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Extracellular GPX4 impairs antitumor immunity via dendritic ZP3 receptors
Jiao Liu1, Xiutao Cai1, Junhao Lin1
1DAMP 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.
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.
Insights
Ferroptosis, a cell death form, releases glutathione peroxidase 4 (GPX4) that suppresses anti-tumor immunity by impairing dendritic cell (DC) function. Blocking this GPX4-ZP3 interaction enhances cancer immunosurveillance.
Area of Science:
- Immunology
- Cancer Biology
- Cell Death
Background:
- Understanding the immunogenic properties of various cell death modalities is crucial for developing effective anti-cancer therapies.
- Ferroptosis, apoptosis, cuproptosis, and necroptosis are distinct forms of cell death with varying immunological consequences.
Purpose of the Study:
- To identify regulatory mechanisms that suppress the immunogenicity of ferroptosis.
- To investigate the role of glutathione peroxidase 4 (GPX4) in ferroptosis-induced immunosuppression.
- To explore therapeutic strategies targeting ferroptosis-mediated immune evasion.
Main Methods:
- Investigated the interaction between cancer cell-released GPX4 and dendritic cell (DC) surface protein zona pellucida glycoprotein 3 (ZP3).
- Analyzed the downstream signaling cascade involving cyclic adenosine monophosphate (cAMP) and protein kinase AMP-activated (PRKA).
- Assessed the impact on DC maturation, activation, and T cell priming in preclinical cancer models.
Main Results:
- Ferroptosis, but not other cell death types, leads to GPX4 release, which binds ZP3 on DCs.
- This interaction activates cAMP-PRKA signaling, inhibiting glycolysis and impairing DC function, resulting in T cell priming defects.
- Disrupting the GPX4-ZP3 interaction restored DC metabolic activity and enhanced anti-tumor immunity.
- Blockade of this pathway improved cancer immunosurveillance and potentiated T cell responses when combined with various cancer therapies.
- High ZP3 expression correlates with poor prognosis in solid tumors, and elevated GPX4/ZP3 levels indicate resistance to therapy.
Conclusions:
- A novel regulatory axis suppresses ferroptosis immunogenicity via GPX4-ZP3 interaction, leading to DC dysfunction and immune evasion.
- Targeting this pathway represents a promising strategy to enhance anti-tumor immunity and improve cancer treatment efficacy.
- GPX4 and ZP3 serve as potential biomarkers for predicting cancer prognosis and therapeutic response.
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