This review highlights tumor electrophysiological hallmarks as therapeutic targets in precision oncology. We examine how membrane potential alterations and ion channel fingerprints drive malignancy, and how targeted intervention—including channel-specific drugs, electric field therapies, and nanodrug delivery systems—can disrupt these processes, particularly when combined with immunomodulation to enhance antitumor responses and overcome treatment resistance. Tumor electrophysiological abnormalities have emerged as critical features of malignancy, driving cancer progression through dynamic modulation of membrane potentials, ion channel networks, and microenvironmental signaling interactions. Studies have shown that depolarization of the transmembrane resting potential (Vm) not only serves as an electrophysiological hallmark of tumor cells but also contributes to the regulation of malignant phenotypes by activating proliferative signaling, maintaining the undifferentiated state of cancer stem cells (CSCs), and promoting metastatic microenvironmental remodeling 1, 2. In recent years, the concept of "ion channel fingerprinting" has uncovered tumor tissue-specific ion channel expression profiles. Furthermore, these fingerprints have elucidated cross-regulatory networks with key signaling pathways, offering novel avenues for targeted interventions 3, 4. Concurrently, electrophysiological remodeling of the tumor microenvironment mediates immunosuppressive metabolic reprogramming via specific ion channels, underscoring the therapeutic relevance of electrical–immune interactions 5. Based on these mechanisms, precision drug designs targeting ion channels, electric field therapies, and nanodelivery systems have shown remarkable progress, though they still face translational challenges such as treatment-related complications and the need for long-term efficacy validation. In this review, we systematically examine the molecular mechanisms underlying tumor electrophysiological abnormalities and corresponding precision therapeutic strategies. We further discuss the clinical translational challenges and future directions, aiming to offer novel insights into tumor therapy. Vm depolarization represents a central electrophysiological hallmark of tumor cells. For example, breast, hepatocellular, and ovarian cancer cells exhibit significantly lower Vm compared to normal tissues, primarily due to elevated intracellular sodium ion concentrations and aberrant membrane ion permeability 1. This depolarized state promotes proliferation and functions as a signal for sustained mitosis, whereas hyperpolarization induces cell cycle arrest, suggesting that Vm acts as an "electrophysiological switch" regulating cellular proliferation. Notably, membrane potential abnormalities are not confined to the plasma membrane but also extend to subcellular organelles. In CSCs, mitochondrial membrane potential displays hyperpolarization, accompanied by a pronounced pH gradient between the matrix and cytoplasm 6. Additionally, global disturbances in membrane potential have been closely linked to tumor metastasis. In cancers such as gastric and colorectal tumors, loss-of-function mutations in the voltage-sensing domain of the NALCN channel reduce sodium leakage currents, which in turn activate key regulators of epithelial–mesenchymal transition (EMT), leading to a nine-fold increase in circulating tumor cells and a 3.5-fold rise in metastatic burden 2. These findings not only elucidate the molecular mechanisms underlying membrane potential abnormalities but also establish a theoretical foundation for therapeutic strategies targeting electrophysiological features. Tumor-specific "ion channel fingerprints" drive malignant phenotypes through interactions with multiple signaling pathways. For example, TRPV1 is highly expressed in multiple myeloma. Its inhibition induces endoplasmic reticulum stress and mitochondrial calcium overload, synergizing with bortezomib to enhance ubiquitin-proteasome system toxicity, thereby overcoming tumor drug resistance 3. In contrast, low TRPV1 expression in gastric cancer reduces the activity of the Ca²⁺/CaMKKβ/AMPK signaling axis, which relieves the inhibition of cyclin D1 and MMP2, promotes tumor invasion, and is significantly correlated with lymph node metastasis and poor prognosis 7. This bidirectional regulatory pattern indicates that ion channel dysfunction must be precisely interpreted within the context of tissue-specific expression. Furthermore, in medulloblastoma, the Kir2.1 channel interacts with Adam10 