2. Academic Validation
  3. Targeted degradation of sICOSL reverses cytotoxic T cells dysfunction

Targeted degradation of sICOSL reverses cytotoxic T cells dysfunction

  • Exp Hematol Oncol. 2025 Jul 24;14(1):100. doi: 10.1186/s40164-025-00692-x.
Zhenghao Wu 1 2 3,  Peng Zheng 4 5,  Ruobing Qi 6,  Yunxiao Xiao 4 5,  Zihan Xi 4,  Lei Dai 7,  Tao Chen 8,  Qianheng Wang 4,  Furong Zhang 4,  Rong Wang 4,  Zimei Tang 4,  Xiangwang Zhao 4,  Jie Tan 4,  Jie Ming 4,  Ping Lei 5,  Chunping Liu 9,  Tao Huang 10
Affiliations

Affiliations

  • 1 Department of Breast and Thyroid Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. wu_zhenghao@126.com.
  • 2 Department of Immunology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. wu_zhenghao@126.com.
  • 3 Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Medical Research Center, Sun Yat-Sen Memorial Hospital Sun Yat-Sen University, Guangzhou, China. wu_zhenghao@126.com.
  • 4 Department of Breast and Thyroid Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
  • 5 Department of Immunology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
  • 6 Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
  • 7 Division of Cardiology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
  • 8 Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Medical Research Center, Sun Yat-Sen Memorial Hospital Sun Yat-Sen University, Guangzhou, China.
  • 9 Department of Breast and Thyroid Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. liucpwhxh@hust.edu.cn.
  • 10 Department of Breast and Thyroid Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. huangtaowh@163.com.
PMID: 40708008 DOI: 10.1186/s40164-025-00692-x
Abstract

Dysfunction of cytotoxic T cells (CTL) remains a major cause of tumor immune evasion and is correlated with poor Cancer survival. Here, we found that increased soluble form of ICOSL (sICOSL) induced CTL dysfunction and was associated with shorter survival of patients with breast Cancer. sICOSL emerged as a formidable adversary to CTLs, by directly triggering ICOS internalization and subsequent degradation-a critical blow to the co-stimulatory machinery essential for CTL activation. Our research shows that dipeptidyl peptidase-4 (DPP4) mainly breaks down sICOSL. Notably, certain chemotherapeutic drugs activate the Histone Methyltransferase Enhancer of zeste homolog 2 (EZH2), which in turn suppresses DPP4 expression. To address this issue, we have developed nanobody-DPP4 fusion proteins that can specifically degrade sICOSL, achieving substrate selectivity and tumor targeting. Overall, This work unveils that sICOSL orchestrates CTL dysfunction, and establishs targeted degradation of sICOSL as a new strategy for immunotherapy.

Keywords

Breast cancer; Cytotoxic T cells; ICOSL; Immune evasion; Protein targeted degradation.

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