免疫疗法与分子靶向治疗相结合在肝细胞癌（HCC）中表现出有希望的治疗效果，但其潜在机制尚不清楚。本研究利用基于多个HCC数据集的生物信息学算法，鉴定出磷酸甘油酸酯酶1 (PGAM1) 作为一种新的免疫代谢靶点。PGAM1在HCC中高度表达，并与不良预后和对免疫疗法反应差相关。体外和体内实验证明，靶向PGAM1抑制了HCC细胞的增长，并通过降低酶活性促进了CD8+ T细胞的浸润。在机制上，PGAM1的抑制通过诱导能量应激和ROS依赖的AKT抑制下调脂联素(LCN2)，从而促进HCC细胞的铁死亡（ferroptosis），同时也可以下调程序性死亡配体1（PD-L1）。此外，一种变构PGAM1抑制剂（KH3）在患者来源异种移植瘤（PDX）模型中表现出良好的抗肿瘤效果，并在皮下和原位HCC模型中增强了抗-PD-1免疫疗法的疗效。综上所述，研究结果表明，通过促进铁死亡和CD8+ T细胞浸润，PGAM1的抑制具有抗肿瘤作用，并且可以与抗-PD-1免疫疗法协同作用于HCC。靶向PGAM1可能是HCC治疗中一种有前景的“一石二鸟”的新策略。©2023 The Authors. Wiley-VCH GmbH出版的《Advanced Science》发表。

The combination of immunotherapy and molecular targeted therapy exhibits promising therapeutic efficacy in hepatocellular carcinoma (HCC), but the underlying mechanism is still unclear. Here, phosphoglycerate mutase 1 (PGAM1) is identified as a novel immunometabolic target by using a bioinformatic algorithm based on multiple HCC datasets. PGAM1 is highly expressed in HCC and associated with a poor prognosis and a poor response to immunotherapy. In vitro and in vivo experiments indicate that targeting PGAM1 inhibited HCC cell growth and promoted the infiltration of CD8+ T-cells due to decreased enzymatic activity. Mechanistically, inhibition of PGAM1 promotes HCC cell ferroptosis by downregulating Lipocalin (LCN2) by inducing energy stress and ROS-dependent AKT inhibition, which can also downregulate Programmed death 1-ligand 1 (PD-L1). Moreover, an allosteric PGAM1 inhibitor (KH3) exhibits good antitumor effects in patient-derived xenograft (PDX) models and enhanced the efficacy of anti-PD-1 immunotherapy in subcutaneous and orthotopic HCC models. Taken together, the findings demonstrate that PGAM1 inhibition exerts an antitumor effect by promoting ferroptosis and CD8+ T-cell infiltration and can synergize with anti-PD-1 immunotherapy in HCC. Targeting PGAM1 can be a promising new strategy of "killing two birds with one stone" for HCC treatment.© 2023 The Authors. Advanced Science published by Wiley-VCH GmbH.