YTHDF2 in peritumoral hepatocytes mediates chemotherapy-induced antitumor immune responses through CX3CL1-mediated CD8+ T cell recruitment
Abstract Peritumoral hepatocytes are critical components of the liver cancer microenvironment, However, the role of peritumoral hepatocytes in the local tumor immune interface and the underlying molecular mechanisms have not been elucidated. YTHDF2, an RNA N 6 -methyladenosine (m6A) reader, is criti...
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| Format: | Article |
| Language: | English |
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BMC
2024-09-01
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| Series: | Molecular Cancer |
| Online Access: | https://doi.org/10.1186/s12943-024-02097-6 |
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| author | Zhenyun Yang Xin Wang Yizhen Fu Weijie Wu Zili Hu Qingyang Lin Wei Peng Yangxun Pan Juncheng Wang Jinbin Chen Dandan Hu Zhongguo Zhou Li Xu Yaojun Zhang Jiajie Hou Minshan Chen |
| author_facet | Zhenyun Yang Xin Wang Yizhen Fu Weijie Wu Zili Hu Qingyang Lin Wei Peng Yangxun Pan Juncheng Wang Jinbin Chen Dandan Hu Zhongguo Zhou Li Xu Yaojun Zhang Jiajie Hou Minshan Chen |
| author_sort | Zhenyun Yang |
| collection | DOAJ |
| description | Abstract Peritumoral hepatocytes are critical components of the liver cancer microenvironment, However, the role of peritumoral hepatocytes in the local tumor immune interface and the underlying molecular mechanisms have not been elucidated. YTHDF2, an RNA N 6 -methyladenosine (m6A) reader, is critical for liver tumor progression. The function and regulatory roles of YTHDF2 in peritumoral hepatocytes are unknown. This study demonstrated that oxaliplatin (OXA) upregulated m6A modification and YTHDF2 expression in hepatocytes. Studies using tumor-bearing liver-specific Ythdf2 knockout mice revealed that hepatocyte YTHDF2 suppresses liver tumor growth through CD8+ T cell recruitment and activation. Additionally, YTHDF2 mediated the response to immunotherapy. Mechanistically, OXA upregulated YTHDF2 expression by activating the cGAS-STING signaling pathway and consequently enhanced the therapeutic outcomes of immunotherapeutic interventions. Ythdf2 stabilized Cx3cl1 transcripts in an m6A-dependent manner, regulating the interplay between CD8+ T cells and the progression of liver malignancies. Thus, this study elucidated the novel role of hepatocyte YTHDF2, which promotes therapy-induced antitumor immune responses in the liver. The findings of this study provide valuable insights into the mechanism underlying the therapeutic benefits of targeting YTHDF2. |
| format | Article |
| id | doaj-art-d42c5b5d80614a50a8cc3c82239ec815 |
| institution | Kabale University |
| issn | 1476-4598 |
| language | English |
| publishDate | 2024-09-01 |
| publisher | BMC |
| record_format | Article |
| series | Molecular Cancer |
| spelling | doaj-art-d42c5b5d80614a50a8cc3c82239ec8152025-02-02T12:11:31ZengBMCMolecular Cancer1476-45982024-09-0123112010.1186/s12943-024-02097-6YTHDF2 in peritumoral hepatocytes mediates chemotherapy-induced antitumor immune responses through CX3CL1-mediated CD8+ T cell recruitmentZhenyun Yang0Xin Wang1Yizhen Fu2Weijie Wu3Zili Hu4Qingyang Lin5Wei Peng6Yangxun Pan7Juncheng Wang8Jinbin Chen9Dandan Hu10Zhongguo Zhou11Li Xu12Yaojun Zhang13Jiajie Hou14Minshan Chen15Department of Liver Surgery, Sun Yat-sen University Cancer CenterDepartment of Liver Surgery, Sun Yat-sen University Cancer CenterDepartment of Liver Surgery, Sun Yat-sen University Cancer CenterDepartment of Liver Surgery, Sun Yat-sen University