SSRP1/SLC3A2 Axis in Arginine Transport: A New Target for Overcoming Immune Evasion and Tumor Progression in Peripheral T‐Cell Lymphoma
Abstract Peripheral T‐cell lymphoma (PTCL) is a heterogeneous group of mature T‐cell malignancies with poor prognosis. Therefore, improved therapies are urgently required to improve patient outcomes. In this study, metabolic inhibitor drug screening reveals that quinacrine elicits excellent antitumo...
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Wiley
2025-06-01
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| Series: | Advanced Science |
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| Online Access: | https://doi.org/10.1002/advs.202415698 |
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| author | Yimin Ren Lei Fan Ling Wang Yanping Liu Jie Zhang Boya Wang Ruize Chen Xiao Chen Lingyu Zhuang Yaping Zhang Handong Sun Jianyong Li Wenyu Shi Hui Jin |
| author_facet | Yimin Ren Lei Fan Ling Wang Yanping Liu Jie Zhang Boya Wang Ruize Chen Xiao Chen Lingyu Zhuang Yaping Zhang Handong Sun Jianyong Li Wenyu Shi Hui Jin |
| author_sort | Yimin Ren |
| collection | DOAJ |
| description | Abstract Peripheral T‐cell lymphoma (PTCL) is a heterogeneous group of mature T‐cell malignancies with poor prognosis. Therefore, improved therapies are urgently required to improve patient outcomes. In this study, metabolic inhibitor drug screening reveals that quinacrine elicits excellent antitumor activity both in vitro and in vivo by downregulating intracellular arginine levels in PTCL. Single‐cell transcriptomic analyses reveal aberrant arginine metabolism in patients with PTCL, characterized by excessive solute carrier family 3 member 2 (SLC3A2) mediated arginine uptake preferentially in tumor cells. High SLC3A2 expression predicts poor outcomes in PTCL, as SLC3A2‐mediated arginine uptake promotes the malignant behaviors of tumor cells and induces tumor immune escape, thereby fueling tumor progression. Mechanistically, high arginine levels induce global metabolic changes, including enhanced oxidative phosphorylation by promoting nascent RNA synthesis. This work identifies structure‐specific recognition protein 1 (SSRP1), which upregulates SLC3A2, as a co‐transcription factor with JUNB. Quinacrine disrupts SLC3A2‐mediated arginine transport by targeting SSRP1. Combining quinacrine with histone deacetylase inhibitors is a promising therapeutic strategy for PTCL. |
| format | Article |
| id | doaj-art-770bb701e8824cbd8146f29f981983f2 |
| institution | OA Journals |
| issn | 2198-3844 |
| language | English |
| publishDate | 2025-06-01 |
| publisher | Wiley |
| record_format | Article |
| series | Advanced Science |
| spelling | doaj-art-770bb701e8824cbd8146f29f981983f22025-08-20T02:32:26ZengWileyAdvanced Science2198-38442025-06-011221n/an/a10.1002/advs.202415698SSRP1/SLC3A2 Axis in Arginine Transport: A New Target for Overcoming Immune Evasion and Tumor Progression in Peripheral T‐Cell LymphomaYimin Ren0Lei Fan1Ling Wang2Yanping Liu3Jie Zhang4Boya Wang5Ruize Chen6Xiao Chen7Lingyu Zhuang8Yaping Zhang9Handong Sun10Jianyong Li11Wenyu Shi12Hui Jin13Lymphoma Center, Department of Hematology, The First Affiliated Hospital with Nanjing Medical University Jiangsu Province Hospital Nanjing 210029 ChinaLymphoma Center, Department of Hematology, The First Affiliated Hospital with Nanjing Medical University Jiangsu Province Hospital Nanjing 210029 ChinaLymphoma Center, Department of Hematology, The First Affiliated Hospital with Nanjing Medical University Jiangsu Province Hospital Nanjing 210029 ChinaLymphoma Center, Department of Hematology, The First Affiliated Hospital with Nanjing Medical University Jiangsu Province Hospital Nanjing 210029 ChinaWuxi School of Medicine Jiangnan University Wuxi 214122 ChinaLymphoma Center, Department of Hematology, The First Affiliated Hospital with Nanjing Medical University Jiangsu Province Hospital Nanjing 210029 ChinaLymphoma Center, Department of Hematology, The First Affiliated