ROR1 CAR-T cells and ferroptosis inducers orchestrate tumor ferroptosis via PC-PUFA2
Abstract Background Lung cancer, particularly non-small cell lung cancer (NSCLC), has high recurrence rates and remains a leading cause of cancer-related death, despite recent advances in its treatment. Emerging therapies, such as chimeric antigen receptor (CAR)-T cell therapy, have shown promise bu...
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BMC
2025-01-01
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| Series: | Biomarker Research |
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| Online Access: | https://doi.org/10.1186/s40364-025-00730-0 |
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| author | Dan Li Wenjie Zhang Ruiheng Wang Shufeng Xie Yixin Wang Wanxin Guo Zixuan Huang Chaoqun Lu Liang Shan Han Liu Lifang Ma Xumin Hou Zhenshu Xu Jiayi Wang |
| author_facet | Dan Li Wenjie Zhang Ruiheng Wang Shufeng Xie Yixin Wang Wanxin Guo Zixuan Huang Chaoqun Lu Liang Shan Han Liu Lifang Ma Xumin Hou Zhenshu Xu Jiayi Wang |
| author_sort | Dan Li |
| collection | DOAJ |
| description | Abstract Background Lung cancer, particularly non-small cell lung cancer (NSCLC), has high recurrence rates and remains a leading cause of cancer-related death, despite recent advances in its treatment. Emerging therapies, such as chimeric antigen receptor (CAR)-T cell therapy, have shown promise but face significant challenges in targeting solid tumors. This study investigated the potential of combining receptor tyrosine kinase-like orphan receptor 1 (ROR1)-targeting CAR-T cells with ferroptosis inducers to promote ferroptosis of tumor cells and enhance anti-tumor efficacy. Methods RNA-seq data and immunofluorescence analysis of relapsed NSCLC patient samples were used to explore ROR1 expression. In addition, ROR1-targeting CAR-T cells were developed to assess cytotoxic activity against ROR1+ tumor cells, and the effect of cytokine stimulation on their efficacy was evaluated. Lipidomics, immunofluorescent histochemistry, and western blotting were used to explore the observed effects. Ferroptosis indicators, including levels of reactive oxygen species, were used to detect the combined effect of CAR-T cells and ferroptosis-inducing drugs. Finally, tumor-bearing mice were used to validate the in vivo efficacy of the combination therapy strategy. Results Tumor cells treated with ferroptosis inducers showed increased sensitivity to Interferon gamma (IFN-γ) secreted by ROR1 CAR-T cells. Furthermore, ROR1 CAR-T cells enhanced the production of phosphatidylcholine with diacyl-polyunsaturated fatty acid tails (PC-PUFA2) by working in tandem with IFN-γ. This enhancement promoted the expression of acyl-CoA synthetase long chain family member 4 (ACSL4), which in turn strengthened the overall anti-tumor response. Conclusions Combining ROR1 CAR-T cells with ferroptosis inducers enhanced anti-tumor efficacy in NSCLC by promoting ferroptosis through increased lipid peroxidation. |
| format | Article |
| id | doaj-art-ee498c920a7c413b825dc3b6708a1e4e |
| institution | Kabale University |
| issn | 2050-7771 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | BMC |
| record_format | Article |
| series | Biomarker Research |
| spelling | doaj-art-ee498c920a7c413b825dc3b6708a1e4e2025-01-26T12:45:39ZengBMCBiomarker Research2050-77712025-01-0113111410.1186/s40364-025-00730-0ROR1 CAR-T cells and ferroptosis inducers orchestrate tumor ferroptosis via PC-PUFA2Dan Li0Wenjie Zhang1Ruiheng Wang2Shufeng Xie3Yixin Wang4Wanxin Guo5Zixuan Huang6Chaoqun Lu7Liang Shan8Han Liu9Lifang Ma10Xumin Hou11Zhenshu Xu12Jiayi Wang13Department of Clinical Laboratory Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University School of MedicineFujian Institute of Hematology, Fujian Provincial Key Laboratory of Hematology,, Fujian Medical University Union HospitalShanghai Institute of Hematology, State Key Laboratory of Medical Genomics, Rui Jin Hospital, School of Medicine, School of Life Sciences and Biotechnology, National Research Center for Translational Medicine at Shanghai, Shanghai Jiao Tong UniversityShanghai Institute of Hematology, State Key Laboratory of Medical Genomics, Rui Jin Hospital, School of Medicine, School of Life Sciences and Biotechnology, National Research Center for Translational Medicine at Shanghai, Shanghai Jiao Tong UniversityShanghai Institute of Hematology, State Key Laboratory of Medical Genomics, Rui Jin Hospital, School of Medicine, School of Life Sciences and Biotechnology, National Research Center for