Cancer cells avoid ferroptosis induced by immune cells via fatty acid binding proteins
Abstract Background Cancer creates an immunosuppressive environment that hampers immune responses, allowing tumors to grow and resist therapy. One way the immune system fights back is by inducing ferroptosis, a type of cell death, in tumor cells through CD8 + T cells. This involves lipid peroxidatio...
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2025-02-01
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| Online Access: | https://doi.org/10.1186/s12943-024-02198-2 |
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| author | Maria Angelica Freitas-Cortez Fatemeh Masrorpour Hong Jiang Iqbal Mahmud Yue Lu Ailing Huang Lisa K. Duong Qi Wang Tiffany A. Voss Claudia S. Kettlun Leyton Bo Wei Wai-Kin Chan Kevin Lin Jie Zhang Efrosini Tsouko Shonik Ganjoo Hampartsoum B. Barsoumian Thomas S. Riad Yun Hu Carola Leuschner Nahum Puebla-Osorio Jing Wang Jian Hu Michael A. Davies Vinay K. Puduvalli Cyrielle Billon Thomas P. Burris Philip L. Lorenzi Boyi Gan James W. Welsh |
| author_facet | Maria Angelica Freitas-Cortez Fatemeh Masrorpour Hong Jiang Iqbal Mahmud Yue Lu Ailing Huang Lisa K. Duong Qi Wang Tiffany A. Voss Claudia S. Kettlun Leyton Bo Wei Wai-Kin Chan Kevin Lin Jie Zhang Efrosini Tsouko Shonik Ganjoo Hampartsoum B. Barsoumian Thomas S. Riad Yun Hu Carola Leuschner Nahum Puebla-Osorio Jing Wang Jian Hu Michael A. Davies Vinay K. Puduvalli Cyrielle Billon Thomas P. Burris Philip L. Lorenzi Boyi Gan James W. Welsh |
| author_sort | Maria Angelica Freitas-Cortez |
| collection | DOAJ |
| description | Abstract Background Cancer creates an immunosuppressive environment that hampers immune responses, allowing tumors to grow and resist therapy. One way the immune system fights back is by inducing ferroptosis, a type of cell death, in tumor cells through CD8 + T cells. This involves lipid peroxidation and enzymes like lysophosphatidylcholine acyltransferase 3 (Lpcat3), which makes cells more prone to ferroptosis. However, the mechanisms by which cancer cells avoid immunotherapy-mediated ferroptosis are unclear. Our study reveals how cancer cells evade ferroptosis and anti-tumor immunity through the upregulation of fatty acid-binding protein 7 (Fabp7). Methods To explore how cancer cells resist immune cell-mediated ferroptosis, we used a comprehensive range of techniques. We worked with cell lines including PD1-sensitive, PD1-resistant, B16F10, and QPP7 glioblastoma cells, and conducted in vivo studies in syngeneic 129 Sv/Ev, C57BL/6, and conditional knockout mice with Rora deletion specifically in CD8+ T cells, Cd8 cre;Rora fl mice. Methods included mass spectrometry-based lipidomics, targeted lipidomics, Oil Red O staining, Seahorse analysis, quantitative PCR, immunohistochemistry, PPARγ transcription factor assays, ChIP-seq, untargeted lipidomic analysis, ROS assay, ex vivo co-culture of CD8+ T cells with cancer cells, ATAC-seq, RNA-seq, Western blotting, co-immunoprecipitation assay, flow cytometry and Imaging Mass Cytometry. Results PD1-resistant tumors upregulate Fabp7, driving protective metabolic changes that shield cells from ferroptosis and evade anti-tumor immunity. Fabp7 decreases the transcription of ferroptosis-inducing genes like Lpcat3 and increases the transcription of ferroptosis-protective genes such as Bmal1 through epigenetic reprogramming. Lipidomic profiling revealed that Fabp7 increases triglycerides and monounsaturated fatty acids (MUFAs), which impede lipid peroxidation and ROS generation. Fabp7 also improves mitochondrial function and fatty acid oxidation (FAO), enhancing cancer cell survival. Furthermore, cancer cells increase Fabp7 expression in CD8+ T cells, disrupting circadian clock gene expression and triggering apoptosis through p53 stabilization. Clinical trial data revealed that higher FABP7 expression correlates with poorer overall survival and progression-free survival in patients undergoing immunotherapy. Conclusions Our study uncovers a novel mechanism by which cancer cells evade immune-mediated ferroptosis through Fabp7 upregulation. This protein reprograms lipid metabolism and disrupts circadian regulation in immune cells, promoting tumor survival and resistance to immunotherapy. Targeting Fabp7 could enhance immunotherapy effectiveness by re-sensitizing resistant tumors to ferroptosis. |
