Exploring landscapes of T cell activation in acidic environment for tumor immunotherapy

Effector T cells are central to anti‑cancer immunity but, within the nutrient‑poor, hypoxic, and acidic tumor microenvironment (TME) sculpted by dysregulated tumor metabolism, they become dysfunctional. Tumor cell-derived lactic acid accumulates in the tumor microenvironment as lactate and protons; while lactate's immunosuppressive effects are well established, the contribution of the accompanying protons remains largely unknown. We hypothesized that extracellular acidity per se programs T cell activation. Here we show that lactate‑independent extracellular acidity-achieved by titrating media with hydrochloric acid or sodium carbonate to tumor‑relevant pH-impairs acquisition of inflammatory effector signatures and curtails clonal expansion in T cells. Collectively, the results indicate that protons may underlie the TME‑driven limitation on T‑cell antitumor activity. Thus, defining the molecular sensors and signaling nodes that transduce proton stress should reveal druggable targets and rational combination strategies for microenvironmental reconditioning to enhance tumor immunotherapy.