Hospital with Nanjing Medical University Jiangsu Province Hospital Nanjing 210029 ChinaLymphoma Center, Department of Hematology, The First Affiliated Hospital with Nanjing Medical University Jiangsu Province Hospital Nanjing 210029 ChinaLymphoma Center, Department of Hematology, The First Affiliated Hospital with Nanjing Medical University Jiangsu Province Hospital Nanjing 210029 ChinaDepartment of Hematology Affiliated Hospital of Nantong University Nantong 226001 ChinaDepartment of Breast, Women's Hospital of Nanjing Medical University Nanjing Women and Children's Healthcare Hospital Nanjing 210004 ChinaLymphoma Center, Department of Hematology, The First Affiliated Hospital with Nanjing Medical University Jiangsu Province Hospital Nanjing 210029 ChinaDepartment of Hematology Affiliated Hospital of Nantong University Nantong 226001 ChinaLymphoma Center, Department of Hematology, The First Affiliated Hospital with Nanjing Medical University Jiangsu Province Hospital Nanjing 210029 ChinaAbstract Peripheral T‐cell lymphoma (PTCL) is a heterogeneous group of mature T‐cell malignancies with poor prognosis. Therefore, improved therapies are urgently required to improve patient outcomes. In this study, metabolic inhibitor drug screening reveals that quinacrine elicits excellent antitumor activity both in vitro and in vivo by downregulating intracellular arginine levels in PTCL. Single‐cell transcriptomic analyses reveal aberrant arginine metabolism in patients with PTCL, characterized by excessive solute carrier family 3 member 2 (SLC3A2) mediated arginine uptake preferentially in tumor cells. High SLC3A2 expression predicts poor outcomes in PTCL, as SLC3A2‐mediated arginine uptake promotes the malignant behaviors of tumor cells and induces tumor immune escape, thereby fueling tumor progression. Mechanistically, high arginine levels induce global metabolic changes, including enhanced oxidative phosphorylation by promoting nascent RNA synthesis. This work identifies structure‐specific recognition protein 1 (SSRP1), which upregulates SLC3A2, as a co‐transcription factor with JUNB. Quinacrine disrupts SLC3A2‐mediated arginine transport by targeting SSRP1. Combining quinacrine with histone deacetylase inhibitors is a promising therapeutic strategy for PTCL.https://doi.org/10.1002/advs.202415698argininedrug repurposingimmune escapeperipheral T‐cell lymphomasolute carriertranscription regulation |
| spellingShingle | Yimin Ren Lei Fan Ling Wang Yanping Liu Jie Zhang Boya Wang Ruize Chen Xiao Chen Lingyu Zhuang Yaping Zhang Handong Sun Jianyong Li Wenyu Shi Hui Jin SSRP1/SLC3A2 Axis in Arginine Transport: A New Target for Overcoming Immune Evasion and Tumor Progression in Peripheral T‐Cell Lymphoma Advanced Science arginine drug repurposing immune escape peripheral T‐cell lymphoma solute carrier transcription regulation |
| title | SSRP1/SLC3A2 Axis in Arginine Transport: A New Target for Overcoming Immune Evasion and Tumor Progression in Peripheral T‐Cell Lymphoma |
| title_full | SSRP1/SLC3A2 Axis in Arginine Transport: A New Target for Overcoming Immune Evasion and Tumor Progression in Peripheral T‐Cell Lymphoma |
| title_fullStr | SSRP1/SLC3A2 Axis in Arginine Transport: A New Target for Overcoming Immune Evasion and Tumor Progression in Peripheral T‐Cell Lymphoma |
| title_full_unstemmed | SSRP1/SLC3A2 Axis in Arginine Transport: A New Target for Overcoming Immune Evasion and Tumor Progression in Peripheral T‐Cell Lymphoma |
| title_short | SSRP1/SLC3A2 Axis in Arginine Transport: A New Target for Overcoming Immune Evasion and Tumor Progression in Peripheral T‐Cell Lymphoma |
| title_sort | ssrp1 slc3a2 axis in arginine transport a new target for overcoming immune evasion and tumor progression in peripheral t cell lymphoma |
| topic | arginine drug repurposing immune escape peripheral T‐cell lymphoma solute carrier transcription regulation |
| url | https://doi.org/10.1002/advs.202415698 |
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