Ribonuclease 1 Induces T‐Cell Dysfunction and Impairs CD8+ T‐Cell Cytotoxicity to Benefit Tumor Growth through Hijacking STAT1
Abstract T‐cell‐based immunotherapy holds promise for eliminating cancer through T‐cell activation. However, prolonged interaction between T cells and tumors and the presence of immunosuppressive factors can diminish T‐cell cytotoxicity, leading to treatment failure. Here, ribonuclease 1 (RNase1), w...
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Wiley
2025-04-01
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| Series: | Advanced Science |
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| Online Access: | https://doi.org/10.1002/advs.202404961 |
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| author | Wen‐Hao Yang Bao‐Yue Huang Hsing‐Yu Rao Peng Ye Bi Chen Hao‐Ching Wang Chih‐Hung Chung Heng‐Hsiung Wu Hung‐Rong Yen Shao‐Chun Wang Jong‐Ho Cha Xiuwen Yan Muh‐Hwa Yang Mien‐Chie Hung |
| author_facet | Wen‐Hao Yang Bao‐Yue Huang Hsing‐Yu Rao Peng Ye Bi Chen Hao‐Ching Wang Chih‐Hung Chung Heng‐Hsiung Wu Hung‐Rong Yen Shao‐Chun Wang Jong‐Ho Cha Xiuwen Yan Muh‐Hwa Yang Mien‐Chie Hung |
| author_sort | Wen‐Hao Yang |
| collection | DOAJ |
| description | Abstract T‐cell‐based immunotherapy holds promise for eliminating cancer through T‐cell activation. However, prolonged interaction between T cells and tumors and the presence of immunosuppressive factors can diminish T‐cell cytotoxicity, leading to treatment failure. Here, ribonuclease 1 (RNase1), which degrades RNA, reduced the expression of effector cytokines and increases immune checkpoint protein levels, inducing T‐cell dysfunction. RNase1 expression is positively associated with exhausted T‐cell gene signatures and immune checkpoint proteins across several cancer types. Cancer cells expressing RNase1 are resistant to CD8+ T‐cell‐mediated killing. RNase1 promotes tumor growth in immunocompetent, but not in immunodeficient, mouse models and inhibits CD8+ T‐cell activity in vivo. Mechanistically, RNase1 enters T cells and deactivates signal transducer and activator of transcription 1 (STAT1), causing T‐cell dysfunction. Loss of RNase1‐STAT1 interaction restores CD8+ T‐cell cytotoxicity. Notably, a study has found RNase1 might activate CD4+ T cells to inhibit breast cancer growth, while another has indicated it causes immunosuppression in liver cancer. The current research shows that RNase1 does not impact CD4+ T cells in vivo. Overall, the study supports the immunosuppressive role of RNase1 in cancer of negatively regulating STAT1 to impair CD8+ T‐cell cytotoxicity. Targeting the RNase1‐STAT1 interaction could prevent CD8+ T‐cell dysfunction in RNase1‐highly expressing cancer patients. |
| format | Article |
| id | doaj-art-ddd5bf58f02b4ec08151fc82c5453170 |
| institution | DOAJ |
| issn | 2198-3844 |
| language | English |
| publishDate | 2025-04-01 |
| publisher | Wiley |
| record_format | Article |
| series | Advanced Science |
| spelling | doaj-art-ddd5bf58f02b4ec08151fc82c54531702025-08-20T03:16:56ZengWileyAdvanced Science2198-38442025-04-011213n/an/a10.1002/advs.202404961Ribonuclease 1 Induces T‐Cell Dysfunction and Impairs CD8+ T‐Cell Cytotoxicity to Benefit Tumor Growth through Hijacking STAT1Wen‐Hao Yang0Bao‐Yue Huang1Hsing‐Yu Rao2Peng Ye3Bi Chen4Hao‐Ching Wang5Chih‐Hung Chung6Heng‐Hsiung Wu7Hung‐Rong Yen8Shao‐Chun Wang9Jong‐Ho Cha10Xiuwen Yan11Muh‐Hwa Yang12Mien‐Chie Hung13Graduate Institute of Cell Biology and Cancer Biology and Precision Therapeutics Center China Medical University Taichung 406040 TaiwanGraduate Institute of Cell Biology and Cancer Biology and Precision Therapeutics Center China Medical University Taichung 406040 TaiwanGraduate Institute of Cell Biology and Cancer Biology and Precision Therapeutics Center China Medical University Taichung 406040 TaiwanAffiliated Cancer Hospital and Institute of Guangzhou Medical University Guangzhou Guangdong 910095 ChinaAffiliated Cancer Hospital and Institute of Guangzhou Medical University Guangzhou Guangdong 910095 ChinaThe PhD Program for Translational Medicine, and Graduate Institute of Translational Medicine College of Medical Science and