Cancer CenterDepartment of Liver Surgery, Sun Yat-sen University Cancer CenterDepartment of Liver Surgery, Sun Yat-sen University Cancer CenterDepartment of Liver Surgery, Sun Yat-sen University Cancer CenterDepartment of Liver Surgery, Sun Yat-sen University Cancer CenterDepartment of Liver Surgery, Sun Yat-sen University Cancer CenterDepartment of Liver Surgery, Sun Yat-sen University Cancer CenterDepartment of Liver Surgery, Sun Yat-sen University Cancer CenterDepartment of Liver Surgery, Sun Yat-sen University Cancer CenterDepartment of Liver Surgery, Sun Yat-sen University Cancer CenterDepartment of Liver Surgery, Sun Yat-sen University Cancer CenterCancer Centre, Faculty of Health Sciences, University of MacauDepartment of Liver Surgery, Sun Yat-sen University Cancer CenterAbstract Peritumoral hepatocytes are critical components of the liver cancer microenvironment, However, the role of peritumoral hepatocytes in the local tumor immune interface and the underlying molecular mechanisms have not been elucidated. YTHDF2, an RNA N 6 -methyladenosine (m6A) reader, is critical for liver tumor progression. The function and regulatory roles of YTHDF2 in peritumoral hepatocytes are unknown. This study demonstrated that oxaliplatin (OXA) upregulated m6A modification and YTHDF2 expression in hepatocytes. Studies using tumor-bearing liver-specific Ythdf2 knockout mice revealed that hepatocyte YTHDF2 suppresses liver tumor growth through CD8+ T cell recruitment and activation. Additionally, YTHDF2 mediated the response to immunotherapy. Mechanistically, OXA upregulated YTHDF2 expression by activating the cGAS-STING signaling pathway and consequently enhanced the therapeutic outcomes of immunotherapeutic interventions. Ythdf2 stabilized Cx3cl1 transcripts in an m6A-dependent manner, regulating the interplay between CD8+ T cells and the progression of liver malignancies. Thus, this study elucidated the novel role of hepatocyte YTHDF2, which promotes therapy-induced antitumor immune responses in the liver. The findings of this study provide valuable insights into the mechanism underlying the therapeutic benefits of targeting YTHDF2.https://doi.org/10.1186/s12943-024-02097-6 |
| spellingShingle | Zhenyun Yang Xin Wang Yizhen Fu Weijie Wu Zili Hu Qingyang Lin Wei Peng Yangxun Pan Juncheng Wang Jinbin Chen Dandan Hu Zhongguo Zhou Li Xu Yaojun Zhang Jiajie Hou Minshan Chen YTHDF2 in peritumoral hepatocytes mediates chemotherapy-induced antitumor immune responses through CX3CL1-mediated CD8+ T cell recruitment Molecular Cancer |
| title | YTHDF2 in peritumoral hepatocytes mediates chemotherapy-induced antitumor immune responses through CX3CL1-mediated CD8+ T cell recruitment |
| title_full | YTHDF2 in peritumoral hepatocytes mediates chemotherapy-induced antitumor immune responses through CX3CL1-mediated CD8+ T cell recruitment |
| title_fullStr | YTHDF2 in peritumoral hepatocytes mediates chemotherapy-induced antitumor immune responses through CX3CL1-mediated CD8+ T cell recruitment |
| title_full_unstemmed | YTHDF2 in peritumoral hepatocytes mediates chemotherapy-induced antitumor immune responses through CX3CL1-mediated CD8+ T cell recruitment |
| title_short | YTHDF2 in peritumoral hepatocytes mediates chemotherapy-induced antitumor immune responses through CX3CL1-mediated CD8+ T cell recruitment |
| title_sort | ythdf2 in peritumoral hepatocytes mediates chemotherapy induced antitumor immune responses through cx3cl1 mediated cd8 t cell recruitment |
| url | https://doi.org/10.1186/s12943-024-02097-6 |
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