Iron Metabolism at the Crossroad of Innate Immune Response and Cancer Progression

Iron represents an indispensable component of every living organism since it plays key roles in a wide variety of physiological processes in the body (erythropoiesis, immune function, and host defense) as well as in several fundamental cellular activities. Iron is essential for the catalytic activity of iron- and heme-containing enzymes that are responsible for cellular respiration, DNA synthesis and repair, transcription, cell cycle, cell signaling and apoptosis, angiogenesis, and epigenetic remodeling, among others. However, due to its ability to lose and accept electrons, iron also participates in potentially deleterious free radical-generating reactions, whereby the redox balance of the cell is disturbed. These reactive oxygen species cause severe oxidative damage to proteins, lipids and most importantly, to the DNA, which may either lead to an odd type of iron-dependent programmed cell death called ferroptosis, or to malignant transformation. Therefore, iron acts as a double-edged sword that, on one hand may promote tumor initiation via the formation of free radicals, while on the other hand acts as an essential nutrient favoring tumor progression. Compared to normal cells, cancer cells indeed exhibit an iron-sequestering phenotype achieved due to the up-regulation of iron import and mobilization pathways, while down-regulating storage and export routes. However, these are not the sole mechanisms cancer cells have developed to satisfy their enhanced request in iron supply. It has become increasingly clear that tumor cells-hijack tumor-infiltrating immune cells to satisfy their enhanced iron demand. Along these lines, tumor-associated macrophages are re-programmed towards an iron-releasing phenotype, characterized by higher expression of the only known iron exporter ferroportin. Moreover, alternative macrophage iron secretion pathways include the recently described iron transporter Lipocalin-2 as well as ferritin in order to favor and enhance tumor progression. Metastatic growth can also be further instructed by the local delivery of transferrin produced by tumor-associated neutrophils, another key component of the innate immunity that is actively involved in boosting cancer-associated inflammation.

All these studies highlight our incomplete understanding of the role of iron metabolism in shaping the innate immune response in favor of tumor development/progression. We welcome the submission of Original Research, Review, Mini Review, Hypothesis & Theory, Perspective, and Clinical Trial articles, focusing on, but not limited to, the following topics:

1. How iron handling by infiltrating innate immune cells affect tumor cell growth in diverse types of cancers
2. How iron can affect the adaptive immune response
3. How targeting iron metabolic pathways may offer new therapeutic strategies to fight cancer
4. How Ferroptosis impacts cancer biology and tumor immunity