广州医科大学王家骥团队近日取得一项新成果。经过不懈努力，他们的论文发现了细胞外GPX4通过树突状ZP3受体损害抗肿瘤免疫。相关论文于2026年1月5日发表在《细胞》杂志上。
课题组确定了抑制铁死亡免疫原性的调控轴。在脱铁症（而不是凋亡、铜中毒或坏死）期间，癌细胞释放谷胱甘肽过氧化物酶4 (GPX4)，该酶与树突状细胞（DCs）表面的透明带糖蛋白3（ZP3）结合，激活3',5' -环腺苷单磷酸(cAMP)-蛋白激酶AMP活化（PRKA）信号级联，抑制糖酵解，损害DCs的成熟和激活，导致T细胞启动缺陷。破坏GPX4和ZP3之间的相互作用可恢复DC代谢活性并增强抗肿瘤免疫。
在临床前模型中，当与化疗、免疫化疗或放疗联合使用时，阻断该途径可改善癌症免疫监视并增强细胞毒性T细胞反应。临床上，在多种实体肿瘤类型中，ZP3的高表达预示着不良预后，而DCs中循环GPX4水平和ZP3表达的升高与一线治疗的耐药相关。这些发现揭示了一种限制肿瘤免疫的免疫抑制危险信号。
研究人员表示，了解不同形式细胞死亡的免疫原性是合理的抗肿瘤治疗发展的关键。
附：英文原文
Title: Extracellular GPX4 impairs antitumor immunity via dendritic ZP3 receptors
Author: Jiao Liu, Xiutao Cai, Junhao Lin, Zhenhui Zhang, Qile Zhou, Xiao Zhang, Lifang Ma, Yayou Miao, Ruoxi Zhang, Chunhua Yu, Yingyi Yang, Yangchun Xie, Rui Kang, Daniel J. Klionsky, Peng Liu, Guido Kroemer, Daolin Tang, Jiayi Wang
Issue&Volume: 2026-01-05
Abstract: Understanding the immunogenic properties of different forms of cell death is critical for rationalized antineoplastic therapeutic development. Here, we identify a regulatory axis that suppresses the immunogenicity of ferroptosis. During ferroptosis, but not apoptosis, cuproptosis, or necroptosis, cancer cells release glutathione peroxidase 4 (GPX4), which binds to zona pellucida glycoprotein 3 (ZP3) on the surface of dendritic cells (DCs), activates the 3′,5′-cyclic adenosine monophosphate (cAMP)-protein kinase AMP-activated (PRKA) signaling cascade, inhibits glycolysis, and impairs maturation and activation of DCs, leading to a T cell priming defect. Disrupting the interaction between GPX4 and ZP3 restores DC metabolic activity and enhances antitumor immunity. In preclinical models, blockade of this pathway improves cancer immunosurveillance and potentiates cytotoxic T cell responses when combined with chemotherapy, immunochemotherapy, or radiotherapy. Clinically, high ZP3 expression predicts poor prognosis across multiple solid tumor types, while increased circulating GPX4 levels and ZP3 expression in DCs correlate with resistance to first-line therapies. These findings reveal an immunosuppressive danger signal that limits tumor immunity.
DOI: 10.1016/j.cell.2025.12.002
Source: https://www.cell.com/cell/abstract/S0092-8674(25)01378-9