Can NaCl predict or even enhance responses to immunotherapy in cancer?

The advent of immune checkpoint blockers (ICB) has transformed cancer treatment, but reliable predictive biomarkers remain limited. Emerging evidence suggests that sodium chloride (NaCl) modulates immune responses and may synergize with ICB in solid tumors. NaCl enhances CD8 T cell activation, boosting their metabolic reprogramming, effector function, and antitumor activity. It also promotes a pro-inflammatory shift in CD4 T cells and inhibits regulatory T cell function, supporting a pro-immunogenic tumor microenvironment. Conversely, NaCl impacts myeloid cells by reducing the suppressive activity of myeloid-derived suppressor cells and altering macrophage polarization. Preclinical studies reveal that dietary NaCl may augment ICB efficacy and highlight its potential as a combinatorial therapeutic strategy. Retrospective clinical data and post-hoc analyses of phase 3 clinical trials indicate that elevated serum sodium levels are associated with improved survival and enhanced response to ICB in cancer patients. These findings suggest that serum sodium could serve as a simple and predictive biomarker for treatment outcomes. However, prolonged high-sodium diet may promote chronic inflammation and cardiovascular disease, raising concerns about long-term safety. Gaps in mechanistic understanding persist regarding the correlation between dietary sodium, serum sodium, and intratumoral NaCl levels. This review discusses current evidence supporting NaCl's immunomodulatory effects and its potential as both a biomarker and therapeutic adjunct in cancer immunotherapy. We advocate for randomized clinical trials to evaluate NaCl-based interventions, given the low associated risks and costs. Clarifying NaCl's role could pave the way for novel, cost-effective strategies to enhance ICB efficacy and improve outcomes for patients with cancer.