Hypoxia and HIFs are especially relevant in the context of EwS because: i) hypoxia is an integral component of the bone microenvironment playing an important role in the development of bone tumors [25–28]; ii) there is a direct interplay between HIF-1-a and EWSR1::FLI1 at the molecular level[29–31]; iii) there is a strong association of extensive tumor necrosis (likely caused by hypoxia) with metastasis and worse patient survival [32]. This evidence concerns the gene HIF1A and neoplasm.