Potassium channels in cancer: from hallmarks to therapeutic targeting

Potassium channels constitute important signaling nodes in the progression of human cancers. Through canonical ion conduction-dependent functions, including intracellular K⁺ homeostasis, membrane potential and associated Ca²⁺ signaling, and cell volume, they influence proliferation, cell death, phenotypic plasticity, invasion and metastasis, metabolic reprogramming, and angiogenesis. Beyond ion conduction, potassium channels may affect malignant phenotypes through non-canonical mechanisms, including conformational signaling, protein interactions, transcriptional regulation, and auxiliary-subunit functions. They also contribute to tumor microenvironment remodeling by regulating immune and stromal cells and altering antitumor immune responses. However, their biological effects vary with channel subtype, tumor type, functional state, and non-canonical protein interactions, resulting in oncogenic or tumor-suppressive activity. This heterogeneity makes it hard to infer channel function from expression levels alone and also limits the development of selective therapeutic strategies. This review integrates evidence on the canonical and non-canonical functions of potassium channels across distinct cellular contexts, explains the mechanistic basis of their opposing effects, and evaluates their therapeutic potential and the major challenges to clinical translation.