High-Salt Tumor Microenvironment: Not as Bad as It Sounds, Not as Good as It Seems.

Recent evidence suggests a high-sodium microenvironment in breast tumors. However, the exact role of this high-sodium microenvironment on tumorigenesis is unknown. Salt (sodium chloride, NaCl) is a well-known inflammatory molecule playing a significant role in various chronic ailments like cardiovascular and autoimmune diseases. Importantly, chronic inflammation is recognized as one of the major hallmarks of carcinogenesis. Breast cancer cell culture-based studies demonstrated that high-salt (HS) treatment (Δ35-50 mM NaCl) induced cancer cell proliferation. However, preclinical murine research showed reduced tumor progression kinetics in mice fed a short-term HS diet (4% NaCl diet, 0-2 weeks prior to the injection of tumor cells). Molecular studies demonstrated that the short-term HS diet induced the inflammatory activation of naïve CD4+ T cells to the Th17/Th1 anti-tumor phenotype. As human health-related adverse outcomes from HS diets usually occur as a consequence of prolonged HS intake over a period of several years, we have developed a novel chronic HS dietary murine tumor model. In this model, tumor cells are sequentially passaged (four cycles) in vivo under high-salt conditions, and tumor kinetics were analyzed in the passage-4 mice. These studies demonstrated enhanced tumor progression (pro-tumor) under chronic HS dietary conditions through the activation of tumor-initiating stem cells, along with the exhaustion of immune cells. Based on the, apparently paradoxical, evidence, we propose a comprehensive unifying hypothesis to elucidate the complex role of a high-sodium microenvironment towards tumor immune sculpting. This understanding will enable novel drug repositioning strategies, the development of unique ion channel-based anti-cancer therapeutics and promote low-salt diet intake in breast cancer patients on immunotherapy.