Pediatric oncology has pioneered key concepts of cancer therapy: aggressive chemotherapy, international standardization, inclusive clinical trials, and minimal residual disease monitoring. However, few targeted therapies are yet available for childhood cancers, and low mutation rates limit the number of suitable drug targets and the impact of immunotherapies. Innovative approaches will be needed, most notably for Ewing sarcoma, which has seen stagnating rates of patient survival. This project is based on the concept that targeted reprogramming of the tumor microenvironment in Ewing sarcoma may help break chemotherapy resistance and thereby improve treatment response and survival. It uses state-of-the-art technologies (single-cell seuqencing, spatial transcriptomics, epigenomics) to establish a comprehensive map of the Ewing sarcoma microenvironment, and co-culture assays to functionally evaluate whether epigenome reprogramming of non-tumor cells can provide a viable strategy for therapeutically targeting the Ewing sarcoma microenvironment. A complementary approach using both prospective and retrospective cohorts is used in order to combine the advantages of both methods, and bioinformatic data integration ensures coherent results. Alignment with the call: Clear hypothesis with translational relevance; Access to Ewing sarcoma patient material; Broad relevance for cancers with low mutation rate; reinforcing Vienna's leadership in translational research.