IFNα Potentiates Anti–PD-1 Efficacy by Remodeling Glucose Metabolism in the Hepatocellular Carcinoma Microenvironment
IFNα Potentiates Anti–PD-1 Efficacy by Remodeling Glucose Metabolism in the Hepatocellular Carcinoma Microenvironment
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IFNα 通过重塑肝细胞癌微环境中的葡萄糖代谢来增强抗 PD-1 功效
作者：
Bo Hu;Mincheng Yu;Xiaolu Ma;Jialei Sun;Chenglong Liu;Chunyan Wang;Suiyi Wu;Peiyao Fu;Zhen Yang;Yungang He;Yuanyuan Zhu;Cheng Huang;Xinrong Yang;Yinghong Shi;Shuangjian Qiu;Huichuan Sun;Andrew X. Zhu;Jian Zhou;Yang Xu;Di Zhu;Jia Fan
抗 PD-1 疗法在肝细胞癌 (HCC) 中的总体缓解率仍然较低。我们发现，联合使用 IFNα 和抗 PD-1 免疫疗法可增强不可切除的 HCC 患者的抗肿瘤活性。在免疫功能正常的原位和自发性 HCC 模型中，IFNα 疗法与抗 PD-1 具有协同作用，并且联合治疗导致细胞毒性 CD27+CD8+ T 细胞显着富集。从机制上讲，IFNα通过抑制HCC细胞中的FosB转录来抑制HIF1α信号传导，导致葡萄糖消耗能力降低，从而建立一个高葡萄糖微环境，通过浸润CD8+ T细胞中的mTOR-FOXM1信号传导促进T细胞共刺激分子Cd27的转录。总之，这些数据表明 IFNα 重新编程 HCC 肿瘤微环境中的葡萄糖代谢，从而释放 T 细胞的细胞毒性能力并增强 PD-1 阻断诱导的免疫反应。我们的研究结果表明，IFNα 和抗 PD-1 联合治疗是 HCC 患者有效的新型联合治疗策略。
The overall response rate for anti–PD-1 therapy remains modest in hepatocellular carcinoma (HCC). We found that a combination of IFNα and anti–PD-1–based immunotherapy resulted in enhanced antitumor activity in patients with unresectable HCC. In both immunocompetent orthotopic and spontaneous HCC models, IFNα therapy synergized with anti–PD-1 and the combination treatment led to significant enrichment of cytotoxic CD27+CD8+ T cells. Mechanistically, IFNα suppressed HIF1α signaling by inhibiting FosB transcription in HCC cells, resulting in reduced glucose consumption capacity and consequentially establishing a high-glucose microenvironment that fostered transcription of the T-cell costimulatory molecule Cd27 via mTOR–FOXM1 signaling in infiltrating CD8+ T cells. Together, these data reveal that IFNα reprograms glucose metabolism within the HCC tumor microenvironment, thereby liberating T-cell cytotoxic capacities and potentiating the PD-1 blockade–induced immune response. Our findings suggest that IFNα and anti–PD-1 cotreatment is an effective novel combination strategy for patients with HCC.