Technology Taipei Medical University Taipei 110301 TaiwanCancer and Immunology Research Center National Yang Ming Chiao Tung University Taipei 112304 TaiwanGraduate Institute of Biomedical Sciences China Medical University Taichung 404328 TaiwanSchool of Chinese Medicine College of Chinese Medicine China Medical University Taichung 404328 TaiwanGraduate Institute of Biomedical Sciences China Medical University Taichung 404328 TaiwanDepartment of Biomedical Science and Engineering Graduate School Inha University Incheon 22212 Republic of KoreaAffiliated Cancer Hospital and Institute of Guangzhou Medical University Guangzhou Guangdong 910095 ChinaInstitute of Clinical Medicine and Cancer and Immunology Research Center National Yang Ming Chiao Tung University Taipei 112304 TaiwanGraduate Institute of Biomedical Sciences Institute of Biochemistry and Molecular Biology Research Center for Cancer Biology Cancer Biology and Precision Therapeutics Center and Center for Molecular Medicine China Medical University Taichung 406040 TaiwanAbstract T‐cell‐based immunotherapy holds promise for eliminating cancer through T‐cell activation. However, prolonged interaction between T cells and tumors and the presence of immunosuppressive factors can diminish T‐cell cytotoxicity, leading to treatment failure. Here, ribonuclease 1 (RNase1), which degrades RNA, reduced the expression of effector cytokines and increases immune checkpoint protein levels, inducing T‐cell dysfunction. RNase1 expression is positively associated with exhausted T‐cell gene signatures and immune checkpoint proteins across several cancer types. Cancer cells expressing RNase1 are resistant to CD8+ T‐cell‐mediated killing. RNase1 promotes tumor growth in immunocompetent, but not in immunodeficient, mouse models and inhibits CD8+ T‐cell activity in vivo. Mechanistically, RNase1 enters T cells and deactivates signal transducer and activator of transcription 1 (STAT1), causing T‐cell dysfunction. Loss of RNase1‐STAT1 interaction restores CD8+ T‐cell cytotoxicity. Notably, a study has found RNase1 might activate CD4+ T cells to inhibit breast cancer growth, while another has indicated it causes immunosuppression in liver cancer. The current research shows that RNase1 does not impact CD4+ T cells in vivo. Overall, the study supports the immunosuppressive role of RNase1 in cancer of negatively regulating STAT1 to impair CD8+ T‐cell cytotoxicity. Targeting the RNase1‐STAT1 interaction could prevent CD8+ T‐cell dysfunction in RNase1‐highly expressing cancer patients.https://doi.org/10.1002/advs.202404961effector cytokineimmune checkpoint proteinribonuclease 1STAT1T‐cell dysfunction |
| spellingShingle | Wen‐Hao Yang Bao‐Yue Huang Hsing‐Yu Rao Peng Ye Bi Chen Hao‐Ching Wang Chih‐Hung Chung Heng‐Hsiung Wu Hung‐Rong Yen Shao‐Chun Wang Jong‐Ho Cha Xiuwen Yan Muh‐Hwa Yang Mien‐Chie Hung Ribonuclease 1 Induces T‐Cell Dysfunction and Impairs CD8+ T‐Cell Cytotoxicity to Benefit Tumor Growth through Hijacking STAT1 Advanced Science effector cytokine immune checkpoint protein ribonuclease 1 STAT1 T‐cell dysfunction |
| title | Ribonuclease 1 Induces T‐Cell Dysfunction and Impairs CD8+ T‐Cell Cytotoxicity to Benefit Tumor Growth through Hijacking STAT1 |
| title_full | Ribonuclease 1 Induces T‐Cell Dysfunction and Impairs CD8+ T‐Cell Cytotoxicity to Benefit Tumor Growth through Hijacking STAT1 |
| title_fullStr | Ribonuclease 1 Induces T‐Cell Dysfunction and Impairs CD8+ T‐Cell Cytotoxicity to Benefit Tumor Growth through Hijacking STAT1 |
| title_full_unstemmed | Ribonuclease 1 Induces T‐Cell Dysfunction and Impairs CD8+ T‐Cell Cytotoxicity to Benefit Tumor Growth through Hijacking STAT1 |
| title_short | Ribonuclease 1 Induces T‐Cell Dysfunction and Impairs CD8+ T‐Cell Cytotoxicity to Benefit Tumor Growth through Hijacking STAT1 |
| title_sort | ribonuclease 1 induces t cell dysfunction and impairs cd8 t cell cytotoxicity to benefit tumor growth through hijacking stat1 |
| topic | effector cytokine immune checkpoint protein ribonuclease 1 STAT1 T‐cell dysfunction |
| url | https://doi.org/10.1002/advs.202404961 |
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