STS2 deficiency revives CD8+T cells from exhaustion and augments checkpoint blockade efficacy in cancer immunotherapy
Background T-cell exhaustion is a major barrier to effective antitumor immunity and limits the efficacy of cancer immunotherapies. This study investigates the role of suppressor of T-cell signaling 2 (STS2, also known as UBASH3A) in regulating CD8+ T-cell exhaustion within the tumor microenvironment...
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| Format: | Article |
| Language: | English |
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BMJ Publishing Group
2025-06-01
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| Series: | Journal for ImmunoTherapy of Cancer |
| Online Access: | https://jitc.bmj.com/content/13/6/e010735.full |
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| author | Chunxiao Li Fei Ma Ying Zhang Ting Wang Hongnan Mo Ning Zhong Dongkui Xu Fangzhou Sun Yantong Zhou Jianbin Guo Zhenguo Zhao Xiaoqi Yang Haili Qian |
| author_facet | Chunxiao Li Fei Ma Ying Zhang Ting Wang Hongnan Mo Ning Zhong Dongkui Xu Fangzhou Sun Yantong Zhou Jianbin Guo Zhenguo Zhao Xiaoqi Yang Haili Qian |
| author_sort | Chunxiao Li |
| collection | DOAJ |
| description | Background T-cell exhaustion is a major barrier to effective antitumor immunity and limits the efficacy of cancer immunotherapies. This study investigates the role of suppressor of T-cell signaling 2 (STS2, also known as UBASH3A) in regulating CD8+ T-cell exhaustion within the tumor microenvironment.Methods We used genetic ablation of STS2 in mouse models to assess tumor control and responses to anti-programmed cell death protein 1 (PD-1) checkpoint blockade therapy. CD8+ tumor-infiltrating lymphocytes (TILs) were characterized through flow cytometry, mass cytometry, and single-cell transcriptomics. Mechanistic studies included co-immunoprecipitation, protein degradation assays, and endocytosis measurements to elucidate the interplay between STS2 and PD-1.Results STS2 expression progressively increased with T-cell exhaustion. Genetic deletion of STS2 enhanced tumor control and improved responses to anti-PD-1 therapy. STS2-deficient CD8+ TILs maintained a more functional state, exhibiting enhanced effector activity, proliferation, and antitumor efficacy while resisting terminal exhaustion. Mechanistically, we discovered that STS2 physically interacts with PD-1 and modulates its expression, endocytosis, and degradation at the protein level.Conclusions Our findings establish STS2 as a multifaceted regulator of T-cell exhaustion and highlight its potential as a therapeutic target for enhancing antitumor immunity and improving cancer immunotherapy outcomes. |
| format | Article |
| id | doaj-art-9936e1bd7e2744d182c4f7585d7d32c1 |
| institution | Kabale University |
| issn | 2051-1426 |
| language | English |
| publishDate | 2025-06-01 |
| publisher | BMJ Publishing Group |
| record_format | Article |
| series | Journal for ImmunoTherapy of Cancer |
| spelling | doaj-art-9936e1bd7e2744d182c4f7585d7d32c12025-08-20T03:27:52ZengBMJ Publishing GroupJournal for ImmunoTherapy of Cancer2051-14262025-06-0113610.1136/jitc-2024-010735STS2 deficiency revives CD8+T cells from exhaustion and augments checkpoint blockade efficacy in cancer immunotherapyChunxiao Li0Fei Ma1Ying Zhang2Ting Wang3Hongnan Mo4Ning Zhong5Dongkui Xu6Fangzhou Sun7Yantong Zhou8Jianbin Guo9Zhenguo Zhao10Xiaoqi Yang11Haili Qian122 Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China2 Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China6 Department of Gynecological Minimal Invasive Center, Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing, China1 State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China2 Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China1 State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China3 Department of VIP, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China1 State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China1 State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China4 Department of Obstetrics and Gynecology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China5 Departments of Orthopedics, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China1 State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China1 State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, ChinaBackground T-cell exhaustion is a major barrier to effective antitumor immunity and limits the efficacy of cancer immunotherapies. This study investigates the role of suppressor of T-cell signaling 2 (STS2, also known as UBASH3A) in regulating CD8+ T-cell exhaustion within the tumor microenvironment.Methods We used genetic ablation of STS2 in mouse models to assess tumor control and responses to anti-programmed cell death protein 1 (PD-1) checkpoint blockade therapy. CD8+ tumor-infiltrating lymphocytes (TILs) were characterized through flow cytometry, mass cytometry, and single-cell transcriptomics. Mechanistic studies included co-immunoprecipitation, protein degradation assays, and endocytosis measurements to elucidate the interplay between STS2 and PD-1.Results STS2 expression progressively increased with T-cell exhaustion. Genetic deletion of STS2 enhanced tumor control and improved responses to anti-PD-1 therapy. STS2-deficient CD8+ TILs maintained a more functional state, exhibiting enhanced effector activity, proliferation, and antitumor efficacy while resisting terminal exhaustion. Mechanistically, we discovered that STS2 physically interacts with PD-1 and modulates its expression, endocytosis, and degradation at the protein level.Conclusions Our findings establish STS2 as a multifaceted regulator of T-cell exhaustion and highlight its potential as a therapeutic target for enhancing antitumor immunity and improving cancer immunotherapy outcomes.https://jitc.bmj.com/content/13/6/e010735.full |
| spellingShingle | Chunxiao Li Fei Ma Ying Zhang Ting Wang Hongnan Mo Ning Zhong Dongkui Xu Fangzhou Sun Yantong Zhou Jianbin Guo Zhenguo Zhao Xiaoqi Yang Haili Qian STS2 deficiency revives CD8+T cells from exhaustion and augments checkpoint blockade efficacy in cancer immunotherapy Journal for ImmunoTherapy of Cancer |
| title | STS2 deficiency revives CD8+T cells from exhaustion and augments checkpoint blockade efficacy in cancer immunotherapy |
| title_full | STS2 deficiency revives CD8+T cells from exhaustion and augments checkpoint blockade efficacy in cancer immunotherapy |
| title_fullStr | STS2 deficiency revives CD8+T cells from exhaustion and augments checkpoint blockade efficacy in cancer immunotherapy |
| title_full_unstemmed | STS2 deficiency revives CD8+T cells from exhaustion and augments checkpoint blockade efficacy in cancer immunotherapy |
| title_short | STS2 deficiency revives CD8+T cells from exhaustion and augments checkpoint blockade efficacy in cancer immunotherapy |
| title_sort | sts2 deficiency revives cd8 t cells from exhaustion and augments checkpoint blockade efficacy in cancer immunotherapy |
| url | https://jitc.bmj.com/content/13/6/e010735.full |
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