Background: Dying tumor cells release intracellular potassium (K⁺), raising extracellular K⁺ ([K⁺]_e) in the tumor microenvironment (TME) to 40-50 mM (high-[K⁺]_e). Here, we investigated the effect of high-[K⁺]_e on T cell functions. Materials and Methods: Functional impacts of high-[K⁺]_e on human T cells were determined by cellular, molecular, and imaging assays. Results: Exposure to high-[K⁺]_e suppressed the proliferation of central memory and effector memory T cells, while T memory stem cells were unaffected. High-[K⁺]_e inhibited T cell cytokine production and dampened antitumor cytotoxicity, by modulating the Akt signaling pathway. High-[K⁺]_e caused significant upregulation of the immune checkpoint protein PD-1 in activated T cells. Although the number of K_Ca3.1 calcium-activated potassium channels expressed in T cells remained unaffected under high-[K⁺]_e, a novel K_Ca3.1 activator, SKA-346, rescued T cells from high-[K⁺]_e-mediated suppression. Conclusion: High-[K⁺]_e represents a so far overlooked secondary checkpoint in cancer. K_Ca3.1 activators could overcome such "ionic-checkpoint"-mediated immunosuppression in the TME, and be administered together with known PD-1 inhibitors and other cancer therapeutics to improve outcomes.

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