γδ T Cell‐mediated Tumor Immunity is Tightly Regulated by STING and TGF‐β Signaling Pathways
Abstract The STING pathway plays a critical role in tumor immunosurveillance. However, the precise mechanisms by which STING regulates gamma delta (γδ) T cell function during tumor progression remain unclear. Herein, we find that tumor‐derived cyclic GMP‐AMP (cGAMP) activates a distinct STING pathwa...
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Wiley
2025-01-01
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| Series: | Advanced Science |
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| Online Access: | https://doi.org/10.1002/advs.202404432 |
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| author | Jing Luo Shengli Wang Quanli Yang Qianqian Fu Chuyun Zhu Tao Li Shuxian Yang Yin Zhao Rong Guo Xiaosong Ben Yuzhen Zheng Sitao Li Guang Yang Hongru Zhang Hui Xiao Zhengfan Jiang Nan Yan Dieter Kabelitz Guodong Sun Zvi Granot Ligong Lu Fuping You Jianlei Hao Zhinan Yin |
| author_facet | Jing Luo Shengli Wang Quanli Yang Qianqian Fu Chuyun Zhu Tao Li Shuxian Yang Yin Zhao Rong Guo Xiaosong Ben Yuzhen Zheng Sitao Li Guang Yang Hongru Zhang Hui Xiao Zhengfan Jiang Nan Yan Dieter Kabelitz Guodong Sun Zvi Granot Ligong Lu Fuping You Jianlei Hao Zhinan Yin |
| author_sort | Jing Luo |
| collection | DOAJ |
| description | Abstract The STING pathway plays a critical role in tumor immunosurveillance. However, the precise mechanisms by which STING regulates gamma delta (γδ) T cell function during tumor progression remain unclear. Herein, we find that tumor‐derived cyclic GMP‐AMP (cGAMP) activates a distinct STING pathway by inducing TBK1‐mediated phosphorylation of Eomes in γδ T cells during the early stage of tumor development is demonstrated. This activation leads to interferon‐gamma (IFN‐γ) production and consequent tumor surveillance. However, at advanced stages of tumor progression, the accumulation of immune‐suppressive cytokine transforming growth factor‐beta (TGF‐β) downregulates STING levels, compromising the function of γδ T cells. Notably, the synergism between TGF‐β inhibition and STING agonists effectively counteracts the immunosuppressive tumor microenvironment, thereby augmenting the antitumoral effects of γδ T cells. These findings present a novel mechanism involving STING‐mediated IFN‐γ production in γδ T cells and hold significant implications for the development of potent immunotherapeutic approaches against cancer. |
| format | Article |
| id | doaj-art-beadada11bd447c9a6e44db30496d65d |
| institution | Kabale University |
| issn | 2198-3844 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Wiley |
| record_format | Article |
| series | Advanced Science |
| spelling | doaj-art-beadada11bd447c9a6e44db30496d65d2025-01-13T15:29:43ZengWileyAdvanced Science2198-38442025-01-01122n/an/a10.1002/advs.202404432γδ T Cell‐mediated Tumor Immunity is Tightly Regulated by STING and TGF‐β Signaling PathwaysJing Luo0Shengli Wang1Quanli Yang2Qianqian Fu3Chuyun Zhu4Tao Li5Shuxian Yang6Yin Zhao7Rong Guo8Xiaosong Ben9Yuzhen Zheng10Sitao Li11Guang Yang12Hongru Zhang13Hui Xiao14Zhengfan Jiang15Nan Yan16Dieter Kabelitz17Guodong Sun18Zvi Granot19Ligong Lu20Fuping You21Jianlei Hao22Zhinan Yin23Guangdong Provincial Key Laboratory of Tumor Interventional Diagnosis and Treatment Zhuhai Institute of Translational Medicine Zhuhai People's Hospital Affiliated with Jinan University Jinan University Zhuhai 519000 P. R. ChinaGuangdong Provincial Key Laboratory of Tumor Interventional Diagnosis and Treatment Zhuhai Institute of Translational Medicine Zhuhai People's Hospital Affiliated with Jinan University Jinan University Zhuhai 519000 P. R. ChinaGuangdong Provincial Key Laboratory of Tumor Interventional Diagnosis and Treatment Zhuhai Institute of Translational Medicine Zhuhai People's Hospital Affiliated with Jinan University Jinan University Zhuhai 519000 P. R. ChinaGuangdong Provincial Key Laboratory of Tumor Interventional Diagnosis and Treatment Zhuhai Institute of Translational Medicine Zhuhai People's Hospital Affiliated with Jinan University Jinan University Zhuhai 519000 P. R. ChinaGuangdong Provincial Key Laboratory of Tumor Interventional Diagnosis and Treatment Zhuhai Institute of Translational Medicine Zhuhai People's Hospital Affiliated with Jinan University Jinan University Zhuhai 519000 P. R. ChinaGuangdong Provincial Key Laboratory of Tumor Interventional Diagnosis and Treatment Zhuhai Institute of Translational Medicine Zhuhai People's Hospital Affiliated with Jinan University Jinan University Zhuhai 519000 P. R. ChinaGuangdong Provincial Key Laboratory of Tumor Interventional Diagnosis and Treatment Zhuhai Institute of Translational Medicine Zhuhai People's Hospital Affiliated with Jinan University Jinan University Zhuhai 519000 P. R. ChinaDepartment of Ophthalmology Tongji Hospital