Figure 1.

Zinc accumulates in cancer cells or macrophages depending on the type of tumor. Zn accumulation is characteristic of breast, esophageal, lung, and digestive cancer, and correlates with increased expression of cellular Zn importing proteins (ZIP), suggesting that this mechanism allows them to survive. In this context, the M2-like macrophages in the tumor microenvironment could render Zn-pool labile and readily accessible to cancer cells by metallothionein MT3 and ZnT efflux transporters. Unlike other cancer types, prostate and skin tumors have zinc levels lower than normal tissues. Malignant prostate cells lose zinc importer protein ZIP1 and the ability to accumulate zinc, this in turn is associated with a metabolic rewiring, an increased activity of mitochondrial aconitase (ACO) and consequent high citrate oxidation and respiration. In skin tumor, TAMs import zinc and sustain high intracellular levels by upregulation of ZIP8 and metallothioneins, so contributing to protection of cancer cells from Zn toxicity. Higher Zn abduction might be inferred as one of the mechanisms through which TAMs sustain high oxidative metabolism of cancer cells. In parts the figures are based on speculations and have been prepared by assembling in-house built cellular metabolic pathway outlines with a modified and adapted version of BioRender images.