Decoding the immune landscape in Ewing sarcoma pathogenesis: The role of tumor infiltrating immune cells and immune milieu

Ewing sarcoma (EwS) is the second most prevalent pediatric bone malignancy, characterized by its aggressive behavior and unfavorable prognosis. The tumor microenvironment (TME) of EwS is shaped by immunosuppressive components, including myeloid-derived suppressor cells, tumor-associated macrophages, and immune checkpoint molecules such as PD-1/PD-L1 and HLA-G. These elements impair anti-tumor immune responses by modulating the function of tumor-infiltrating immune cells, such as regulatory T cells (Tregs), CD8+ T cells, and natural killer cells. Chemokines, including CXCL9 and CXCL12, and cytokines, such as transforming growth factor-beta and interleukin-10, further contribute to immune suppression and promote metastatic dissemination. Recent advances in immunotherapy have highlighted the therapeutic potential of modulating immune cells and signaling pathways to enhance anti-tumor immunity. This review provides a comprehensive analysis of the complex immune landscape within the EwS TME, focusing on the mechanistic roles of key immune components and their potential as therapeutic targets. Understanding these interactions could pave the way for innovative treatment strategies to improve clinical outcomes in patients with EwS.