γδ T Cell‐mediated Tumor Immunity is Tightly Regulated by STING and TGF‐β Signaling Pathways
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.
Authors
- Guodong Sun (ORCID: https://orcid.org/0000-0001-5336-368X)
- Zhengfan Jiang (ORCID: https://orcid.org/0000-0002-1247-1382)
- Jing Luo (ORCID: https://orcid.org/0000-0003-2702-120X)
- Ligong Lu (ORCID: https://orcid.org/0000-0003-1405-0052)
- Rong Guo
- Zvi Granot (ORCID: https://orcid.org/0000-0001-9692-5785)
- Jianlei Hao (ORCID: https://orcid.org/0000-0003-4600-3082)
- Hui Xiao (ORCID: https://orcid.org/0000-0001-5304-243X)
- Guang Yang (ORCID: https://orcid.org/0000-0002-5889-3978)
- Xiaosong Ben (ORCID: https://orcid.org/0000-0003-1155-7202)
- Dieter Kabelitz (ORCID: https://orcid.org/0000-0002-4160-7103)
- Fuping You (ORCID: https://orcid.org/0000-0002-7444-729X)
- Qianqian Fu
- Sitao Li (ORCID: https://orcid.org/0000-0002-4035-8635)
- Zhinan Yin (ORCID: https://orcid.org/0000-0001-6524-8777)
- Nan Yan (ORCID: https://orcid.org/0000-0002-0637-3989)
- Tao Li (ORCID: https://orcid.org/0000-0001-5080-3352)
- Hongru Zhang (ORCID: https://orcid.org/0000-0002-6516-0502)
- Shengli Wang (ORCID: https://orcid.org/0000-0003-1816-9982)
- Chuyun Zhu
- Yin Zhao (ORCID: https://orcid.org/0000-0003-1098-3250)
- Shuxian Yang (ORCID: https://orcid.org/0000-0002-0918-2926)
- Yuzhen Zheng (ORCID: https://orcid.org/0000-0002-5260-6798)
- Quanli Yang
Institutions
- Sun Yat-sen University (CN)
- Jinan University (CN)
- Hebrew University of Jerusalem (IL)
- Chinese Academy of Sciences (CN)
- Peking University (CN)
- Nankai University (CN)
- Christian-Albrechts-Universität zu Kiel (DE)
- Sixth Affiliated Hospital of Sun Yat-sen University (CN)
- Zhuhai People's Hospital (CN)
- University Hospital Schleswig-Holstein (DE)
- First Affiliated Hospital of Gannan Medical University (CN)
- Guangdong Academy of Medical Sciences (CN)
- Guangdong Provincial People's Hospital (CN)
- Tongji Hospital (CN)
- Huazhong University of Science and Technology (CN)
- The University of Texas Southwestern Medical Center (US)
- University of Lübeck (DE)
Publication Details
- Journal
- Advanced Science
- Published
- 2024-11-21
- DOI
- https://doi.org/10.1002/advs.202404432
- Citations
- 12
- Primary Topic
- interferon and immune responses
- Type
- article
- Field-Weighted Citation Impact
- 2.89
Funders
- Deutsche Forschungsgemeinschaft
- National Natural Science Foundation of China
- Natural Science Foundation of Hubei Province
- Tsinghua University
- Higher Education Discipline Innovation Project
- National Key Research and Development Program of China