Extracellular GPX4 impairs antitumor immunity via dendritic ZP3 receptors

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

doi:10.1016/j.cell.2025.12.002

Extracellular GPX4 impairs antitumor immunity via dendritic ZP3 receptors

Cell. 2026 Jan 5:S0092-8674(25)01378-9. doi: 10.1016/j.cell.2025.12.002. Online ahead of print.

Authors

Jiao Liu¹, Xiutao Cai², Junhao Lin², Zhenhui Zhang², Qile Zhou², Xiao Zhang³, Lifang Ma⁴, Yayou Miao³, Ruoxi Zhang⁵, Chunhua Yu⁵, Yingyi Yang⁵, Yangchun Xie⁶, Rui Kang⁵, Daniel J Klionsky⁷, Peng Liu⁸, Guido Kroemer⁹, Daolin Tang¹⁰, Jiayi Wang¹¹

Affiliations

¹ DAMP Laboratory, Department of Critical Care Medicine, State Key Laboratory of Respiratory Disease, Guangdong Provincial Key Laboratory of Protein Modification and Disease, Guangdong Key Laboratory of Multi-Organ Injury Prevention, The Third Affiliated Hospital, Guangzhou Medical University, Guangzhou, Guangdong 510150, China. Electronic address: 2018683073@gzhmu.edu.cn.
² DAMP Laboratory, Department of Critical Care Medicine, State Key Laboratory of Respiratory Disease, Guangdong Provincial Key Laboratory of Protein Modification and Disease, Guangdong Key Laboratory of Multi-Organ Injury Prevention, The Third Affiliated Hospital, Guangzhou Medical University, Guangzhou, Guangdong 510150, China.
³ Shanghai Institute of Thoracic Oncology, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200030, China.
⁴ Department of Clinical Laboratory, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200030, China.
⁵ Center for DAMP Biology, Department of Surgery, UT Southwestern Medical Center, Dallas, TX 75390, USA.
⁶ Department of Oncology, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410008, China.
⁷ Life Sciences Institute and Department of Molecular, Cellular and Developmental Biology, University of Michigan, Ann Arbor, MI 48109, USA.
⁸ Centre de Recherche des Cordeliers, Equipe labellisée par la Ligue contre le cancer, Université de Paris Cité, Sorbonne Université, INSERM U1138, Institut Universitaire de France, Paris, France; Metabolomics and Cell Biology Platforms, Gustave Roussy Cancer Campus, 94800 Villejuif, France.
⁹ Centre de Recherche des Cordeliers, Equipe labellisée par la Ligue contre le cancer, Université de Paris Cité, Sorbonne Université, INSERM U1138, Institut Universitaire de France, Paris, France; Metabolomics and Cell Biology Platforms, Gustave Roussy Cancer Campus, 94800 Villejuif, France; Institut du Cancer Paris CARPEM, Department of Biology, Pôle de Biologie, Hôpital Européen Georges Pompidou, AP-HP, 75015 Paris, France. Electronic address: kroemer@orange.fr.
¹⁰ Center for DAMP Biology, Department of Surgery, UT Southwestern Medical Center, Dallas, TX 75390, USA. Electronic address: daolin.tang@utsouthwestern.edu.
¹¹ Shanghai Institute of Thoracic Oncology, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200030, China; Department of Clinical Laboratory, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200030, China; Medical Science Laboratory, College of Health Science and Technology, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China. Electronic address: jiayi.wang@sjtu.edu.cn.

PMID: 41494530
DOI: 10.1016/j.cell.2025.12.002

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.

Keywords: cancer therapy; cell death; immunogenicity; oxidative stress; zona pellucida family.