Tongji Medical College Huazhong University of Science and Technology Wuhan Hubei 430030 P. R. ChinaDepartment of Obstetrics and Gynecology The First Affiliated Hospital of Gannan Medical University Ganzhou Jiangxi 341000 P. R. ChinaDepartment of Thoracic Surgery Guangdong Provincial People's Hospital Guangdong Academy of Medical Sciences Guangzhou 510080 P. R. ChinaDepartment of Pediatrics The Sixth Affiliated Hospital Sun Yat‐sen University Guangzhou 510655 P. R. ChinaDepartment of Pediatrics The Sixth Affiliated Hospital Sun Yat‐sen University Guangzhou 510655 P. R. ChinaDepartment of Pathogen biology School of Medicine Jinan University Guangzhou 510632 P. R. ChinaNankai International Advanced Research Institute College of Life Sciences Nankai University Tianjin 300071 P. R. ChinaShanghai Institute of Immunity and Infection, Chinese Academy of Sciences Shanghai 200031 P. R. ChinaKey Laboratory of Cell Proliferation and Differentiation of the Ministry of Education School of Life Sciences Peking University Beijing 100871 ChinaDepartment of Immunology University of Texas Southwestern Medical Center Dallas TX 75390 USAInstitute of Immunology University of Kiel and University Hospital Schleswig‐Holstein Campus Kiel 24105 Kiel GermanyGuangdong Provincial Key Laboratory of Spine and Spinal Cord Reconstruction The Fifth Affiliated Hospital of Jinan University Heyuan 517000 P. R. ChinaDepartment of Developmental Biology and Cancer Research Institute for Medical Research Israel Canada Hebrew University Medical School Ein Kerem Jerusalem 9112102 IsraelGuangdong Provincial Key Laboratory of Tumor Interventional Diagnosis and Treatment Zhuhai Institute of Translational Medicine Zhuhai People's Hospital Affiliated with Jinan University Jinan University Zhuhai 519000 P. R. ChinaDepartment of Immunology Institute of Systems Biomedicine School of Basic Medical Sciences Peking University Health Science Center Beijing 100191 P. R. ChinaGuangdong Provincial Key Laboratory of Tumor Interventional Diagnosis and Treatment Zhuhai Institute of Translational Medicine Zhuhai People's Hospital Affiliated with Jinan University Jinan University Zhuhai 519000 P. R. ChinaGuangdong Provincial Key Laboratory of Tumor Interventional Diagnosis and Treatment Zhuhai Institute of Translational Medicine Zhuhai People's Hospital Affiliated with Jinan University Jinan University Zhuhai 519000 P. R. ChinaAbstract The STING pathway plays a critical role in tumor immunosurveillance. However, the precise mechanisms by which STING regulates gamma delta (γδ) T cell function during tumor progression remain unclear. Herein, we find that tumor‐derived cyclic GMP‐AMP (cGAMP) activates a distinct STING pathway by inducing TBK1‐mediated phosphorylation of Eomes in γδ T cells during the early stage of tumor development is demonstrated. This activation leads to interferon‐gamma (IFN‐γ) production and consequent tumor surveillance. However, at advanced stages of tumor progression, the accumulation of immune‐suppressive cytokine transforming growth factor‐beta (TGF‐β) downregulates STING levels, compromising the function of γδ T cells. Notably, the synergism between TGF‐β inhibition and STING agonists effectively counteracts the immunosuppressive tumor microenvironment, thereby augmenting the antitumoral effects of γδ T cells. These findings present a novel mechanism involving STING‐mediated IFN‐γ production in γδ T cells and hold significant implications for the development of potent immunotherapeutic approaches against cancer.https://doi.org/10.1002/advs.202404432EomesIFN‐γSTINGtumor immunityγδ T cells |
| spellingShingle | Jing Luo Shengli Wang Quanli Yang Qianqian Fu Chuyun Zhu Tao Li Shuxian Yang Yin Zhao Rong Guo Xiaosong Ben Yuzhen Zheng Sitao Li Guang Yang Hongru Zhang Hui Xiao Zhengfan Jiang Nan Yan Dieter Kabelitz Guodong Sun Zvi Granot Ligong Lu Fuping You Jianlei Hao Zhinan Yin γδ T Cell‐mediated Tumor Immunity is Tightly Regulated by STING and TGF‐β Signaling Pathways Advanced Science Eomes IFN‐γ STING tumor immunity γδ T cells |
| title | γδ T Cell‐mediated Tumor Immunity is Tightly Regulated by STING and TGF‐β Signaling Pathways |
| title_full | γδ T Cell‐mediated Tumor Immunity is Tightly Regulated by STING and TGF‐β Signaling Pathways |
| title_fullStr | γδ T Cell‐mediated Tumor Immunity is Tightly Regulated by STING and TGF‐β Signaling Pathways |
| title_full_unstemmed | γδ T Cell‐mediated Tumor Immunity is Tightly Regulated by STING and TGF‐β Signaling Pathways |
| title_short | γδ T Cell‐mediated Tumor Immunity is Tightly Regulated by STING and TGF‐β Signaling Pathways |
| title_sort | γδ t cell mediated tumor immunity is tightly regulated by sting and tgf β signaling pathways |
| topic | Eomes IFN‐γ STING tumor immunity γδ T cells |
| url | https://doi.org/10.1002/advs.202404432 |
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