ULBP2 CAR-T cells enhance gastric cancer immunotherapy by inhibiting CAF activation
Abstract Gastric cancer (GC) is characterised by a dense stromal microenvironment, lack of therapeutic targets, and limited effective treatment options, collectively leading to a poor prognosis. Here, we identify UL16 binding protein 2 (ULBP2) as a potential therapeutic target in GC. Mechanistically...
Saved in:
| Main Authors: | , , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Nature Publishing Group
2025-08-01
|
| Series: | Cell Death and Disease |
| Online Access: | https://doi.org/10.1038/s41419-025-07905-5 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1849761106176770048 |
|---|---|
| author | Wentao Zhang Wen Ren Shuyan Guo Haobo Han Weiwen Cai Haowen Bai Long Li Xiangyan Jiang Xin Zheng Tiansheng Zhang Yan Wang Huili Ye Hongtai Cao Wengui Shi Huinian Zhou Zeyuan Yu Long Qin Zuoyi Jiao |
| author_facet | Wentao Zhang Wen Ren Shuyan Guo Haobo Han Weiwen Cai Haowen Bai Long Li Xiangyan Jiang Xin Zheng Tiansheng Zhang Yan Wang Huili Ye Hongtai Cao Wengui Shi Huinian Zhou Zeyuan Yu Long Qin Zuoyi Jiao |
| author_sort | Wentao Zhang |
| collection | DOAJ |
| description | Abstract Gastric cancer (GC) is characterised by a dense stromal microenvironment, lack of therapeutic targets, and limited effective treatment options, collectively leading to a poor prognosis. Here, we identify UL16 binding protein 2 (ULBP2) as a potential therapeutic target in GC. Mechanistically, ULBP2 overexpression activates the TGF-β signalling pathway, promoting the activation of cancer-associated fibroblasts (CAFs) and tumor progression in GC. Furthermore, we developed ULBP2 CAR-T cells and assessed their therapeutic potential in GC cell lines, organoids, cell line-derived xenograft (CDX) and patient-derived xenograft (PDX) mouse models. We showed that ULBP2 CAR-T cells effectively eliminated GC cell lines and organoids and, either alone or in combination with an anti-PD-1 antibody, significantly inhibited tumor growth and prolonged survival in both CDX and PDX mouse models. In conclusion, ULBP2 contributes to GC progression by promoting TGF-β mediated CAF activation, which collectively reinforce the dense stromal microenvironment. Targeting ULBP2 suppresses tumor growth, reduces stromal deposition, and promotes T cell infiltration, thereby enhancing the efficacy of immunotherapy in GC. |
| format | Article |
| id | doaj-art-2cb7935f2a3e4a8294c51b181c965092 |
| institution | DOAJ |
| issn | 2041-4889 |
| language | English |
| publishDate | 2025-08-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death and Disease |
| spelling | doaj-art-2cb7935f2a3e4a8294c51b181c9650922025-08-20T03:06:09ZengNature Publishing GroupCell Death and Disease2041-48892025-08-0116111510.1038/s41419-025-07905-5ULBP2 CAR-T cells enhance gastric cancer immunotherapy by inhibiting CAF activationWentao Zhang0Wen Ren1Shuyan Guo2Haobo Han3Weiwen Cai4Haowen Bai5Long Li6Xiangyan Jiang7Xin Zheng8Tiansheng Zhang9Yan Wang10Huili Ye11Hongtai Cao12Wengui Shi13Huinian Zhou14Zeyuan Yu15Long Qin16Zuoyi Jiao17Cuiying Biomedical Research Center, The Second Hospital & Clinical Medical School, Lanzhou UniversityCuiying Biomedical Research Center, The Second Hospital & Clinical Medical School, Lanzhou UniversityCuiying Biomedical Research Center, The Second Hospital & Clinical Medical School, Lanzhou UniversityCuiying Biomedical Research Center, The Second Hospital & Clinical Medical School, Lanzhou UniversityCuiying Biomedical Research Center, The Second Hospital & Clinical Medical School, Lanzhou UniversityCuiying Biomedical Research Center, The Second Hospital & Clinical Medical School, Lanzhou UniversityDepartment of General Surgery, The Second Hospital & Clinical Medical School, Lanzhou UniversityCuiying Biomedical Research Center, The Second Hospital & Clinical Medical School, Lanzhou UniversityStudent Affairs Office, The Second Hospital & Clinical Medical School, Lanzhou UniversityLanzhou Huazhitiancheng Biotechnologies Co., LtdCuiying Biomedical Research Center, The Second Hospital & Clinical Medical School, Lanzhou UniversityCuiying Biomedical Research Center, The Second Hospital & Clinical Medical School, Lanzhou UniversityDepartment of General Surgery, The Second Hospital & Clinical Medical School, Lanzhou