cIAP1 inhibitor of apoptosis is a tumor suppressor in Ewing sarcoma

Ewing sarcoma (EwS) is a highly aggressive pediatric malignancy driven by EWSR1::ETS fusion oncoproteins -primarily EWSR1::FLI1- which deregulate genes essential for differentiation, proliferation, and cell survival. To uncover key downstream targets of this fusion involved in cell differentiation, we combined transcriptomic profiling of EwS cell lines following EWSR1::ETS inhibition with gene ontology analysis, a clinically annotated gene expression dataset derived from EwS patient material and network analyses. This integrative approach identified inhibitor of apoptosis protein 1 (cIAP1, alias BIRC2) as an EWSR1::FLI1-suppressed gene. Despite its known oncogenic role in many cancers, cIAP1 showed minimal expression in EwS. Using inducible cIAP1 re-expression models in EwS cells, we demonstrated that cIAP1 re-expression suppresses proliferation, clonogenic growth, and 3D spheroid formation in vitro. Transcriptomic and proteomic analyses revealed that low cIAP1 expression enhances proliferation-related gene signatures, which are inhibited upon cIAP1 re-expression. In vivo xenograft models revealed that cIAP1 re-expression significantly reduces tumor growth, mitotic activity, and Ki-67 positivity, while increasing tumor necrosis and apoptosis. These findings highlight an unexpected tumor-suppressive role for cIAP1 in fusion-driven EwS, contrasting with its pro-survival function in other cancers. Collectively, our results identify cIAP1 as a prognostically relevant, EWSR1::FLI1-regulated hub whose re-expression disrupts tumor progression, offering a potential therapeutic strategy to restore tumor-suppressive pathways in EwS.