LAUSR

Simple Summary Malignant central nervous system (CNS) cancers are notoriously difficult to treat, with just one-third of patients surviving five years post-diagnosis. Their location within the brain and brainstem presents several challenges to successful treatment, including surgical inaccessibility and designing effective therapies that pass the brain’s protective barrier. Furthermore, high-grade CNS cancer is also prone to recurrence, and the secondary tumours that arise are highly resistant to treatment. Potassium ion channels are a class of transmembrane proteins involved in maintaining the electrical microenvironment of cells. In cancers, these proteins are known to play a significant role in the development of cancer hallmarks like proliferation, invasion, and adaptive drug resistance. Our review explores the relationship between potassium ion channel function and the progression of malignant CNS cancers. Targeting these proteins presents a promising, novel treatment strategy, with several FDA-approved potassium ion channel-targeting drugs already in clinical use for various CNS disorders. Abstract Malignant central nervous system (CNS) cancers are among the most difficult to treat, with low rates of survival and a high likelihood of recurrence. This is primarily due to their location within the CNS, hindering adequate drug delivery and tumour access via surgery. Furthermore, CNS cancer cells are highly plastic, an adaptive property that enables them to bypass targeted treatment strategies and develop drug resistance. Potassium ion channels have long been implicated in the progression of many cancers due to their integral role in several hallmarks of the disease. Here, we will explore this relationship further, with a focus on malignant CNS cancers, including high-grade glioma (HGG). HGG is the most lethal form of primary brain tumour in adults, with the majority of patient mortality attributed to drug-resistant secondary tumours. Hence, targeting proteins that are integral to cellular plasticity could reduce tumour recurrence, improving survival. This review summarises the role of potassium ion channels in malignant CNS cancers, specifically how they contribute to proliferation, invasion, metastasis, angiogenesis, and plasticity. We will also explore how specific modulation of these proteins may provide a novel way to overcome drug resistance and improve patient outcomes.