Integrative analysis of T cell-associated markers in Ewing sarcoma reveals prognostic signatures and immune dynamics.
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BACKGROUND: Ewing sarcoma (ES) is a rare and aggressive pediatric bone malignancy with poor prognosis, driven by therapy-resistant tumor microenvironments (TME). The TME plays a critical role in tumor progression through a complex and dynamic network of reciprocal interactions among immune cells (dysfunctional T cells, immunosuppressive macrophages), stromal components (cancer-associated fibroblasts), and tumor cells. These interactions collectively shape the immune landscape, promote immune evasion, and contribute to therapeutic resistance. Identifying reliable prognostic markers remains a critical challenge. METHODS: Here we performed an integrated single-cell RNA sequencing, WGCNA, and bulk RNA-seq analyses to investigate tumor-immune interactions. Differentially expressed genes (DEGs) intersected with T cell markers identified a total of 174 T cell-associated genes. Functional enrichment analysis and molecular subtyping were performed to explore immune-related pathways. A prognostic model based on CLEC11A, BDP1, and ID3 was constructed using Cox regression and validated in external datasets. Immune infiltration was assessed using the CIBERSORT algorithm. RESULTS: T cell marker analyses revealed key roles in pathways such as PI3K-Akt signaling and immune modulation. Molecular subtyping identified two clusters with distinct immune microenvironments: Cluster C1 (immunosuppressive phenotype and poorer prognosis) and Cluster C2 (functionally active immune profile associated with better prognosis). The prognostic model demonstrated high predictive accuracy for 1-, 3-, and 5-year survival (AUC: 0.85, 0.82, 0.78). Additionally, a higher tumor mutation burden (TMB) with low survival rate has been observed in High-risk group. Immune infiltration analysis showed higher CD8+ T cell and dendritic cell activity and immune checkpoint expression in low-risk groups. Experimental validation demonstrated that ID3 silencing inhibited tumor cell proliferation and induced cell cycle arrest in ES cell lines. CONCLUSION: Together, our study identified CLEC11A, BDP1, and ID3 as key T cell associated prognostic markers and developed a validated model to predict survival outcomes in ES. Insights into T cell markers and tumor-immune dynamics offer promising advances in prognostic assessment and immunotherapy for ES. Furthermore, the role of ID3 in immune evasion and tumor proliferation underscores its potential as a therapeutic target, providing new avenues for immune checkpoint regulation and personalized treatment strategies.