Targeted degradation of sICOSL reverses cytotoxic T cells dysfunction

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.

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Publication Details

Journal
Experimental Hematology and Oncology
Published
2025-07-24
DOI
https://doi.org/10.1186/s40164-025-00692-x
Primary Topic
Peptidase Inhibition and Analysis
Type
article
Field-Weighted Citation Impact
0.00

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article

Targeted degradation of sICOSL reverses cytotoxic T cells dysfunction

Peng Zheng, Zimei Tang, Jie Tan, Xiangwang Zhao et al.
Experimental Hematology and Oncology
Peptidase Inhibition and Analysis
article

Targeted degradation of sICOSL reverses cytotoxic T cells dysfunction

Peng Zheng, Zimei Tang, Jie Tan, Xiangwang Zhao, Zhenghao Wu, Jie Ming, Qianheng Wang, Yunxiao Xiao, Zihan Xi, Tao Chen, Furong Zhang, Rong Wang, Chunping Liu, Lei Dai, Tao Huang, Ruobing Qi
article en

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.

Experimental Hematology and OncologyVol. 14(1)
Union Hospital (HK), Sun Yat-sen University (CN), Sun Yat-sen Memorial Hospital (CN), Wuhan Union Hospital (CN), Tongji Hospital (CN), Union Hospital (CN), Huazhong University of Science and Technology (CN)
National Natural Science Foundation of China, Natural Science Foundation of Hubei Province
Good health and well-being
Openalex Percentile: Top 73%
Peptidase Inhibition and Analysis
DOIOpen Access PDFOpenAlex
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