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GITR activation potentiates anti-tumor immunity of tumor-infiltrating lymphocytes expanded from glioblastoma by rescuing exhaustion

Oncogene volume 45, pages 1087–1099 (2026)Cite this article

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Abstract

Autologous tumor-infiltrating lymphocyte (TIL) therapy holds transformative potential for solid tumors, yet its efficacy in glioblastoma remains limited by T cell exhaustion and immunosuppression. In the current study, we optimized an effective and reliable method for in vitro expansion of TILs from glioblastoma lesions and assessed their tumor-killing capacity both in vitro and in vivo. Single-cell RNA sequencing (scRNA-seq) of expanded TILs uncovered their heterogeneity and identified a cytotoxic tissue-resident memory (TRM) CD8+ TIL subset with a unique exhaustion signature. Notably, the co-stimulatory factor GITR (encoded by TNFRSF18) is highly expressed not only on immunosuppressive regulatory T (Treg) cells but also on exhausted CD8+ TILs. GITR agonism via αGITR antibody achieved dual effects: it directly enhanced CD8+ TIL activation while simultaneously abrogating Treg-mediated immunosuppression. This dual-action mechanism synergized with αPD-1 therapy to amplify TIL reactivation, significantly enhancing tumor control in vivo. Mechanistically, GITR activation potentiated anti-tumor responses by promoting immunological synapse (IS) formation and function in TILs via the NF-κB/KALRN signaling axis. Our findings established GITR as a crucial regulator of CD8+ TIL anti-tumor immunity, positioning GITR targeting as a novel strategy to improve TIL therapy for glioblastoma, with promising implications for clinical application.

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Fig. 1: Expanded TILs exert an anti-tumor reactivity in vitro.
Fig. 2: Expanded TILs attenuate subcutaneous glioblastoma-PDX tumor growth in vivo.
Fig. 3: A single-cell atlas of glioma CD8 + T cells of expanded TILs.
Fig. 4: T cell receptor distribution and clonality analysis.
Fig. 5: GITR is highly expressed on TILs with exhausted phenotypes in glioma.
Fig. 6: GITR co-stimulation enhances the anti-tumor functions of expanded TILs and CAR-T cells.
Fig. 7: GITR activation potentiates anti-tumor responses by inducing IS formation via NF-κB/KALRN axis.

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Acknowledgements

This research was funded by National Natural Science Foundation of China (grant number: 82273341), Shenzhen Medical Research Funds (grant number: A2303056), National Natural Science Foundation of China (grant number: 82372890), Shenzhen Science and Technology Program (grant number: GJHZ20220913144209018, SGCX20250526154203004, JCYJ20240813145327036, JCYJ20240813145316022, JCYJ20250604185241054, JCYJ20250604183605007) and Research Foundation of Shenzhen Hospital of Southern Medical University (grant number: 22H3ATF02, 22H3ATF07). The human agonistic αGITR antibody was kindly provided by Innovent Biologics, Inc.

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  1. These authors contributed equally: Jiayi Zhou, Yinggui Yang, Ran Ye.

Authors and Affiliations

  1. Department of Neurosurgery, The Clinical Innovation & Research Centre, Shenzhen Hospital, Southern Medical University, Shenzhen, Guangdong, China

    Jiayi Zhou, Yinggui Yang, Ran Ye, Jiani Lin, Jiangfan Peng & Zhuohao Liu

  2. The First People’s Hospital of Foshan (Foshan Hospital Affiliated to Southern University of Science and Technology), School of Medicine, Southern University of Science and Technology, Foshan, Guangdong, China

    Jiayi Zhou

  3. Shenzhen School of Clinical Medicine, Southern Medical University, Shenzhen, Guangdong, China

    Jiayi Zhou, Yinggui Yang, Ran Ye, Jiani Lin, Jiangfan Peng & Zhuohao Liu

  4. Department of Oncology, Shenzhen Hospital, Southern Medical University, Shenzhen, Guangdong, China

    Huiyi Feng

  5. Department of Pathology, Shenzhen Hospital, Southern Medical University, Shenzhen, Guangdong, China

    Xiaojuan Pei & Mingzhen Li

  6. Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, China

    Xiaojuan Pei & Mingzhen Li

  7. Department of Neurosurgery, Shenzhen Yantian District People’s Hospital, Shenzhen, Guangdong, China

    Xinzhi Yang

  8. Department of Surgery, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China

    Peter Yat Ming Woo, Danny Tat Ming Chan & Dinglan Wu

  9. State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, China

    Penghui Zhou

  10. Department of Neurosurgery, Longgang Central Hospital of Shenzhen, Shenzhen, Guangdong, China

    Jie Mao

  11. Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong, China

    Dinglan Wu

  12. Shenzhen Research Institute, The Chinese University of Hong Kong, Shenzhen, Guangdong, China

    Dinglan Wu

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Contributions

JZ and RY performed most of the experiments. YY established the protocol of TIL expansion and cytotoxicity assessment. JL, HF, ML, and JP performed some of the experiments. XP, XY, and PZ provided technical supports. JM collected the clinical human samples. DW and ZL designed the experiments, supervised the work, wrote the manuscript, and contributed to conceptual advice. DW, ZL, JM, PW, and DC revised the manuscript.

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Correspondence to Jie Mao, Zhuohao Liu or Dinglan Wu.

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Zhou, J., Yang, Y., Ye, R. et al. GITR activation potentiates anti-tumor immunity of tumor-infiltrating lymphocytes expanded from glioblastoma by rescuing exhaustion. Oncogene 45, 1087–1099 (2026). https://doi.org/10.1038/s41388-026-03705-z

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