via a non-ion channel-dependent mechanism, enhances S2 cleavage of Notch2, and promotes nuclear translocation of N2ICD, thereby activating the C-Myc/Slug axis and driving EMT and metastasis, ultimately contributing to a marked reduction in 5-year patient survival 4. This cross-regulatory "ion channel-signaling pathway" network underscores the therapeutic potential of targeting specific ion channel fingerprints in precision oncology. Electrophysiological remodeling of the tumor microenvironment modulates immunosuppression via ionic gradients and signal transduction networks. For example, elevated potassium levels in the interstitial fluid reprogram the metabolic state of tumor-associated macrophages (TAMs) through Kir2.1, suppressing inflammatory genes such as TNF-α and IL-1β, while promoting oxidative phosphorylation and the secretion of immunosuppressive factors 8. Notably, this metabolic reprogramming is not an isolated event. Blockade of the phagocytic receptor MerTK activates P2X7R in response to ATP released by apoptotic cells, triggering Na⁺/Ca²⁺ influx and K⁺ efflux. This facilitates the uptake of tumor-derived cGAMP by macrophages and activates the STING pathway, thereby enhancing antitumor immunity 5. In glioblastoma (GBM), this form of electrophysiological modulation has also been linked to chemoresistance. The EAG2–Kvβ2 potassium channel complex is enriched at the tumor–brain interface, promoting proliferation, invasion, and chemoresistance by modulating calcium transients 9. These findings highlight the link between electrophysiological abnormalities and immune evasion within the tumor microenvironment, offering new insights into combination therapeutic strategies (Figure 1). Significant advances have been made in therapeutic strategies targeting tumor-specific "ion channel fingerprints." In structure-guided drug development, the peptide K90-114TAT, designed based on the crystal structure of Kvβ2, inhibited the EAG2–Kvβ2 interaction and significantly reduced tumor size across various glioma models, including temozolomide-resistant subtypes 9. Additionally, strategies that exploit tumor-specific electrochemical gradient differences have demonstrated distinct therapeutic advantages. For instance, the synthetic K⁺/H⁺ transporter Compound 2 recognizes the mitochondrial matrix–cytosolic pH gradient and membrane potential hyperpolarization, triggering a rapid surge in reactive oxygen species (ROS) within 30 s and selectively eliminating CD133⁺ ovarian CSCs 6. Modulation of noncoding RNAs offers another dimension of intervention. For example, in breast cancer, lncRNA BC069792 upregulates KCNQ4 protein expression by sponging miR-658/4739, thereby relieving its repression of KCNQ4. This leads to inhibition of JAK2 expression and AKT phosphorylation, ultimately reducing tumor cell proliferation and metastatic potential 10. Collectively, these strategies demonstrate the feasibility of translating basic research into clinical applications by targeting the ion channel network through multiple regulatory axes. Tumor treating fields (TTFields) enhance therapeutic efficacy through synergistic, multi-faceted mechanisms. TTFields disrupt microtubule polymerization and interfere with Septin localization via alternating electric fields, leading to aberrant mitosis in cancer cells. Additionally, they increase the permeability of cell membranes and the blood–brain barrier, thereby enhancing drug delivery efficiency 11. In terms of clinical translation, notable breakthroughs have been achieved in the combinatorial application of TTFields. Studies have shown that combining TTFields with temozolomide significantly improves the prognosis of newly diagnosed GBM patients 12. For refractory tumors such as pancreatic cancer, combining electric field therapy with nanotechnology further enhances therapeutic efficacy. ROS-responsive nanomicelles co-loaded with the PARP inhibitor Olaparib and the ATM inhibitor AZD0156 inhibit DNA damage repair, thereby sensitizing pancreatic cancer cells to irreversible electroporation (IRE)-mediated cell death and significantly prolonging survival in mouse models of pancreatic cancer 13. These multidimensional innovations and synergistic effects offer novel perspectives for optimizing the entire continuum of electric field-based tumor therapies, from mechanistic studies to clinical translation (Figure 2). Combination therapeutic strategies based on tumor electrophysiological characteristics exhibit the potential for synergistic, multi-mechanistic effects. In the context of