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

## TL;DR

A high-salt diet stops melanoma growth by making cancer cells behave more like normal cells, without needing immune help.

## Contribution

The study reveals a new mechanism where high salt diet causes melanoma re-differentiation and metabolic shutdown, independent of immune cells.

## Key findings

- High-salt diet upregulates TSC2, causing metabolic shutdown in melanoma cells.
- MITF upregulation leads to melanogenesis and cell cycle arrest in melanoma cells.
- Melanoma cells re-differentiate into a normal melanocytic state under high-salt conditions.

## Abstract

High salt diet (HSD) is known to reduce cancer growth in some tumor models, which has been attributed to tissue accumulation of sodium that enhances local anti-tumor immunity. Here, we show that a HSD inhibits melanoma growth independent of sodium accumulation and immune cells in skin and lung. 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 de-differentiation of melanoma cells and promoted their re-differentiation into a “normal” melanocytic state. These findings suggest that the anti-tumor effect of HSD may be tumor-specific and in some cases immune cell-independent.