Figure 3.

Macrophage iron metabolism and immune response in the tumor microenvironment. Within the microenvironment macrophage phenotype is influenced by iron metabolism, and both iron and immune status are correlated with tumor growth and therapy response. Along a gradient of tumor iron concentration established according to systemic metabolic background and mode of therapy, macrophages can adopt various polarization states spanning a continuum between M1 anti-tumor/proinflammatory activation and M2 pro-tumor wound-healing states. Low tumor iron is associated with reduced tumor growth and favors M2-like macrophage polarization with increased expression of ferroportin, lipocalin 2 and transferrin receptor, and reduced ferritin content. High tumor iron is similarly associated with reduced tumor growth and favors M1-like macrophage polarization with lower expression of ferroportin, lipocalin 2 and transferrin receptor, and increases in ferritin iron storage. Between these two extremes the heterogeneous distribution of macrophage polarization states supports an intermediate iron regime where iron-addicted cancer cells expressing low levels of ferroportin, and high levels of ferritin, lipocalin 2 and transferrin receptor co-opt macrophage’s innate role in iron handling to support malignancy.