Translational Medicine at Shanghai, Shanghai Jiao Tong UniversityShanghai Institute of Thoracic Oncology, Shanghai Chest Hospital, Shanghai Jiao Tong University School of MedicineShanghai Institute of Hematology, State Key Laboratory of Medical Genomics, Rui Jin Hospital, School of Medicine, School of Life Sciences and Biotechnology, National Research Center for Translational Medicine at Shanghai, Shanghai Jiao Tong UniversityShanghai Institute of Hematology, State Key Laboratory of Medical Genomics, Rui Jin Hospital, School of Medicine, School of Life Sciences and Biotechnology, National Research Center for Translational Medicine at Shanghai, Shanghai Jiao Tong UniversityDepartment of Clinical Laboratory Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University School of MedicineShanghai Institute of Hematology, State Key Laboratory of Medical Genomics, Rui Jin Hospital, School of Medicine, School of Life Sciences and Biotechnology, National Research Center for Translational Medicine at Shanghai, Shanghai Jiao Tong UniversityDepartment of Clinical Laboratory Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University School of MedicineHospital’s Office, Shanghai Chest Hospital, Shanghai Jiao Tong University School of MedicineFujian Institute of Hematology, Fujian Provincial Key Laboratory of Hematology,, Fujian Medical University Union HospitalDepartment of Clinical Laboratory Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University School of MedicineAbstract Background Lung cancer, particularly non-small cell lung cancer (NSCLC), has high recurrence rates and remains a leading cause of cancer-related death, despite recent advances in its treatment. Emerging therapies, such as chimeric antigen receptor (CAR)-T cell therapy, have shown promise but face significant challenges in targeting solid tumors. This study investigated the potential of combining receptor tyrosine kinase-like orphan receptor 1 (ROR1)-targeting CAR-T cells with ferroptosis inducers to promote ferroptosis of tumor cells and enhance anti-tumor efficacy. Methods RNA-seq data and immunofluorescence analysis of relapsed NSCLC patient samples were used to explore ROR1 expression. In addition, ROR1-targeting CAR-T cells were developed to assess cytotoxic activity against ROR1+ tumor cells, and the effect of cytokine stimulation on their efficacy was evaluated. Lipidomics, immunofluorescent histochemistry, and western blotting were used to explore the observed effects. Ferroptosis indicators, including levels of reactive oxygen species, were used to detect the combined effect of CAR-T cells and ferroptosis-inducing drugs. Finally, tumor-bearing mice were used to validate the in vivo efficacy of the combination therapy strategy. Results Tumor cells treated with ferroptosis inducers showed increased sensitivity to Interferon gamma (IFN-γ) secreted by ROR1 CAR-T cells. Furthermore, ROR1 CAR-T cells enhanced the production of phosphatidylcholine with diacyl-polyunsaturated fatty acid tails (PC-PUFA2) by working in tandem with IFN-γ. This enhancement promoted the expression of acyl-CoA synthetase long chain family member 4 (ACSL4), which in turn strengthened the overall anti-tumor response. Conclusions Combining ROR1 CAR-T cells with ferroptosis inducers enhanced anti-tumor efficacy in NSCLC by promoting ferroptosis through increased lipid peroxidation.https://doi.org/10.1186/s40364-025-00730-0Lung cancerROR1CAR-TFerroptosisPC-PUFA2 |
| spellingShingle | Dan Li Wenjie Zhang Ruiheng Wang Shufeng Xie Yixin Wang Wanxin Guo Zixuan Huang Chaoqun Lu Liang Shan Han Liu Lifang Ma Xumin Hou Zhenshu Xu Jiayi Wang ROR1 CAR-T cells and ferroptosis inducers orchestrate tumor ferroptosis via PC-PUFA2 Biomarker Research Lung cancer ROR1 CAR-T Ferroptosis PC-PUFA2 |
| title | ROR1 CAR-T cells and ferroptosis inducers orchestrate tumor ferroptosis via PC-PUFA2 |
| title_full | ROR1 CAR-T cells and ferroptosis inducers orchestrate tumor ferroptosis via PC-PUFA2 |
| title_fullStr | ROR1 CAR-T cells and ferroptosis inducers orchestrate tumor ferroptosis via PC-PUFA2 |
| title_full_unstemmed | ROR1 CAR-T cells and ferroptosis inducers orchestrate tumor ferroptosis via PC-PUFA2 |
| title_short | ROR1 CAR-T cells and ferroptosis inducers orchestrate tumor ferroptosis via PC-PUFA2 |
| title_sort | ror1 car t cells and ferroptosis inducers orchestrate tumor ferroptosis via pc pufa2 |
| topic | Lung cancer ROR1 CAR-T Ferroptosis PC-PUFA2 |
| url | https://doi.org/10.1186/s40364-025-00730-0 |
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