Sodium chloride in the tumor microenvironment enhances T cell metabolic fitness and cytotoxicity

The efficacy of antitumor immunity is associated with the metabolic state of cytotoxic T cells, which is highly amenable to perturbation by the tumor microenvironment. It is therefore of tremendous interest to bypass immunosuppressive signaling in the tumor microenvironment and to identify factors that augment T cell immunometabolism, cytotoxic effector functions and eventually tumor killing. Whether ionic signals serve as aberrant immune signals and influence the adaptive human antitumor immune response is still largely unexplored. We demonstrate a significant enrichment of sodium in solid tumors of breast cancer patients, which leaves a transcriptomic imprint on intratumoral immune cells. Sodium chloride (NaCl) enhanced the activation state and effector functions of human CD8+ memory T cells. These functional alterations were associated with improved metabolic fitness, in particular with an increase in glycolysis and oxidative phosphorylation and overall nutrient uptake. These NaCl-induced effects translated into increased tumor cell killing in vitro and in a tumor mouse model in vivo. We therefore propose NaCl as a positive regulator of acute antitumor immunity, which could be harnessed for ex vivo conditioning of adoptively transferred T cells in the future.