biostudies-literatureWu HNatural Science Foundation of Beijing Municipality (Beijing Natural Science Foundation)1609-1620https://www.ebi.ac.uk/biostudies/studies/S-EPMC11091087biostudies-literatureUnknown130(10)<h4>Background</h4>Chordomas are rare osseous neoplasms with a dismal prognosis when they recur. Here we identified cell surface proteins that could potentially serve as novel immunotherapeutic targets in patients with chordoma.<h4>Methods</h4>Fourteen chordoma samples from patients attending Xuanwu Hospital Capital Medical University were subjected to single-cell RNA sequencing. Target molecules were identified on chordoma cells and cancer metastasis-related signalling pathways characterised. VEGFR-targeting CAR-T cells and VEGFR CAR-T cells with an additional TGF-β scFv were synthesised and their in vitro antitumor activities were evaluated, including in a primary chordoma organoid model.<h4>Results</h4>Single-cell transcriptome sequencing identified the chordoma-specific antigen VEGFR and TGF-β as therapeutic targets. VRGFR CAR-T cells and VEGFR/TGF-β scFv CAR-T cells recognised antigen-positive cells and exhibited significant antitumor effects through CAR-T cell activation and cytokine secretion. Furthermore, VEGFR/TGF-β scFv CAR-T cells showed enhanced and sustained cytotoxicity of chordoma cell lines in vitro compared with VRGFR CAR-T cells.<h4>Conclusions</h4>This study provides a comprehensive single-cell landscape of human chordoma and highlights its heterogeneity and the role played by TGF-β in chordoma progression. Our findings substantiate the potential of VEGFR as a target for CAR-T cell therapies in chordoma which, together with modulated TGF-β signalling, may augment the efficacy of CAR-T cells.British journal of cancerSingle-cell sequencing reveals VEGFR as a potential target for CAR-T cell therapy in chordoma.PMC11091087No.L212039Li XQi MChen ZLiu PDu YZhang CZhang BDuan WWu HfalseSingle-cell sequencing reveals VEGFR as a potential target for CAR-T cell therapy in chordoma.<h4>Background</h4>Chordomas are rare osseous neoplasms with a dismal prognosis when they recur. Here we identified cell surface proteins that could potentially serve as novel immunotherapeutic targets in patients with chordoma.<h4>Methods</h4>Fourteen chordoma samples from patients attending Xuanwu Hospital Capital Medical University were subjected to single-cell RNA sequencing. Target molecules were identified on chordoma cells and cancer metastasis-related signalling pathways characterised. VEGFR-targeting CAR-T cells and VEGFR CAR-T cells with an additional TGF-β scFv were synthesised and their in vitro antitumor activities were evaluated, including in a primary chordoma organoid model.<h4>Results</h4>Single-cell transcriptome sequencing identified the chordoma-specific antigen VEGFR and TGF-β as therapeutic targets. VRGFR CAR-T cells and VEGFR/TGF-β scFv CAR-T cells recognised antigen-positive cells and exhibited significant antitumor effects through CAR-T cell activation and cytokine secretion. Furthermore, VEGFR/TGF-β scFv CAR-T cells showed enhanced and sustained cytotoxicity of chordoma cell lines in vitro compared with VRGFR CAR-T cells.<h4>Conclusions</h4>This study provides a comprehensive single-cell landscape of human chordoma and highlights its heterogeneity and the role played by TGF-β in chordoma progression. Our findings substantiate the potential of VEGFR as a target for CAR-T cell therapies in chordoma which, together with modulated TGF-β signalling, may augment the efficacy of CAR-T cells.2024-01-01T00:00:00Z2024 Jun2025-07-13T03:04:31.554Z2025-07-13T03:04:31.554ZS-EPMC110910873860524710.1038/s41416-024-02635-5