Ewing sarcoma (ES) is a rare but extremely aggressive bone and soft-tissue tumor. Clinical outcomes for patients with metastatic or recurrent ES remain poor, particularly for patients who are resistant to chemotherapy. This underscores an urgent need for alternative treatment strategies for these patients. A deep and comprehensive understanding of the cell-cell communications in ES may help identify new therapeutic approaches.We first applied single-cell RNA sequencing (scRNA-seq) data analysis to map the cell-cell communication network within the ES tumor microenvironment (TME). Then, based on the cell-cell communication map, we inferred that multi-kinase anti-angiogenic inhibitors might effectively treat ES. Therefore, we investigated the anti-tumor efficacy of a novel multi-kinase inhibitor, KC1036, which primarily targets VEGFR2, MET, and AXL in ES cancer cell lines. The efficacy of KC1036 in ES was further validated in cell line-derived xenograft (CDX) models and a treatment-naïve patient-derived xenograft (PDX) model.We plotted a comprehensive cell-cell communication map of ES, where ES was characterized by highly immunosuppressive TME, strong autocrine signal NPY-NPY1R in tumor cells, wide activation of receptor kinase signaling pathways in cancer-associated fibroblasts (CAFs) (e.g., AXL, MET, FGFR, PDGFR, and KIT), and robust activation of tumor angiogenesis pathways (e.g., VEGFA/B-VEGFR1/2). Multi-kinase inhibitor KC1036 effectively inhibited ES tumor growth in both CDX and PDX models with superior efficacy compared to pazopanib, cabozantinib, and doxorubicin (DOX).The novel anti-angiogenic inhibitor, KC1036, is effective in treating ES in the preclinical models.© 2025. The Author(s), under exclusive licence to Springer Nature B.V.