<p>Ewing sarcoma (ES) is an aggressive pediatric tumor that presents an important major chimeric transcript factor (TF), EWSR1::FLI1. Such a TF can control the induction of cancer stem cells (CSCs) in ES, which are frequently associated with drug resistance and treatment failure in several types of cancer. However, the dynamics of this induction mechanism still need to be clarified. This study aims to investigate CSC activation in ES using a logical model that extends the previously published regulatory network in ES by integrating key molecular players involved in CSC induction. To construct the model, logical formalism was used to infer the states of each component through the logical operators AND, OR, and NOT. In addition, bioinformatics analyses of transcriptomic data from public databases were performed to validate the model results. The model specifically describes time-dependent changes in the upregulation and downregulation of gene signatures characteristic of the mesenchymal differentiation program. The results indicate that the EWSR1::FLI1/miR-145 regulatory circuit drives the activation of intermediate cell states and uncover a previously unexplored let-7/c-Myc regulatory circuit that promotes the acquisition of full stemness. Notably, these intermediate states are commonly associated with increased metastatic potential in cancer. Therefore, this research extends the understanding of CSC induction in ES, highlighting the possible presence of intermediate states that could serve as targets for new therapeutic strategies.</p>