role in hepatocellular carcinoma (HCC) progression through the regulation of liver cancer stem cells (LCSCs) in HCC. The present study explored the role and potential mechanism of mitochondrial programmed cell death-ligand 1 (PD-L1) and its regulation of ferroptosis in modulating the cancer stemness of LCSCs. It was shown that mimicking TME IFN-γ exposure increased the LCSCs ratio and cancer stemness phenotypes in HCC cells. IFN-γ exposure inhibited sorafenib (Sora)-induced ferroptosis by enhancing glutathione peroxidase 4 (GPX4) expression as well reactive oxygen species (ROS) and lipid peroxidation (LPO) generation in LCSCs. Furthermore, IFN-γ exposure upregulated PD-L1 expression and its mitochondrial translocation, inducing dynamin-related protein 1 (Drp1)-dependent mitochondrial fission and correlating with glycolytic metabolism reprogramming in LCSCs. The genetic intervention of PD-L1 promoted ferroptosis-dependent anti-tumor effects of Sora, reduced glycolytic metabolism reprogramming, and inhibited cancer stemness of HCC in vitro and in vivo. Our results revealed a novel mechanism that IFN-γ exposure-induced mitochondrial translocation of PD-L1 enhanced glycolytic reprogramming to mediate the GPX4-dependent ferroptosis resistance and cancer stemness in LCSCs. This study provided new insights into the role of mitochondrial PD-L1-Drp1-GPX4 signal axis in regulating IFN-γ exposure-associated cancer stemness in LCSCs and verified that PD-L1-targeted intervention in combination with Sora might achieve promising synergistic anti-HCC effects.
摘要：
最近的证据表明，肿瘤微环境（TME）中的多效性细胞因子干扰素-γ（IFN-γ）通过调节肝癌干细胞（LCSCs）在肝细胞癌（HCC）的进展中起着积极作用。本研究探讨了线粒体程序性细胞死亡配体1（PD-L1）及其对铁凋亡的调控在调节LCSCs癌干性中的作用和潜在机制。研究表明，模拟TMEIFN-γ暴露会增加HCC细胞中的LCSC比率和癌症干性表型。IFN-γ暴露通过增强谷胱甘肽过氧化物酶4（GPX4）表达以及LCSC中的活性氧（ROS）和脂质过氧化（LPO）生成来抑制索拉非尼（Sora）诱导的铁凋亡。此外，IFN-γ暴露上调PD-L1表达及其线粒体易位,在LCSCs中诱导动态蛋白相关蛋白1（Drp1）依赖性线粒体裂变并与糖酵解代谢重编程相关。PD-L1的遗传干预促进了Sora的铁凋亡依赖性抗肿瘤作用，减少糖酵解代谢重编程，并在体外和体内抑制HCC的癌症干细胞性。我们的研究结果揭示了一种新的机制，即IFN-γ暴露诱导的PD-L1线粒体易位增强糖酵解重编程，以介导LCSC中GPX4依赖性的铁凋亡抗性和癌症干性。这项研究为线粒体PD-L1-Drp1-GPX4信号轴在调节LCSCs中IFN-γ暴露相关癌症干性中的作用提供了新的见解，并验证了PD-L1靶向干预与Sora联合可能实现有希望的协同抗HCC作用。
