A High-salt diet induces immune-independent re-differentiation of melanoma, metabolic shut down and cell-cycle arrest

A high salt diet (HSD) is known to reduce cancer growth in some models, due to accumulation of sodium in the skin, which enhanced local anti-tumor immunity. Here we show that a HSD inhibits melanoma growth in both skin and lung, independent from sodium accumulation and from immune cells. Melanoma cells from mice on a HSD upregulated the metabolic inhibitor Tuberous sclerosis complex 2 (TSC2), causing metabolic shutdown, despite nutrient availability. Furthermore, Microphthalmia-associated transcription factor (MITF), a crucial regulator of melanoma metabolism and differentiation, was upregulated, resulting in enhanced melanogenesis and cell cycle arrest. Thus, a HSD reversed the dedifferentiation of melanoma tumor cells and promoted their re-differentiation into a “normal”, melanocytic state. These findings suggest the anti-tumor effects of a HSD may be tumor specific and in some cases immune-independent.