Tumor -speaking electrophysiological anomalies, characterized by potential membrane deregulation, remodeling of the network of ion channels and microenvironmental signaling interactions, are critical malignancy motors. A central characteristic is the depolarization of the transmembrane (VM) rest potential, a characteristic of tumor cells which promotes proliferation, maintains the undifferentiated states of stem cells (CSC) and facilitates metastatic remodeling. These anomalies extend beyond the plasma membrane: the CSCs have potential hyperpolarization of the mitochondrial membrane with a pronounced pH gradient between the matrix and the cytoplasm, improving their malignant properties.
The “fingerprints” specific to the tumor “interact with the key signals to train a malignant tumor. TRPV1, for example, acts bidirectionally: in multiple myeloma, its inhibition induces stress of the endoplasmic reticulum and an overload of mitochondrial calcium, in synergy with bortezomib to overcome the resistance to drugs. In gastric cancer, a low expression of TRPV1 reduces Ca²⁺ / Camkkβ / ampk activity, relieving the inhibition of cycline D1 and MMP2 to promote invasion and correlate with a bad prognosis. In the Medulloblastoma, Kir2.1 interacts with Adam10 via non ion channel mechanisms, improving the Notch2 divide and activating the C-MYC / Limace axis, leading EMT, metastases and reducing survival to 5 years. The electrophysiological removal of tumor microenvironnement also module Module also immunosuppression: high reprograms of interstitial potassium tumors (TAM) via KIR2.1, suppressing inflammatory genes while promoting the secretion of immunosuppressive factors. In glioblastoma, the EAG2-KVβ2 complex at the tumor-end interface improves proliferation, invasion and chemoresistance by transitional modulation of calcium.
Precision therapies targeting these anomalies have gradually advanced. Drugs guided by structure like K90-114TAT, designed from the crystalline structure of KVβ2, inhibit EAG2-KVβ2 interactions, reducing the size of tumors in glioma models, including temozolomide resistant subtypes. Compounds operating electrochemical gradients, such as the compound of the K⁺ / H⁺ transporter, target mitochondrial pH gradients and hyperpolarization in CSCs, triggering ROS overvoltage to eliminate CD133⁺ CSC. Therapies on the electric fields (TTFIELDS) disrupt mitosis by interfering with microtubules and septine, while increasing the permeability of the membrane and blood-blood barrier to improve the administration of drugs; The combination of Ttfields with the temozolomide improves the prognosis for glioblastoma. Multimodal approaches, such as Kir2.1 inhibitors with PD-1 antibodies to reverse Tam M2 polarization, or irreversible electroporation (IRE) with TLR3 / 9 agonists and a PD-1 blockage to increase the cytotoxicity of CD8⁺ T lymphocytes, show a strong synergy.
Clinical applications have made progress. A pan -European study on electrochemotherapy (ECT) for melly skin tumors reported high response rates, Kaposi sarcome and basal carcinoma best responded. Irreversible high frequency electroporation (Fire H) effectively ablates localized prostate cancer while preserving the function with light complications. Nanodélition systems like M-UCn-T release nitric oxide in response to light and almost infrared glutathion, activating the endoplasmic TRPV1 reticulum to induce the release of calcium and immunogenic cell death, suppressing gliomas without systemic toxicity.
Translation challenges persist: ire with T γδ cell therapy prolongs survival but risks gastrointestinal bleeding and bile obstruction, limiting use in high-risk patients. The Fire needs greater studies to validate long-term efficiency between tumors. Future guidelines include TRPV1 modulation delivery systems sensitive to pH targeting bone marrow to reduce neuropathic pain, dynamic surveillance platforms according to immune cells and advanced nanoparticles like M-UCN-T (92% tumor suppression). These innovations aim to advance precision electrophysiological tumor therapy.