Tumour electrophysiological abnormalities, characterised by membrane potential dysregulation, ion channel network remodelling, and microenvironmental signalling interactions, are critical drivers of malignancy.

A central feature is the depolarization of the transmembrane resting potential (Vm), a hallmark of tumour cells that promotes proliferation, maintains cancer stem cell (CSCs) undifferentiated states, and facilitates metastatic remodelling.

These abnormalities extend beyond the plasma membrane: CSCs exhibit mitochondrial membrane potential hyperpolarization with a pronounced pH gradient between the matrix and cytoplasm, enhancing their malignant properties.

​Tumour-specific "ion channel fingerprints" interact with key signalling pathways to drive malignancy.

TRPV1, for instance, acts bidirectionally: in multiple myeloma, its inhibition induces endoplasmic reticulum stress and mitochondrial calcium overload, synergizing with bortezomib to overcome drug resistance.

In gastric cancer, low TRPV1 expression reduces Ca²⁺/CaMKKβ/AMPK activity, relieving cyclin D1 and MMP2 inhibition to promote invasion and correlate with poor prognosis.

In medulloblastoma, Kir2.1 interacts with Adam10 via non-ion channel mechanisms, enhancing Notch2 cleavage and activating the C-Myc/Slug axis, driving EMT, metastasis, and reducing 5-year survival.

The tumour microenvironment’s electrophysiological remodelling also modulates immunosuppression: elevated interstitial potassium reprograms tumour-associated macrophages (TAMs) via Kir2.1, suppressing inflammatory genes while promoting immunosuppressive factor secretion.

In glioblastoma, the EAG2-Kvβ2 complex at the tumour-brain interface enhances proliferation, invasion, and chemoresistance through calcium transient modulation.

​Precision therapies targeting these abnormalities have advanced significantly.

Structure-guided drugs like K90-114TAT, designed from Kvβ2’s crystal structure, inhibit EAG2-Kvβ2 interactions, reducing tumour size in glioma models, including temozolomide-resistant subtypes.

Compounds exploiting electrochemical gradients, such as the K⁺/H⁺ transporter Compound 2, target mitochondrial pH gradients and hyperpolarization in CSCs, triggering ROS surges to eliminate CD133⁺ ovarian CSCs.

Electric field therapies (TTFields) disrupt mitosis by interfering with microtubules and Septin, while increasing membrane and blood-brain barrier permeability to enhance drug delivery; combining TTFields with temozolomide improves glioblastoma prognosis.

Multimodal approaches, like Kir2.1 inhibitors with PD-1 antibodies to reverse TAM M2 polarisation, or irreversible electroporation (IRE) with TLR3/9 agonists and PD-1 blockade to boost CD8⁺ T cell cytotoxicity, show strong synergy.

​Clinical applications have made strides.

A pan-European study on electrochemotherapy (ECT) for cutaneous malignancies reported high response rates, with Kaposi's sarcoma and basal cell carcinoma responding best.

High-frequency irreversible electroporation (H-FIRE) effectively ablates localised prostate cancer while preserving function with mild complications.

Nanodelivery systems like M-UCN-T release nitric oxide in response to near-infrared light and glutathione, activating endoplasmic reticulum TRPV1 to induce calcium release and immunogenic cell death, suppressing gliomas without systemic toxicity.

​Translational challenges persist: IRE with γδ T-cell therapy prolongs survival but risks gastrointestinal bleeding and biliary obstruction, limiting use in high-risk patients.

H-FIRE needs larger studies to validate long-term efficacy across tumours.

Future directions include pH-responsive TRPV1 modulator delivery systems targeting the bone marrow to reduce neuropathic pain, dynamic monitoring platforms tracking immune cells, and advanced nanoparticle systems like M-UCN-T (92% tumour suppression).

These innovations aim to advance precision electrophysiological tumour therapy.

Source: FAR Publishing Limited