2. Academic Validation
  3. Targeting the TRIM21-PD-1 axis potentiates immune checkpoint blockade and CAR-T cell therapy

Targeting the TRIM21-PD-1 axis potentiates immune checkpoint blockade and CAR-T cell therapy

  • Mol Ther. 2025 Mar 5;33(3):1073-1090. doi: 10.1016/j.ymthe.2025.01.047.
Jie Shi 1,  Zijian Zhang 2,  Hsin-Yi Chen 3,  Yingmeng Yao 1,  Shanwen Ke 1,  Kechun Yu 1,  Jiangzhou Shi 4,  Xiangling Xiao 1,  Chuan He 1,  Bolin Xiang 1,  Yishuang Sun 1,  Minling Gao 1,  Xixin Xing 1,  Haisheng Yu 1,  Xiyong Wang 1,  Wei-Chien Yuan 5,  Bugi Ratno Budiarto 6,  Shih-Yu Chen 3,  Tongcun Zhang 4,  Yu-Ru Lee 7,  Haichuan Zhu 8,  Jinfang Zhang 9
Affiliations

Affiliations

  • 1 Department of Radiation and Medical Oncology, Medical Research Institute, Frontier Science Center for Immunology and Metabolism, Hubei Key Laboratory of Tumor Biological Behavior, Hubei Provincial Clinical Research Center for Cancer, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan 430071, China; Taikang Center for Life and Medical Sciences, Wuhan University, Wuhan 430071, China.
  • 2 Institute of Biology and Medicine, College of Life Sciences and Health, Wuhan University of Science and Technology, Wuhan 430065, China; Key Laboratory of Tropical Biological Resources of Ministry of Education, School of Pharmaceutical Sciences, Hainan University, Haikou 570228, China.
  • 3 Institute of Biomedical Sciences, Academia Sinica, Taipei 115201, Taiwan.
  • 4 Institute of Biology and Medicine, College of Life Sciences and Health, Wuhan University of Science and Technology, Wuhan 430065, China.
  • 5 Department of Life Sciences and Institute of Genome Sciences, National Yang Ming Chiao Tung University, Taipei 112304, Taiwan; Cancer and Immunology Research Center, National Yang Ming Chiao Tung University, Taipei 112304, Taiwan.
  • 6 Institute of Biomedical Sciences, Academia Sinica, Taipei 115201, Taiwan; Taiwan International Graduate Program in Molecular Medicine, National Yang Ming Chiao Tung University and Academia Sinica, Taipei 112304, Taiwan.
  • 7 Institute of Biomedical Sciences, Academia Sinica, Taipei 115201, Taiwan. Electronic address: yrlee@ibms.sinica.edu.tw.
  • 8 Institute of Biology and Medicine, College of Life Sciences and Health, Wuhan University of Science and Technology, Wuhan 430065, China. Electronic address: zhuhaichuan@wust.edu.cn.
  • 9 Department of Radiation and Medical Oncology, Medical Research Institute, Frontier Science Center for Immunology and Metabolism, Hubei Key Laboratory of Tumor Biological Behavior, Hubei Provincial Clinical Research Center for Cancer, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan 430071, China; Taikang Center for Life and Medical Sciences, Wuhan University, Wuhan 430071, China. Electronic address: jinfang_zhang@whu.edu.cn.
PMID: 39905727 DOI: 10.1016/j.ymthe.2025.01.047
Abstract

Dysregulation of T cells is a major limitation for the clinical success of T cell-based Cancer immunotherapies, such as Immune Checkpoint blockade and chimeric antigen receptor (CAR)-T cell therapy. Understanding the underlying mechanisms for regulating T cell functions can facilitate designing therapeutic strategies to improve immunotherapies. Here, we report that TRIM21 impairs CD8+ T cell activation and anti-tumor immunity. Mechanistically, TRIM21 catalyzes the K63-linked ubiquitination on programmed cell death-1 (PD-1) at K233, leading to stabilization of PD-1 through antagonizing its K48-linked ubiquitination and degradation. Thus, TRIM21 knockout (KO) significantly decreases PD-1 expression and enhances the activation of cytotoxic CD8+ T cells, which sensitizes tumors to anti-CTLA-4 immunotherapy. Notably, TRIM21 KO anti-CD19 CAR-T cells exhibit improved anti-tumor efficacy. These results reveal the molecular mechanism by which TRIM21-mediated K63-linked ubiquitination on PD-1 restrains the activation of CD8+ T cells, highlighting that targeting the TRIM21-PD-1 axis as a potential therapeutic strategy to potentiate Cancer Immunotherapy.

Keywords

CAR-T therapy; K63-linked ubiquitination; PD-1; TRIM21; cancer immunotherapy.

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