IL-17-producing γδ T cells in the tumor microenvironment promote radioresistance in mice

Yue Deng; Xixi Liu; Xiao Yang; Wenwen Wei; Jiacheng Wang; Zheng Yang; Yajie Sun; Yan Hu; Haibo Zhang; Yijun Wang; Zhanjie Zhang; Lu Wen; Fang Huang; Kunyu Yang; Chao Wan

doi:10.1172/JCI193945

¹Cancer Center, Huazhong University of Science and Technology, Wuhan, China

²Department of Radiation Oncology, Hangzhou Medical College, Hangzhou, China

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¹Cancer Center, Huazhong University of Science and Technology, Wuhan, China

²Department of Radiation Oncology, Hangzhou Medical College, Hangzhou, China

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¹Cancer Center, Huazhong University of Science and Technology, Wuhan, China

²Department of Radiation Oncology, Hangzhou Medical College, Hangzhou, China

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¹Cancer Center, Huazhong University of Science and Technology, Wuhan, China

²Department of Radiation Oncology, Hangzhou Medical College, Hangzhou, China

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¹Cancer Center, Huazhong University of Science and Technology, Wuhan, China

²Department of Radiation Oncology, Hangzhou Medical College, Hangzhou, China

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¹Cancer Center, Huazhong University of Science and Technology, Wuhan, China

²Department of Radiation Oncology, Hangzhou Medical College, Hangzhou, China

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¹Cancer Center, Huazhong University of Science and Technology, Wuhan, China

²Department of Radiation Oncology, Hangzhou Medical College, Hangzhou, China

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¹Cancer Center, Huazhong University of Science and Technology, Wuhan, China

²Department of Radiation Oncology, Hangzhou Medical College, Hangzhou, China

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¹Cancer Center, Huazhong University of Science and Technology, Wuhan, China

²Department of Radiation Oncology, Hangzhou Medical College, Hangzhou, China

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¹Cancer Center, Huazhong University of Science and Technology, Wuhan, China

²Department of Radiation Oncology, Hangzhou Medical College, Hangzhou, China

Find articles by Wang, Y. in: PubMed | Google Scholar

¹Cancer Center, Huazhong University of Science and Technology, Wuhan, China

²Department of Radiation Oncology, Hangzhou Medical College, Hangzhou, China

Find articles by Zhang, Z. in: PubMed | Google Scholar

¹Cancer Center, Huazhong University of Science and Technology, Wuhan, China

²Department of Radiation Oncology, Hangzhou Medical College, Hangzhou, China

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¹Cancer Center, Huazhong University of Science and Technology, Wuhan, China

²Department of Radiation Oncology, Hangzhou Medical College, Hangzhou, China

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¹Cancer Center, Huazhong University of Science and Technology, Wuhan, China

²Department of Radiation Oncology, Hangzhou Medical College, Hangzhou, China

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¹Cancer Center, Huazhong University of Science and Technology, Wuhan, China

²Department of Radiation Oncology, Hangzhou Medical College, Hangzhou, China

Find articles by Wan, C. in: PubMed | Google Scholar |

J Clin Invest. https://doi.org/10.1172/JCI193945.
Copyright © 2025, Deng et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

Published October 7, 2025 - Version history

The immunosuppressive tumor microenvironment (TME) drives radioresistance, but the role of γδ T cells in regulating radiosensitivity remains incompletely understood. In this study, we found that γδ T cell infiltration in the TME substantially increased after radiotherapy and contributed to radioresistance. Depletion of γδ T cells enhanced radiosensitivity. Single-cell RNA sequencing revealed that γδ T cells in the post-radiotherapy TME were characterized by the expression of Zbtb16, Il23r, and Il17a, and served as the primary source of IL-17A. These γδ T cells promoted radioresistance by recruiting myeloid-derived suppressor cells and suppressing T cell activation. Mechanistically, radiotherapy-induced tumor cell-derived microparticles containing dsDNA activated the cGAS-STING/NF-κB signaling pathway in macrophages, upregulating the expression of the chemokine CCL20, which was critical for γδ T cell recruitment. Targeting γδ T cells and IL-17A enhanced radiosensitivity and improved the efficacy of radiotherapy combined with anti-PD-1 immunotherapy, providing potential therapeutic strategies to overcome radioresistance.

Version 1 (October 7, 2025): In-Press Preview

IL-17-producing γδ T cells in the tumor microenvironment promote radioresistance in mice

Yue Deng,¹ Xixi Liu,¹ Xiao Yang,¹ Wenwen Wei,¹ Jiacheng Wang,¹ Zheng Yang,¹ Yajie Sun,¹ Yan Hu,¹ Haibo Zhang,² Yijun Wang,¹ Zhanjie Zhang,¹ Lu Wen,¹ Fang Huang,¹ Kunyu Yang,¹ and Chao Wan¹

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IL-17-producing γδ T cells in the tumor microenvironment promote radioresistance in mice

Yue Deng,1 Xixi Liu,1 Xiao Yang,1 Wenwen Wei,1 Jiacheng Wang,1 Zheng Yang,1 Yajie Sun,1 Yan Hu,1 Haibo Zhang,2 Yijun Wang,1 Zhanjie Zhang,1 Lu Wen,1 Fang Huang,1 Kunyu Yang,1 and Chao Wan1

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Yue Deng,¹ Xixi Liu,¹ Xiao Yang,¹ Wenwen Wei,¹ Jiacheng Wang,¹ Zheng Yang,¹ Yajie Sun,¹ Yan Hu,¹ Haibo Zhang,² Yijun Wang,¹ Zhanjie Zhang,¹ Lu Wen,¹ Fang Huang,¹ Kunyu Yang,¹ and Chao Wan¹