High Extracellular K⁺ Skews T-Cell Differentiation Towards Tumour Promoting Th2 and T_reg Subsets

Potassium ions (K⁺) released from dying necrotic tumour cells accumulate in the tumour microenvironment (TME) and increase the local K⁺ concentration to 50 mM (high-[K⁺]_e). Here, we demonstrate that high-[K⁺]_e decreases expression of the T-cell receptor subunits CD3ε and CD3ζ and co-stimulatory receptor CD28 and thereby dysregulates intracellular signal transduction cascades. High-[K⁺]_e also alters the metabolic profiles of T-cells, limiting the metabolism of glucose and glutamine, consistent with functional exhaustion. These changes skew T-cell differentiation, favouring Th2 and iT_reg subsets that promote tumour growth while restricting antitumour Th1 and Th17 subsets. Similar phenotypes were noted in T-cells present within the necrosis-prone core versus the outer zones of hepatocellular carcinoma (HCC)/colorectal carcinoma (CRC) tumours as analysed by GeoMx digital spatial profiling and flow-cytometry. Our results thus expand the understanding of the contribution of high-[K⁺]_e to the immunosuppressive milieu in the TME.