Patient-derived vascularized organoid-on-a-chip model for therapeutic response assessment in synovial sarcoma

Synovial sarcoma (SS) lacks effective therapies and physiologically relevant models that faithfully recapitulate the tumor microenvironment. Here, we established synovial sarcoma patient-derived organoids (SPDOs) that preserved the histological, genomic, and transcriptomic features of their parental tumors. Single-cell transcriptomic analysis of paired pre- and post-treatment tumors revealed increased treatment-associated transcriptional remodeling of malignant cells, vascular remodeling, and disruption of tumor-stromal communication following chemotherapy and anti-angiogenic therapy. Guided by these findings, we incorporated cancer-associated fibroblasts (CAFs) and endothelial cells to generate stromal-vascular SPDOs and subsequently established a vascularized SPDO-on-a-chip (VSC) model capable of supporting perfusable vascular networks. Anlotinib markedly disrupted vascular architecture, while the VSC model exhibited distinct drug-response profiles compared with conventional organoids, highlighting the importance of incorporating stromal and endothelial components into preclinical drug evaluation. In a representative clinical case, ex vivo drug responses in the VSC model were concordant with the observed response to doxorubicin-based chemotherapy and anlotinib treatment. In addition, targeted drug testing demonstrated that pazopanib and vorinostat differentially modulated immune-related pathways and SS18-SSX-associated transcriptional programs. Collectively, the VSC model provides a scalable and physiologically relevant platform for studying tumor-vascular interactions and supporting therapeutic response assessment in SS.