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      Ferroptosis in cancer and cancer immunotherapy

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          Abstract

          The hallmark of tumorigenesis is the successful circumvention of cell death regulation for achieving unlimited replication and immortality. Ferroptosis is a newly identified type of cell death dependent on lipid peroxidation which differs from classical programmed cell death in terms of morphology, physiology and biochemistry. The broad spectrum of injury and tumor tolerance are the main reasons for radiotherapy and chemotherapy failure. The effective rate of tumor immunotherapy as a new treatment method is less than 30%. Ferroptosis can be seen in radiotherapy, chemotherapy, and tumor immunotherapy; therefore, ferroptosis activation may be a potential strategy to overcome the drug resistance mechanism of traditional cancer treatments. In this review, the characteristics and causes of cell death by lipid peroxidation in ferroptosis are briefly described. In addition, the three metabolic regulations of ferroptosis and its crosstalk with classical signaling pathways are summarized. Collectively, these findings suggest the vital role of ferroptosis in immunotherapy based on the interaction of ferroptosis with tumor immunotherapy, chemotherapy and radiotherapy, thus, indicating the remarkable potential of ferroptosis in cancer treatment.

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          Most cited references229

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          Ferroptosis: an iron-dependent form of nonapoptotic cell death.

          Nonapoptotic forms of cell death may facilitate the selective elimination of some tumor cells or be activated in specific pathological states. The oncogenic RAS-selective lethal small molecule erastin triggers a unique iron-dependent form of nonapoptotic cell death that we term ferroptosis. Ferroptosis is dependent upon intracellular iron, but not other metals, and is morphologically, biochemically, and genetically distinct from apoptosis, necrosis, and autophagy. We identify the small molecule ferrostatin-1 as a potent inhibitor of ferroptosis in cancer cells and glutamate-induced cell death in organotypic rat brain slices, suggesting similarities between these two processes. Indeed, erastin, like glutamate, inhibits cystine uptake by the cystine/glutamate antiporter (system x(c)(-)), creating a void in the antioxidant defenses of the cell and ultimately leading to iron-dependent, oxidative death. Thus, activation of ferroptosis results in the nonapoptotic destruction of certain cancer cells, whereas inhibition of this process may protect organisms from neurodegeneration. Copyright © 2012 Elsevier Inc. All rights reserved.
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            Regulation of ferroptotic cancer cell death by GPX4.

            Ferroptosis is a form of nonapoptotic cell death for which key regulators remain unknown. We sought a common mediator for the lethality of 12 ferroptosis-inducing small molecules. We used targeted metabolomic profiling to discover that depletion of glutathione causes inactivation of glutathione peroxidases (GPXs) in response to one class of compounds and a chemoproteomics strategy to discover that GPX4 is directly inhibited by a second class of compounds. GPX4 overexpression and knockdown modulated the lethality of 12 ferroptosis inducers, but not of 11 compounds with other lethal mechanisms. In addition, two representative ferroptosis inducers prevented tumor growth in xenograft mouse tumor models. Sensitivity profiling in 177 cancer cell lines revealed that diffuse large B cell lymphomas and renal cell carcinomas are particularly susceptible to GPX4-regulated ferroptosis. Thus, GPX4 is an essential regulator of ferroptotic cancer cell death. Copyright © 2014 Elsevier Inc. All rights reserved.
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              Signatures of T cell dysfunction and exclusion predict cancer immunotherapy response

              Cancer treatment by immune checkpoint blockade (ICB) can bring long-lasting clinical benefits, but only a fraction of patients respond to treatment. To predict ICB response, we developed TIDE, a computational method to model two primary mechanisms of tumor immune evasion: the induction of T cell dysfunction in tumors with high infiltration of cytotoxic T lymphocytes (CTL) and the prevention of T cell infiltration in tumors with low CTL level. We identified signatures of T cell dysfunction from large tumor cohorts by testing how the expression of each gene in tumors interacts with the CTL infiltration level to influence patient survival. We also modeled factors that exclude T cell infiltration into tumors using expression signatures from immunosuppressive cells. Using this framework and pre-treatment RNA-Seq or NanoString tumor expression profiles, TIDE predicted the outcome of melanoma patients treated with first-line anti-PD1 or anti-CTLA4 more accurately than other biomarkers such as PD-L1 level and mutation load. TIDE also revealed new candidate ICB resistance regulators, such as SERPINB9 , demonstrating utility for immunotherapy research.
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                Author and article information

                Contributors
                zhangchong@zucc.edu.cn
                zhoufangfang@suda.edu.cn
                zjdxcj@126.com
                zhanglong.2003@tsinghua.org.cn
                Journal
                Cancer Commun (Lond)
                Cancer Commun (Lond)
                10.1002/(ISSN)2523-3548
                CAC2
                Cancer Communications
                John Wiley and Sons Inc. (Hoboken )
                2523-3548
                08 February 2022
                February 2022
                : 42
                : 2 ( doiID: 10.1002/cac2.v42.2 )
                : 88-116
                Affiliations
                [ 1 ] Epartment of urology surgery Zhejiang hospital Zhejiang University School of Medicine Hangzhou China
                [ 2 ] School of Medicine Zhejiang University City College Hangzhou Zhejiang 310015 China
                [ 3 ] School of MOE Key Laboratory of Biosystems Homeostasis & Protection and Innovation Center for Cell Signaling Network Life Sciences Institute Zhejiang University Hangzhou Zhejiang 310058 China
                [ 4 ] Institutes of Biology and Medical Science Soochow University Suzhou 215123 P. R. China
                [ 5 ] Department of Orthopaedic Surgery the Third Affiliated Hospital of Wenzhou Medical University Rui'an Jiangsu 325000 P. R. China
                Author notes
                [*] [* ] Correspondence

                Long Zhang, School of MOE Key Laboratory of Biosystems Homeostasis & Protection and Innovation Center for Cell Signaling Network, Life Sciences Institute, Zhejiang University, Hangzhou, Zhejiang, 310058, P. R. China.

                E‐mail: zhanglong.2003@ 123456tsinghua.org.cn

                Jun Chen, Department of urology surgery, Zhejiang hospital, Zhejiang University School of Medicine, Hangzhou, China.

                E‐mail: zjdxcj@ 123456126.com

                Fangfang Zhou, Institutes of Biology and Medical Science, Soochow University, Suzhou, Jiangsu, 215123, P. R. China.

                E‐mail: zhoufangfang@ 123456suda.edu.cn

                Chong Zhang, School of Medicine, Zhejiang University City College, Hangzhou, Zhejiang, 310015, P. R. China.

                E‐mail: zhangchong@ 123456zucc.edu.cn

                [†]

                These authors contributed equally to this work.

                Author information
                https://orcid.org/0000-0002-8113-5585
                https://orcid.org/0000-0001-8139-0474
                Article
                CAC212250
                10.1002/cac2.12250
                8822596
                35133083
                15583445-ef0d-4676-87e9-b092221b5739
                © 2022 The Authors. Cancer Communications published by John Wiley & Sons Australia, Ltd. on behalf of Sun Yat‐sen University Cancer Center

                This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.

                History
                : 16 October 2021
                : 12 August 2021
                : 30 December 2021
                Page count
                Figures: 5, Tables: 4, Pages: 29, Words: 18026
                Categories
                Review
                Reviews
                Custom metadata
                2.0
                February 2022
                Converter:WILEY_ML3GV2_TO_JATSPMC version:6.1.1 mode:remove_FC converted:08.02.2022

                cancer,ferroptosis,immunotherapy
                cancer, ferroptosis, immunotherapy

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