| format | Article |
| id | doaj-art-7cabec9d9cc447cc8eba56e16ed4380b |
| institution | Kabale University |
| issn | 1476-4598 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | BMC |
| record_format | Article |
| series | Molecular Cancer |
| spelling | doaj-art-7cabec9d9cc447cc8eba56e16ed4380b2025-02-09T12:15:53ZengBMCMolecular Cancer1476-45982025-02-0124112610.1186/s12943-024-02198-2Cancer cells avoid ferroptosis induced by immune cells via fatty acid binding proteinsMaria Angelica Freitas-Cortez0Fatemeh Masrorpour1Hong Jiang2Iqbal Mahmud3Yue Lu4Ailing Huang5Lisa K. Duong6Qi Wang7Tiffany A. Voss8Claudia S. Kettlun Leyton9Bo Wei10Wai-Kin Chan11Kevin Lin12Jie Zhang13Efrosini Tsouko14Shonik Ganjoo15Hampartsoum B. Barsoumian16Thomas S. Riad17Yun Hu18Carola Leuschner19Nahum Puebla-Osorio20Jing Wang21Jian Hu22Michael A. Davies23Vinay K. Puduvalli24Cyrielle Billon25Thomas P. Burris26Philip L. Lorenzi27Boyi Gan28James W. Welsh29Children’s Research Institute, University of Texas Southwestern Medical CenterDepartment of Radiation Oncology, UT MD Anderson Cancer CenterDepartment of Radiation Oncology, UT MD Anderson Cancer CenterDepartment of Bioinformatics and Computational Biology, Metabolomics Core Facility, The University of Texas MD Anderson Cancer CenterDepartment of Epigenetics and Molecular Carcinogenesis, The University of Texas MD Anderson Cancer CenterDepartment of Radiation Oncology, UT MD Anderson Cancer CenterDepartment of Radiation Oncology, UT MD Anderson Cancer CenterDepartment of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer CenterDepartment of Radiation Oncology, UT MD Anderson Cancer CenterDepartment of Hematology, The University of Texas MD Anderson Cancer CenterDepartment of Bioinformatics and Computational Biology, Metabolomics Core Facility, The University of Texas MD Anderson Cancer CenterDepartment of Bioinformatics and Computational Biology, Metabolomics Core Facility, The University of Texas MD Anderson Cancer CenterDepartment of Epigenetics and Molecular Carcinogenesis, The University of Texas MD Anderson Cancer CenterDepartment of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer CenterDepartment of Orthopedic Surgery, Baylor College of MedicineDepartment of Radiation Oncology, UT MD Anderson Cancer CenterDepartment of Radiation Oncology, UT MD Anderson Cancer CenterDepartment of Radiation Oncology, UT MD Anderson Cancer CenterDepartment of Radiation Oncology, UT MD Anderson Cancer CenterDepartment of Radiation Oncology, UT MD Anderson Cancer CenterDepartment of Radiation Oncology, UT MD Anderson Cancer CenterDepartment of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer CenterDepartment of Cancer Biology, The University of Texas MD Anderson Cancer CenterDepartment of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer CenterDepartment of Neuro-Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer CenterCenter for Clinical Pharmacology, Washington University School of Medicine and St. Louis College of Pharmacy at University of Health and SciencesUniversity of Florida Genetics InstituteDepartment of Bioinformatics and Computational Biology, Metabolomics Core Facility, The University of Texas MD Anderson Cancer CenterDepartment of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer CenterDepartment of Radiation Oncology, UT MD Anderson Cancer CenterAbstract Background Cancer creates an immunosuppressive environment that hampers immune responses, allowing tumors to grow and resist therapy. One way the immune system fights back is by inducing ferroptosis, a type of cell death, in tumor cells through CD8 + T cells. This involves lipid