Table 1_GPX2+ tumor cells recruit LGALS1+ B cells via CCL26-CCR3 axis to promote immunosuppression and tumor progression in hepatocellular carcinoma.xlsx

The molecular link between Hepatitis B virus (HBV) infection and hepatocellular carcinoma (HCC) progression remains elusive. Here, we identify glutathione peroxidase 2 (GPX2) as a pivotal mediator of this process. Single-cell analysis of HBV-positive HCC reveals a distinct GPX2+ CSC population characterized by high MYC and CD44 expression. We demonstrate that GPX2 preserves stemness intrinsically by mitigating ROS-mediated c-MYC nuclear-cytoplasmic distribution, while extrinsically fostering immune evasion via the CCL26-CCR3 signaling axis. specifically, GPX2-derived CCL26 recruits and educates B cells towards an immunosuppressive LGALS1+ state, which predicts adverse patient outcomes. In vivo, GPX2 overexpression accelerates tumorigenesis, whereas targeting CCR3 with ALK4290 sensitizes tumors to anti-PD-1 checkpoint blockade. These findings delineate a dual mechanism whereby GPX2 couples oxidative stress regulation to immune modulation, positioning the GPX2-B cell axis as a promising therapeutic target for HBV-driven liver cancer.

乙型肝炎病毒（HBV）感染与肝细胞癌（HCC）进展之间的分子关联至今仍不明晰。本研究证实谷胱甘肽过氧化物酶2（GPX2）是该过程的关键调控介质。对HBV阳性HCC的单细胞分析显示，存在一类独特的GPX2阳性癌症干细胞（Cancer Stem Cell, CSC）群体，其特征为高表达MYC与CD44。研究表明，GPX2可通过缓解活性氧（Reactive Oxygen Species, ROS）介导的c-MYC核质分布异常，内在地维持干细胞干性；同时通过CCL26-CCR3信号轴，外在地促进肿瘤免疫逃逸。具体而言，GPX2介导产生的CCL26可招募并诱导B细胞分化为免疫抑制性半乳糖凝集素1阳性（LGALS1+）表型，该表型与患者不良预后相关。在体实验中，GPX2过表达可加速肿瘤发生；而用ALK4290靶向CCR3，则可使肿瘤对抗PD-1免疫检查点阻断治疗敏感。本研究揭示了GPX2通过双重机制将氧化应激调控与免疫调控相耦联，从而确立了GPX2-B细胞轴作为HBV相关性肝癌的潜在治疗靶点。