2. Academic Validation
  3. Ribonuclease 1 Induces T-Cell Dysfunction and Impairs CD8+ T-Cell Cytotoxicity to Benefit Tumor Growth through Hijacking STAT1

Ribonuclease 1 Induces T-Cell Dysfunction and Impairs CD8+ T-Cell Cytotoxicity to Benefit Tumor Growth through Hijacking STAT1

  • Adv Sci (Weinh). 2025 Feb 11:e2404961. doi: 10.1002/advs.202404961.
Wen-Hao Yang 1,  Bao-Yue Huang 1,  Hsing-Yu Rao 1,  Peng Ye 2 3,  Bi Chen 2,  Hao-Ching Wang 4,  Chih-Hung Chung 5,  Heng-Hsiung Wu 6,  Hung-Rong Yen 7,  Shao-Chun Wang 6,  Jong-Ho Cha 8,  Xiuwen Yan 2,  Muh-Hwa Yang 9 10,  Mien-Chie Hung 11
Affiliations

Affiliations

  • 1 Graduate Institute of Cell Biology and Cancer Biology and Precision Therapeutics Center, China Medical University, Taichung, 406040, Taiwan.
  • 2 Affiliated Cancer Hospital and Institute of Guangzhou Medical University, Guangzhou, Guangdong, 910095, China.
  • 3 Infection Medicine Research Institute of Panyu District, The Affiliated Panyu Central Hospital of Guangzhou Medical University, Guangzhou, Guangdong, 910095, China.
  • 4 The PhD Program for Translational Medicine, and Graduate Institute of Translational Medicine, College of Medical Science and Technology, Taipei Medical University, Taipei, 110301, Taiwan.
  • 5 Cancer and Immunology Research Center, National Yang Ming Chiao Tung University, Taipei, 112304, Taiwan.
  • 6 Graduate Institute of Biomedical Sciences, China Medical University, Taichung, 404328, Taiwan.
  • 7 School of Chinese Medicine, College of Chinese Medicine, China Medical University, Taichung, 404328, Taiwan.
  • 8 Department of Biomedical Science and Engineering, Graduate School, Inha University, Incheon, 22212, Republic of Korea.
  • 9 Institute of Clinical Medicine and Cancer and Immunology Research Center, National Yang Ming Chiao Tung University, Taipei, 112304, Taiwan.
  • 10 Department of Oncology, Taipei Veterans General Hospital, Taipei, 112201, Taiwan.
  • 11 Graduate 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, Taiwan.
PMID: 39932384 DOI: 10.1002/advs.202404961
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.

Keywords

STAT1; T‐cell dysfunction; effector cytokine; immune checkpoint protein; ribonuclease 1.

Figures
Products
Inhibitors & Agonists
Other Products