Iron and metabolic rewiring in cancer

Iron enables tumor cells to maintain pro-tumoral functions including DNA synthesis and repair, drug resistance and metabolic processes such as oxidative phosphorylation and regulation of reactive oxygen species. To meet these demands, tumor cells rewire iron metabolism to increase iron uptake and use. Therefore, disrupting iron metabolism either by limiting availability or by exploiting iron accumulation to induce ferroptosis, might be a promising strategy for cancer therapy. Recent studies suggest that other cell populations in the tumor microenvironment, including immune cells and cancer-associated fibroblasts, depend on iron and can contribute to iron dysregulation in tumors. Here, we will discuss how iron-dependent pathways contribute to tumor development, with a focus on iron sulfur cluster proteins and heme and their effects on metabolism. In addition, we will describe the relevance of iron crosstalk within the tumor microenvironment in promoting tumor growth, metabolic reprogramming and immune evasion. Finally, we will explore the therapeutic potential of targeting iron-dependent processes beyond the scope of ferroptosis.