Targeted degradation of sICOSL reverses cytotoxic T cells dysfunction
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. sIC...
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| Format: | Article |
| Language: | English |
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BMC
2025-07-01
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| Series: | Experimental Hematology & Oncology |
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| Online Access: | https://doi.org/10.1186/s40164-025-00692-x |
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| author | Zhenghao Wu Peng Zheng Ruobing Qi Yunxiao Xiao Zihan Xi Lei Dai Tao Chen Qianheng Wang Furong Zhang Rong Wang Zimei Tang Xiangwang Zhao Jie Tan Jie Ming Ping Lei Chunping Liu Tao Huang |
| author_facet | Zhenghao Wu Peng Zheng Ruobing Qi Yunxiao Xiao Zihan Xi Lei Dai Tao Chen Qianheng Wang Furong Zhang Rong Wang Zimei Tang Xiangwang Zhao Jie Tan Jie Ming Ping Lei Chunping Liu Tao Huang |
| author_sort | Zhenghao Wu |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-fa0c248f07ff4a98923e975f34a242db |
| institution | Kabale University |
| issn | 2162-3619 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | BMC |
| record_format | Article |
| series | Experimental Hematology & Oncology |
| spelling | doaj-art-fa0c248f07ff4a98923e975f34a242db2025-08-20T04:01:52ZengBMCExperimental Hematology & Oncology2162-36192025-07-0114112110.1186/s40164-025-00692-xTargeted degradation of sICOSL reverses cytotoxic T cells dysfunctionZhenghao Wu0Peng Zheng1Ruobing Qi2Yunxiao Xiao3Zihan Xi4Lei Dai5Tao Chen6Qianheng Wang7Furong Zhang8Rong Wang9Zimei Tang10Xiangwang Zhao11Jie Tan12Jie Ming13Ping Lei14Chunping Liu15Tao Huang16Department of Breast and Thyroid Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and TechnologyDepartment of Breast and Thyroid Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and TechnologyDepartment of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and TechnologyDepartment of Breast and Thyroid Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and TechnologyDepartment of Breast and Thyroid Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and TechnologyDivision of Cardiology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and TechnologyGuangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Medical Research Center, Sun Yat-Sen Memorial Hospital Sun Yat-Sen UniversityDepartment of Breast and Thyroid Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and TechnologyDepartment of Breast and Thyroid Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and TechnologyDepartment of Breast and Thyroid Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and TechnologyDepartment of Breast and Thyroid Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and TechnologyDepartment of Breast and Thyroid Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and TechnologyDepartment of Breast and Thyroid Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and TechnologyDepartment of Breast and Thyroid Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and TechnologyDepartment of Immunology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and TechnologyDepartment of Breast and Thyroid Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and TechnologyDepartment of Breast and Thyroid Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and TechnologyAbstract 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.https://doi.org/10.1186/s40164-025-00692-xBreast cancerCytotoxic T cellsImmune evasionProtein targeted degradationICOSL |
| spellingShingle | Zhenghao Wu Peng Zheng Ruobing Qi Yunxiao Xiao Zihan Xi Lei Dai Tao Chen Qianheng Wang Furong Zhang Rong Wang Zimei Tang Xiangwang Zhao Jie Tan Jie Ming Ping Lei Chunping Liu Tao Huang Targeted degradation of sICOSL reverses cytotoxic T cells dysfunction Experimental Hematology & Oncology Breast cancer Cytotoxic T cells Immune evasion Protein targeted degradation ICOSL |
| title | Targeted degradation of sICOSL reverses cytotoxic T cells dysfunction |
| title_full | Targeted degradation of sICOSL reverses cytotoxic T cells dysfunction |
| title_fullStr | Targeted degradation of sICOSL reverses cytotoxic T cells dysfunction |
| title_full_unstemmed | Targeted degradation of sICOSL reverses cytotoxic T cells dysfunction |
| title_short | Targeted degradation of sICOSL reverses cytotoxic T cells dysfunction |
| title_sort | targeted degradation of sicosl reverses cytotoxic t cells dysfunction |
| topic | Breast cancer Cytotoxic T cells Immune evasion Protein targeted degradation ICOSL |
| url | https://doi.org/10.1186/s40164-025-00692-x |
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