UniversityCuiying Biomedical Research Center, The Second Hospital & Clinical Medical School, Lanzhou UniversityDepartment of General Surgery, The Second Hospital & Clinical Medical School, Lanzhou UniversityDepartment of General Surgery, The Second Hospital & Clinical Medical School, Lanzhou UniversityCuiying Biomedical Research Center, The Second Hospital & Clinical Medical School, Lanzhou UniversityCuiying Biomedical Research Center, The Second Hospital & Clinical Medical School, Lanzhou UniversityAbstract Gastric cancer (GC) is characterised by a dense stromal microenvironment, lack of therapeutic targets, and limited effective treatment options, collectively leading to a poor prognosis. Here, we identify UL16 binding protein 2 (ULBP2) as a potential therapeutic target in GC. Mechanistically, ULBP2 overexpression activates the TGF-β signalling pathway, promoting the activation of cancer-associated fibroblasts (CAFs) and tumor progression in GC. Furthermore, we developed ULBP2 CAR-T cells and assessed their therapeutic potential in GC cell lines, organoids, cell line-derived xenograft (CDX) and patient-derived xenograft (PDX) mouse models. We showed that ULBP2 CAR-T cells effectively eliminated GC cell lines and organoids and, either alone or in combination with an anti-PD-1 antibody, significantly inhibited tumor growth and prolonged survival in both CDX and PDX mouse models. In conclusion, ULBP2 contributes to GC progression by promoting TGF-β mediated CAF activation, which collectively reinforce the dense stromal microenvironment. Targeting ULBP2 suppresses tumor growth, reduces stromal deposition, and promotes T cell infiltration, thereby enhancing the efficacy of immunotherapy in GC.https://doi.org/10.1038/s41419-025-07905-5 |
| spellingShingle | Wentao Zhang Wen Ren Shuyan Guo Haobo Han Weiwen Cai Haowen Bai Long Li Xiangyan Jiang Xin Zheng Tiansheng Zhang Yan Wang Huili Ye Hongtai Cao Wengui Shi Huinian Zhou Zeyuan Yu Long Qin Zuoyi Jiao ULBP2 CAR-T cells enhance gastric cancer immunotherapy by inhibiting CAF activation Cell Death and Disease |
| title | ULBP2 CAR-T cells enhance gastric cancer immunotherapy by inhibiting CAF activation |
| title_full | ULBP2 CAR-T cells enhance gastric cancer immunotherapy by inhibiting CAF activation |
| title_fullStr | ULBP2 CAR-T cells enhance gastric cancer immunotherapy by inhibiting CAF activation |
| title_full_unstemmed | ULBP2 CAR-T cells enhance gastric cancer immunotherapy by inhibiting CAF activation |
| title_short | ULBP2 CAR-T cells enhance gastric cancer immunotherapy by inhibiting CAF activation |
| title_sort | ulbp2 car t cells enhance gastric cancer immunotherapy by inhibiting caf activation |
| url | https://doi.org/10.1038/s41419-025-07905-5 |
| work_keys_str_mv | AT wentaozhang ulbp2cartcellsenhancegastriccancerimmunotherapybyinhibitingcafactivation AT wenren ulbp2cartcellsenhancegastriccancerimmunotherapybyinhibitingcafactivation AT shuyanguo ulbp2cartcellsenhancegastriccancerimmunotherapybyinhibitingcafactivation AT haobohan ulbp2cartcellsenhancegastriccancerimmunotherapybyinhibitingcafactivation AT weiwencai ulbp2cartcellsenhancegastriccancerimmunotherapybyinhibitingcafactivation AT haowenbai ulbp2cartcellsenhancegastriccancerimmunotherapybyinhibitingcafactivation AT longli ulbp2cartcellsenhancegastriccancerimmunotherapybyinhibitingcafactivation AT xiangyanjiang ulbp2cartcellsenhancegastriccancerimmunotherapybyinhibitingcafactivation AT xinzheng ulbp2cartcellsenhancegastriccancerimmunotherapybyinhibitingcafactivation AT tianshengzhang ulbp2cartcellsenhancegastriccancerimmunotherapybyinhibitingcafactivation AT yanwang ulbp2cartcellsenhancegastriccancerimmunotherapybyinhibitingcafactivation AT huiliye ulbp2cartcellsenhancegastriccancerimmunotherapybyinhibitingcafactivation AT hongtaicao ulbp2cartcellsenhancegastriccancerimmunotherapybyinhibitingcafactivation AT wenguishi ulbp2cartcellsenhancegastriccancerimmunotherapybyinhibitingcafactivation AT huinianzhou ulbp2cartcellsenhancegastriccancerimmunotherapybyinhibitingcafactivation AT zeyuanyu ulbp2cartcellsenhancegastriccancerimmunotherapybyinhibitingcafactivation AT longqin ulbp2cartcellsenhancegastriccancerimmunotherapybyinhibitingcafactivation AT zuoyijiao ulbp2cartcellsenhancegastriccancerimmunotherapybyinhibitingcafactivation |