Can the Tumor Microenvironment Alter Ion Channels? Unraveling Their Role in Cancer

Abstract

Neoplastic cells are characterized by metabolic reprogramming, known as the Warburg effect, in which glucose metabolism is predominantly directed toward aerobic glycolysis, with reduced mitochondrial oxidative phosphorylation and increased lactate production even in the presence of oxygen. This phenomenon provides cancer cells with a proliferative advantage, allowing them to rapidly produce energy (in the form of ATP) and generate metabolic intermediates necessary for the biosynthesis of macromolecules essential for cell growth. It is important to understand the role of ion channels in the tumor context since they participate in various physiological processes and in the regulation of the tumor microenvironment. These changes may contribute to the development and transformation of cancer cells, as well as affect the communication between cells and the surrounding microenvironment, including impaired or altered expression and functionality of ion channels. Therefore, the aim of this review is to elucidate the impact of the tumor microenvironment on the electrical properties of the cellular membranes in several cancers as a possible therapeutic target.

Keywords: KATP; TRPM5; connexins; ion channels; pannexins; tumor microenvironment.

Figure 1

Crosstalk and regulation of ion channels in the tumor microenvironment (TME). This schematic illustrates the interactions of various ion channels in the tumor microenvironment (TME) of a cancer cell. Connexin (Cx) facilitates ATP transfer between adjacent cells, promoting intercellular communication. The K_ATP channel is inhibited by ATP but activated by intracellular and extracellular lactate. Pannexin (Panx) mediates ATP release into the extracellular space, where ATP binds to the purinergic receptor P2X, triggering an increase in intracellular Ca²⁺ levels, stored in the endoplasmic reticulum. Elevated Ca²⁺ concentration activates TRPM5, but its activity is suppressed by protons in the acidic TME. Lactate, transported via monocarboxylate transporters (MCT), contributes to microenvironmental modulation, influencing ion homeostasis, signaling, and tumor progression. Red arrows indicate the activation, red T bars indicate inhibition of the channels, and black arrows indicate the passage of the molecules through the channels in the extracellular and intracellular matrix. Image created with BioRender.com (accessed on 11 March 2025).

Figure 2

Comparison between the structures of pannexins (Panx) and connexins (Cx). Four transmembrane regions are linked by two extracellular loops and a single cytoplasmic loop with both the N- and C-terminal ends positioned within the cytosol. On the left, pannexins form hemichannels, containing two cysteine (Cys) loops, and one of them undergoes glycosylation (tree-like structure) and releases chemical signals (<1.5 kDa) into the extracellular environment, such as adenosine triphosphate (ATP), nicotinamide adenine dinucleotide (NAD⁺), adenosine 3′,5′-cyclic monophosphate (cAMP), ions (Ca²⁺, K⁺, Na⁺, Cl⁻), prostaglandins (PGs), and neurotransmitters such as gamma-aminobutyric acid (GABA) and glutamate. On the right, connexins undergo cell–cell interactions, containing three cysteine residues in each of their extracellular loops, allowing the direct exchange of small molecules (<1 kDa) such as glucose, second messengers like inositol 1,4,5-trisphosphate (IP₃), ATP, cAMP, ions (Ca²⁺, K⁺, Na⁺, Cl⁻), and small amino acids between adjacent cells. Image created with BioRender.com (accessed on 26 March 2025).