{"title":"CAR T cells engineered to secrete IFN-κ induce tumor ferroptosis via an IFNAR/STAT1/ACSL4 axis.","authors":"Yaoxin Gao, Shasha Liu, Yifan Huang, Hui Wang, Yuyu Zhao, Xuyang Cui, Yajing Peng, Feng Li, Yi Zhang","doi":"10.1158/2326-6066.CIR-24-0130","DOIUrl":null,"url":null,"abstract":"<p><p>Ferroptosis is an iron-dependent form of cell death that influences cancer immunity. Therapeutic modulation of ferroptosis is considered a potential strategy to enhance the efficacy of other cancer therapies, including immunotherapies such as chimeric antigen receptor (CAR) T cell therapy. In this study, we demonstrated that IFN-κ influenced the induction of ferroptosis. IFN-κ could enhance the sensitivity of tumor cells to ferroptosis induced by the small molecule compound erastin and the polyunsaturated fatty acid arachidonic acid. Mechanistically, IFN-κ in combination with arachidonic acid induced immunogenic tumor ferroptosis via an IFNAR/STAT1/ACSL4 axis. Moreover, CAR T cells engineered to express IFN-κ showed increased antitumor efficiency against H460 cells (antigen positive) and H322 cells (antigen negative) both in vitro and in vivo. We conclude that IFN-κ is a potential cytokine that could be harnessed to enhance the antitumor function of CAR T cells by inducing tumor ferroptosis.</p>","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":null,"pages":null},"PeriodicalIF":8.1000,"publicationDate":"2024-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Cancer immunology research","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1158/2326-6066.CIR-24-0130","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"IMMUNOLOGY","Score":null,"Total":0}
引用次数: 0
Abstract
Ferroptosis is an iron-dependent form of cell death that influences cancer immunity. Therapeutic modulation of ferroptosis is considered a potential strategy to enhance the efficacy of other cancer therapies, including immunotherapies such as chimeric antigen receptor (CAR) T cell therapy. In this study, we demonstrated that IFN-κ influenced the induction of ferroptosis. IFN-κ could enhance the sensitivity of tumor cells to ferroptosis induced by the small molecule compound erastin and the polyunsaturated fatty acid arachidonic acid. Mechanistically, IFN-κ in combination with arachidonic acid induced immunogenic tumor ferroptosis via an IFNAR/STAT1/ACSL4 axis. Moreover, CAR T cells engineered to express IFN-κ showed increased antitumor efficiency against H460 cells (antigen positive) and H322 cells (antigen negative) both in vitro and in vivo. We conclude that IFN-κ is a potential cytokine that could be harnessed to enhance the antitumor function of CAR T cells by inducing tumor ferroptosis.
期刊介绍:
Cancer Immunology Research publishes exceptional original articles showcasing significant breakthroughs across the spectrum of cancer immunology. From fundamental inquiries into host-tumor interactions to developmental therapeutics, early translational studies, and comprehensive analyses of late-stage clinical trials, the journal provides a comprehensive view of the discipline. In addition to original research, the journal features reviews and opinion pieces of broad significance, fostering cross-disciplinary collaboration within the cancer research community. Serving as a premier resource for immunology knowledge in cancer research, the journal drives deeper insights into the host-tumor relationship, potent cancer treatments, and enhanced clinical outcomes.
Key areas of interest include endogenous antitumor immunity, tumor-promoting inflammation, cancer antigens, vaccines, antibodies, cellular therapy, cytokines, immune regulation, immune suppression, immunomodulatory effects of cancer treatment, emerging technologies, and insightful clinical investigations with immunological implications.