{
  "abstract": "Background Ferroptosis plays a critical role in immune regulation and tumor microenvironment remodeling. However, its therapeutic potential in enhancing immune checkpoint inhibitor (ICI) efficacy remains incompletely understood and warrants further investigation.Methods To investigate the potential of ferroptosis in improving ICI response, we constructed a machine learning-based predictive model using ferroptosis-related genes and analyzed large-scale single-cell RNA sequencing datasets. Mechanistic studies were performed to examine the role of interferon (IFN)-γ signaling in ferroptosis sensitization, including functional validation in vitro and in vivo. Lipidomic, transcriptomic, chromatin Immunoprecipitation sequencing (ChIP-seq) and Cleavage Under Targets and Tagmentation analyses were employed to dissect downstream pathways, focusing on IRF1 and AGPAT3.Results Our model successfully predicted ICI response based on ferroptosis-related gene signatures, identifying IFN-γ as a key enhancer of ferroptosis sensitivity in tumor cells. IFN-γ treatment induced activation of the transcription factor IRF1, which in turn upregulated AGPAT3 expression, driving lipid remodeling and accumulation of polyunsaturated ether phospholipids. This lipid remodeling significantly increased tumor cell susceptibility to ferroptosis and enhanced ICI efficacy. Loss of AGPAT3 impaired IFN-γ-mediated tumor elimination both in vitro and in vivo. Clinically, higher AGPAT3 expression in tumors was associated with increased immune activation and improved overall survival in ICI-treated patients.Conclusion The IFN-γ-IRF1-AGPAT3 axis represents an important antitumor mechanism that promotes ferroptosis. Targeting this pathway in combination with our ferroptosis-driver model prediction may improve ICI efficacy and patient outcomes.",
  "authors": [
    {
      "affiliations": [
        "Department of Medical Oncology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China"
      ],
      "name": "Chuan Liu"
    },
    {
      "affiliations": [
        "Department of Interventional Radiology, Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Zhejiang Key Laboratory of Imaging and Interventional Medicine, Hangzhou, Zhejiang, China"
      ],
      "name": "Chuan Hu"
    },
    {
      "affiliations": [
        "State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Zhejiang University, Hangzhou, China"
      ],
      "name": "Jinlin Cheng"
    },
    {
      "affiliations": [
        "CAS Center for Excellence in Molecular Plant Sciences, Shanghai, China"
      ],
      "name": "Duanfeng Xin"
    },
    {
      "affiliations": [
        "Department of Medical Oncology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China"
      ],
      "name": "Sujie Jin"
    },
    {
      "affiliations": [
        "Changzhou Third People's Hospital, Changzhou Medical Center, Nanjing Medical University, Changzhou, China"
      ],
      "name": "Weihong Tian"
    },
    {
      "affiliations": [
        "Zhejiang Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, Zhejiang Key Laboratory of Frontier Medical Research on Cancer Metabolism, and Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China",
        "Institute of Fundamental and Transdisciplinary Research, Cancer Center, Zhejiang University, Hangzhou, Zhejiang, China"
      ],
      "name": "Shan Li"
    },
    {
      "affiliations": [
        "Department of Medical Oncology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China"
      ],
      "name": "Yuzhi Jin"
    },
    {
      "affiliations": [
        "Department of Medical Oncology, Hangzhou Cancer Hospital, Hangzhou, Zhejiang, China"
      ],
      "name": "Yu Liu"
    },
    {
      "affiliations": [
        "Department of Hepato-Pancreato-Biliary & Gastric Medical Oncology, Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, Zhejiang, China"
      ],
      "name": "Wei Wu"
    },
    {
      "affiliations": [
        "Department of Medical Oncology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China"
      ],
      "name": "Shuqiang Hao"
    },
    {
      "affiliations": [
        "Department of Medical Oncology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China"
      ],
      "name": "Hui Ren"
    },
    {
      "affiliations": [
        "Department of Medical Oncology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China",
        "National Key Laboratory of Advanced Drug Delivery and Release Systems, Zhejiang University, Hangzhou, Zhejiang, China"
      ],
      "name": "Xiaomeng Dai"
    },
    {
      "affiliations": [
        "Department of Medical Oncology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China"
      ],
      "name": "Lulu Liu"
    },
    {
      "affiliations": [
        "Department of Medical Oncology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China"
      ],
      "name": "Jian Ruan"
    },
    {
      "affiliations": [
        "Department of Medical Oncology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China",
        "National Key Laboratory of Advanced Drug Delivery and Release Systems, Zhejiang University, Hangzhou, Zhejiang, China"
      ],
      "name": "Weijia Fang"
    },
    {
      "affiliations": [
        "Department of Medical Oncology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China",
        "National Key Laboratory of Advanced Drug Delivery and Release Systems, Zhejiang University, Hangzhou, Zhejiang, China"
      ],
      "name": "Xuanwen Bao"
    },
    {
      "affiliations": [
        "Department of Genetics, Yale School of Medicine, New Haven, Connecticut, USA"
      ],
      "name": "Shan Xin"
    },
    {
      "affiliations": [
        "Department of Medical Oncology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China",
        "National Key Laboratory of Advanced Drug Delivery and Release Systems, Zhejiang University, Hangzhou, Zhejiang, China"
      ],
      "name": "Peng Zhao"
    }
  ],
  "title": "AGPAT3 reshapes tumor cell vulnerability to IFNγ-mediated ferroptosis and enhances immunotherapy efficacy through lipid remodeling",
  "uid": "339a35e8-761d-5c18-b0da-56457784bd21"
}