High potassium enhances the immunosuppressive function of myeloid‐derived suppressor cells via Kir4.1‐dependent metabolic reprogramming and promotes tumor immune escape

Despite advances in cancer immunotherapy, low response rates remain a critical clinical challenge. Myeloid-derived suppressor cells (MDSCs) drive tumor immune evasion by directly suppressing antitumor immunity, positioning them as prime therapeutic targets to improve immunotherapy efficacy. While dysregulated ionic microenvironments, particularly elevated potassium, are emerging as broad-spectrum immunomodulators, the role of high potassium in regulating MDSC function remains poorly understood. Here, we demonstrate that elevated extracellular potassium reprograms MDSC differentiation toward an immunosuppressive phenotype via the activation of the inwardly rectifying potassium channel Kir4.1. Mechanistically, Kir4.1 triggers metabolic rewiring by upregulating fatty acid-binding protein 3, thereby enhancing fatty acid uptake and oxidation to fuel the production of immunosuppressive molecules. In preclinical models, pharmacological inhibition of Kir4.1 with VU0134992 reversed MDSC-mediated T cell suppression, remodeled the tumor microenvironment, and synergized with anti-PD-1 therapy to achieve superior antitumor responses. Clinically, elevated Kir4.1 expression in tumor-infiltrating MDSCs correlates with an adverse prognosis in patients with lung and gastric cancer. Our study establishes Kir4.1 as a critical metabolic regulator governing MDSC functionality and proposes targeting potassium signaling as a strategy to overcome resistance to cancer immunotherapies.