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...
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| Main Authors: | , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Nature Publishing Group
2025-08-01
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| Series: | Cell Death and Disease |
| Online Access: | https://doi.org/10.1038/s41419-025-07905-5 |
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| Summary: | 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. |
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| ISSN: | 2041-4889 |