peroxidation and enzymes like lysophosphatidylcholine acyltransferase 3 (Lpcat3), which makes cells more prone to ferroptosis. However, the mechanisms by which cancer cells avoid immunotherapy-mediated ferroptosis are unclear. Our study reveals how cancer cells evade ferroptosis and anti-tumor immunity through the upregulation of fatty acid-binding protein 7 (Fabp7). Methods To explore how cancer cells resist immune cell-mediated ferroptosis, we used a comprehensive range of techniques. We worked with cell lines including PD1-sensitive, PD1-resistant, B16F10, and QPP7 glioblastoma cells, and conducted in vivo studies in syngeneic 129 Sv/Ev, C57BL/6, and conditional knockout mice with Rora deletion specifically in CD8+ T cells, Cd8 cre;Rora fl mice. Methods included mass spectrometry-based lipidomics, targeted lipidomics, Oil Red O staining, Seahorse analysis, quantitative PCR, immunohistochemistry, PPARγ transcription factor assays, ChIP-seq, untargeted lipidomic analysis, ROS assay, ex vivo co-culture of CD8+ T cells with cancer cells, ATAC-seq, RNA-seq, Western blotting, co-immunoprecipitation assay, flow cytometry and Imaging Mass Cytometry. Results PD1-resistant tumors upregulate Fabp7, driving protective metabolic changes that shield cells from ferroptosis and evade anti-tumor immunity. Fabp7 decreases the transcription of ferroptosis-inducing genes like Lpcat3 and increases the transcription of ferroptosis-protective genes such as Bmal1 through epigenetic reprogramming. Lipidomic profiling revealed that Fabp7 increases triglycerides and monounsaturated fatty acids (MUFAs), which impede lipid peroxidation and ROS generation. Fabp7 also improves mitochondrial function and fatty acid oxidation (FAO), enhancing cancer cell survival. Furthermore, cancer cells increase Fabp7 expression in CD8+ T cells, disrupting circadian clock gene expression and triggering apoptosis through p53 stabilization. Clinical trial data revealed that higher FABP7 expression correlates with poorer overall survival and progression-free survival in patients undergoing immunotherapy. Conclusions Our study uncovers a novel mechanism by which cancer cells evade immune-mediated ferroptosis through Fabp7 upregulation. This protein reprograms lipid metabolism and disrupts circadian regulation in immune cells, promoting tumor survival and resistance to immunotherapy. Targeting Fabp7 could enhance immunotherapy effectiveness by re-sensitizing resistant tumors to ferroptosis.https://doi.org/10.1186/s12943-024-02198-2FABP7FerroptosisLpcat3Bmal1Circadian clockImmunotherapy |
| spellingShingle | Maria Angelica Freitas-Cortez Fatemeh Masrorpour Hong Jiang Iqbal Mahmud Yue Lu Ailing Huang Lisa K. Duong Qi Wang Tiffany A. Voss Claudia S. Kettlun Leyton Bo Wei Wai-Kin Chan Kevin Lin Jie Zhang Efrosini Tsouko Shonik Ganjoo Hampartsoum B. Barsoumian Thomas S. Riad Yun Hu Carola Leuschner Nahum Puebla-Osorio Jing Wang Jian Hu Michael A. Davies Vinay K. Puduvalli Cyrielle Billon Thomas P. Burris Philip L. Lorenzi Boyi Gan James W. Welsh Cancer cells avoid ferroptosis induced by immune cells via fatty acid binding proteins Molecular Cancer FABP7 Ferroptosis Lpcat3 Bmal1 Circadian clock Immunotherapy |
| title | Cancer cells avoid ferroptosis induced by immune cells via fatty acid binding proteins |
| title_full | Cancer cells avoid ferroptosis induced by immune cells via fatty acid binding proteins |
| title_fullStr | Cancer cells avoid ferroptosis induced by immune cells via fatty acid binding proteins |
| title_full_unstemmed | Cancer cells avoid ferroptosis induced by immune cells via fatty acid binding proteins |
| title_short | Cancer cells avoid ferroptosis induced by immune cells via fatty acid binding proteins |
| title_sort | cancer cells avoid ferroptosis induced by immune cells via fatty acid binding proteins |
| topic | FABP7 Ferroptosis Lpcat3 Bmal1 Circadian clock Immunotherapy |
| url | https://doi.org/10.1186/s12943-024-02198-2 |
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