Abstract

Tenosynovial giant cell tumor (TGCT), as a mesenchymal disorder, continues to pose diagnostic challenges due to its dual inflammatory and neoplastic pathological features. Current therapeutic strategies, including synovectomy, radiotherapy, and adjuvant CSF1R inhibitors, demonstrate limited efficacy in preventing and treating disease recurrence, highlighting the urgent need to elucidate its underlying pathogenic drivers. In this study, we employed single-cell RNA sequencing on human diffuse TGCT synovial tissues, integrated with in vitro fibroblast-like synoviocytes (FLS)-macrophages coculture models and functional assays, to comprehensively analyze cellular crosstalk and malignant-like behaviors, validated through molecular profiling and pharmacological interventions. Integrated molecular profiling unveiled a pathogenic reciprocal crosstalk between synovial macrophages and FLS in TGCT. M2-polarized macrophages promoted FLS invasiveness through SEMA4A/PLXNB2 signaling, mediated by the PLXNB2/RAP2A/YAP1 axis. Single-cell transcriptomics further identified a macrophage-induced MMP1 + MMP3 + FLS subpopulation with potent pro-invasive activity. Conversely, FLS induced M2 polarization via GAS6–MERTK activation, highlighting a self-sustaining signaling circuit contributing to TGCT progression. These results provide new insights into TGCT pathogenesis and identify potential candidate targets for interrupting its self-sustaining pathogenic loop, which deserve further in vivo validation.