2. Academic Validation
  3. ROR1 CAR-T cells and ferroptosis inducers orchestrate tumor ferroptosis via PC-PUFA2

ROR1 CAR-T cells and ferroptosis inducers orchestrate tumor ferroptosis via PC-PUFA2

  • Biomark Res. 2025 Jan 23;13(1):17. doi: 10.1186/s40364-025-00730-0.
Dan Li 1,  Wenjie Zhang 2,  Ruiheng Wang 3,  Shufeng Xie 3,  Yixin Wang 3,  Wanxin Guo 4,  Zixuan Huang 3,  Chaoqun Lu 3,  Liang Shan 1,  Han Liu 3,  Lifang Ma 5 6,  Xumin Hou 7,  Zhenshu Xu 8,  Jiayi Wang 9 10
Affiliations

Affiliations

  • 1 Department of Clinical Laboratory Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200030, China.
  • 2 Fujian Institute of Hematology, Fujian Provincial Key Laboratory of Hematology,, Fujian Medical University Union Hospital, Fuzhou, 350001, China.
  • 3 Shanghai 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 University, Shanghai, 200030, China.
  • 4 Shanghai Institute of Thoracic Oncology, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200030, China.
  • 5 Department of Clinical Laboratory Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200030, China. malifang0606118@126.com.
  • 6 Shanghai Institute of Thoracic Oncology, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200030, China. malifang0606118@126.com.
  • 7 Hospital's Office, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200030, China. hxmchest@163.com.
  • 8 Fujian Institute of Hematology, Fujian Provincial Key Laboratory of Hematology,, Fujian Medical University Union Hospital, Fuzhou, 350001, China. xuzs@fjmu.edu.cn.
  • 9 Department of Clinical Laboratory Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200030, China. jiayi.wang@sjtu.edu.cn.
  • 10 Shanghai Institute of Thoracic Oncology, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200030, China. jiayi.wang@sjtu.edu.cn.
PMID: 39849645 DOI: 10.1186/s40364-025-00730-0
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.

Keywords

CAR-T; Ferroptosis; Lung cancer; PC-PUFA2; ROR1.

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