Iron and Cancer

Iron is required for numerous essential processes, including DNA synthesis, DNA repair, and cellular metabolism. Cancer cells frequently demonstrate an enhanced demand for iron when compared to slowly cycling non-cancer cells due to their increased reliance on these processes. Manifestations of this demand include up-regulation of iron import, decrease in iron export, alterations in iron intracellular trafficking, as well as alterations in "iron gene" expression signatures that can predict prognosis. Cells of the tumor microenvironment, including T cells, tumor-associated macrophages, and cancer-associated fibroblasts, crosstalk with tumor cells to further modulate tumor iron status. Dietary iron, particularly heme iron, has been associated with increased cancer risk, although the influence of iron on immune cells of the microenvironment may modulate this risk. Tumor cell reliance on iron creates therapeutic opportunities. For example, the excess iron accumulated by cancer cells renders them susceptible to agents that induce ferroptosis, an iron-dependent form of cell death. In addition, significant progress has been made in the design of agents to target tumor cell iron dependence in other ways, including small molecule iron chelators and agents that target iron uptake, some of which are in current clinical trials. Recent discoveries, such as the key role of iron recycling in KRAS-mutated pancreatic cancer, are expected to further accelerate the transition of such agents to the clinic.