Extracellular GPX4 impairs antitumor immunity via dendritic ZP3 receptors.

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.