CD8+ T cells control tumors but inevitably become dysfunctional. Ionic metabolism is emerging as a regulator of CD8+ T cells in anti-tumor immunity. We show that sodium chloride (NaCl) counteracts T-cell dysfunction to promote cancer regression. NaCl supplementation during CD8+ T-cell culture induced potent effector differentiation, IFN-g production and cytotoxicity while maintaining gene networks responsible for stem-like plasticity. Accordingly, adoptive transfer of tumor-specific T cells resulted in superior anti-tumor immunity in a humanized model. In mice, high-salt diet reduced growth of experimental tumors in a CD8+ T cell-dependent manner, by inhibiting terminal differentiation, and by enhancing the effector potency of CD8+ T cells. Mechanistically, NaCl enhanced glutamine consumption that was critical for transcriptional, epigenetic and functional reprogramming. In humans, CD8+ T cells undergoing antigen recognition in tumors and predicting favorable response to checkpoint blockade immunotherapy resembled those induced by NaCl. Thus, NaCl metabolism is a major regulator of CD8+ T-cell effector function, with potential translation in cancer immunotherapy.