Fig. 7

Schematic illustration of the effects of iron chelation and eribulin. Iron depletion can inhibit ribonucleotide reductase (RR) activity that results in suppressed DNA synthesis. Importantly, Iron depletion induces hypoxia and consequently promotes the expression of HIF-1α. HIF-1α can initiate the transcription of genes involved in angiogenesis and iron uptake, namely, VEGF and TfR, respectively. Iron chelation can also result in elevated p53 protein levels via the HIF-1α. Increased p53 stability then results in G1/S arrest and apoptosis via downstream effectors including p21. Furthermore, HIF-1α mediates EMT by upregulating Snail and TWIST1 expression. Increased p53 also induce various EMT transcription factors including ZEB-1 and miR200, and these factors upregulate PD-L1 expression. Eribulin treatment improves tumor immune microenvironment such as hypoxia, EMT and immune check point induced by iron depletion