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ResearchIn-Press PreviewOncologyTherapeutics Open Access | 10.1172/jci.insight.190531

IL-21 enhances the cytotoxicity of intratumoral CD8+ T cells improving radiation efficacy

Xinyang Li,1 Xueqi Xie,1 Baochao Wei,2 Xiaozheng Sun,1 Minxin Chen,1 Rufei Liu,1 Qingxu Tao,1 Yiheng Huang,1 Qian Wang,1 Shuangshuang Ma,1 Ling Wei,1 Rong Xiao,1 Zhaoyun Liu,1 Jinming Yu,1 Meng Wu,1 and Dawei Chen1

1Department of Radiation Oncology and Shandong Provincial Key Laboratory of , Shandong Cancer Hospital and Institute Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, China

2Cancer Center, Shandong University, Jinan, China

Find articles by Li, X. in: PubMed | Google Scholar

1Department of Radiation Oncology and Shandong Provincial Key Laboratory of , Shandong Cancer Hospital and Institute Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, China

2Cancer Center, Shandong University, Jinan, China

Find articles by Xie, X. in: PubMed | Google Scholar

1Department of Radiation Oncology and Shandong Provincial Key Laboratory of , Shandong Cancer Hospital and Institute Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, China

2Cancer Center, Shandong University, Jinan, China

Find articles by Wei, B. in: PubMed | Google Scholar

1Department of Radiation Oncology and Shandong Provincial Key Laboratory of , Shandong Cancer Hospital and Institute Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, China

2Cancer Center, Shandong University, Jinan, China

Find articles by Sun, X. in: PubMed | Google Scholar

1Department of Radiation Oncology and Shandong Provincial Key Laboratory of , Shandong Cancer Hospital and Institute Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, China

2Cancer Center, Shandong University, Jinan, China

Find articles by Chen, M. in: PubMed | Google Scholar

1Department of Radiation Oncology and Shandong Provincial Key Laboratory of , Shandong Cancer Hospital and Institute Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, China

2Cancer Center, Shandong University, Jinan, China

Find articles by Liu, R. in: PubMed | Google Scholar

1Department of Radiation Oncology and Shandong Provincial Key Laboratory of , Shandong Cancer Hospital and Institute Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, China

2Cancer Center, Shandong University, Jinan, China

Find articles by Tao, Q. in: PubMed | Google Scholar

1Department of Radiation Oncology and Shandong Provincial Key Laboratory of , Shandong Cancer Hospital and Institute Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, China

2Cancer Center, Shandong University, Jinan, China

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

1Department of Radiation Oncology and Shandong Provincial Key Laboratory of , Shandong Cancer Hospital and Institute Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, China

2Cancer Center, Shandong University, Jinan, China

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

1Department of Radiation Oncology and Shandong Provincial Key Laboratory of , Shandong Cancer Hospital and Institute Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, China

2Cancer Center, Shandong University, Jinan, China

Find articles by Ma, S. in: PubMed | Google Scholar

1Department of Radiation Oncology and Shandong Provincial Key Laboratory of , Shandong Cancer Hospital and Institute Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, China

2Cancer Center, Shandong University, Jinan, China

Find articles by Wei, L. in: PubMed | Google Scholar

1Department of Radiation Oncology and Shandong Provincial Key Laboratory of , Shandong Cancer Hospital and Institute Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, China

2Cancer Center, Shandong University, Jinan, China

Find articles by Xiao, R. in: PubMed | Google Scholar

1Department of Radiation Oncology and Shandong Provincial Key Laboratory of , Shandong Cancer Hospital and Institute Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, China

2Cancer Center, Shandong University, Jinan, China

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

1Department of Radiation Oncology and Shandong Provincial Key Laboratory of , Shandong Cancer Hospital and Institute Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, China

2Cancer Center, Shandong University, Jinan, China

Find articles by Yu, J. in: PubMed | Google Scholar

1Department of Radiation Oncology and Shandong Provincial Key Laboratory of , Shandong Cancer Hospital and Institute Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, China

2Cancer Center, Shandong University, Jinan, China

Find articles by Wu, M. in: PubMed | Google Scholar |

1Department of Radiation Oncology and Shandong Provincial Key Laboratory of , Shandong Cancer Hospital and Institute Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, China

2Cancer Center, Shandong University, Jinan, China

Find articles by Chen, D. in: PubMed | Google Scholar

Published January 8, 2026 - More info

JCI Insight. https://doi.org/10.1172/jci.insight.190531.
Copyright © 2026, Li 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 January 8, 2026 - Version history
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Abstract

Radiotherapy is a critical modality in cancer treatment, not only to eradicate cancer cells but also to trigger anti-tumor immunity. Interleukin-21 (IL-21), an immunomodulatory cytokine with potential in cancer therapy, has unexplored synergy with radiotherapy. Our study, leveraging human cancer databases and tissue microarrays, identified a positive correlation between IL-21 and radiotherapy outcomes, particularly in tumor microenvironment (TME) activation. In mouse tumor models, IL-21 combined with radiation significantly enhances TME, boosting CD8+ T cell activation and function, reducing tumor burden, and extending survival. Single-cell transcriptome sequencing revealed that the combination of IL-21 and radiation increased the cytotoxicity of effector and memory CD8+ T cells and prevented their exhaustion. These effects were further validated in humanized mice, where IL-21 combined with radiation reduced A549 tumor growth and enhanced CD8+ T cell function. Post-neoadjuvant radiotherapy samples from patients with esophageal cancer showed a positive correlation between IL-21 levels and CD8+ T cell infiltration. Our findings suggest that IL-21 is a promising adjuvant to radiotherapy, potentially improving the treatment efficacy through TME enhancement. This study provides a foundation for future clinical exploration of IL-21 for enhancing radiotherapy.

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graphical abstract
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View Figure S1. The expression of IL21 in TME is correlated with favorable prognosis. Figure S2. The expression of IL21 in TME is correlated with favorable radiotherapy prognosis. Figure S3. The expression of IL21 in TME is correlated with favorable radiotherapy prognosis of HNSC patients and increased CD8+ T cell infiltration. Figure S4. Exogenous IL-21 administration synergistically enhances radiation efficacy with demonstrated safety. Figure S5. IL-21 combined with radiation reshapes the TME and increases the infiltration of CD8+ T cells. Figure S6. Gating strategies of flow cytometry analysis and flow cytometry histograms of Gzmb and IFN-γ expression in CD8+ T cells. Figure S7. Flow cytometric analysis of different subsets of immune cells in TME of MC38 and CMT167 tumors. Figure S8. Flow cytometric analysis of different subsets of immune cells in TME of MCA205 and B16 tumors. Figure S9. IL-21 directly boosts the activation and cytotoxicity of CD8+ T cells. Table S1. Patient Information of Lung Adenocarcinoma Tissue Microarray. Table S2. Clinical information of patients with esophageal squamous cell carcinoma administrated with neoadjuvant radiotherapy.

Version history
  • Version 1 (January 8, 2026): In-Press Preview
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