immunomodulation, the Kir2.1 inhibitor ML133, in combination with a PD-1 antibody, reverses the M2-polarized phenotype of TAMs and remodels the immunosuppressive microenvironment 8. IRE, in combination with TLR3/9 agonists and PD-1 blockade, enhances CD8⁺ T cell cytotoxicity and promotes the clearance of distant metastatic lesions via activation of the cGAS–STING pathway 14. These examples illustrate the deep integration of electrophysiological interventions with immune and metabolic regulation, offering new avenues for precision therapy. A pan-European multicenter study on the treatment of cutaneous malignancies demonstrated that electrochemotherapy (ECT) achieved high objective and complete response rates. However, efficacy varied significantly by histologic subtype, with Kaposi's sarcoma and basal cell carcinoma exhibiting the highest remission rates, followed by breast cancer skin metastases as the next most responsive category 15. Optimization of technical parameters is essential to improving treatment efficacy. For example, wired electrodes are preferred for small lesions, whereas intravenous drug administration is recommended for larger ones. Lesions located in previously irradiated areas tend to have lower response rates compared to nonirradiated areas, underscoring the need to tailor the delivery strategy based on lesion characteristics 15. These findings provide an evidence-based rationale for the personalized application of ECT. Clinical validation of the precision ablation technique, high-frequency irreversible electroporation (H-FIRE), has demonstrated effective and localized tumor ablation in the treatment of low- to intermediate-risk, localized prostate cancer, while significantly preserving urinary and sexual function and causing mostly mild complications 16. The synergistic effect of ablation technology combined with immunomodulation has also been validated in more challenging cases of locally advanced pancreatic cancer. IRE combined with a Vγ9Vδ2 T cell-based therapeutic regimen significantly prolonged patient survival and reduced tumor marker levels compared with monotherapy, underscoring its synergistic potential 17. These findings provide a rationale for the individualized application of electric field-based ablation technologies and the optimization of combination therapeutic strategies. The nanodelivery system M-UCN-T releases nitric oxide in response to near-infrared light and glutathione, specifically activating endoplasmic reticulum-localized TRPV1 channels and inducing calcium release and a cytoplasmic calcium surge, ultimately leading to mitochondrial damage and immunogenic cell death. It exhibits potent tumor-suppressive effects in a glioma model by significantly enhancing antitumor immune cell infiltration without inducing systemic toxicity 18. This offers a novel strategy for precise intervention in tumor electrophysiological networks. This breakthrough represents the deep integration of nanotechnology and electrophysiological modulation, laying a technical foundation for future clinical translation. Although IRE combined with γδ T-cell therapy significantly prolongs survival, complications associated with IRE (e.g., gastrointestinal bleeding, biliary obstruction) limit its clinical applicability in high-risk patients and may preclude its use in those with severe comorbidities 17. In addition, although H-FIRE enables precise ablation and functional preservation in prostate cancer 16, larger-scale studies are still needed to validate its long-term efficacy and applicability across heterogeneous tumor types. Future development of tumor electrophysiological therapies will likely focus on three key innovative directions: (1) pH-responsive TRPV1 modulator–based smart delivery systems that specifically target the bone marrow microenvironment (pH 6.5–7.0), effectively reducing the risk of neuropathic pain 19; (2) dynamic monitoring platforms that integrate multiparameter flow cytometry with imaging-guided navigation, enabling real-time tracking of immune cell subsets (e.g., M2 macrophages) to address treatment response variability driven by tumor microenvironment heterogeneity 14; (3) a biomimetic nanoparticle system (M-UCN-T) with a four-level targeting structure, achieving a tumor suppression rate of up to 92% 18. Its subcellular-level precision in regulation provides a strong foundation for future clinical translation. The synergistic advancement of these technologies is expected to propel tumor therapy into a new era of precision electrophysiological modulation. Electrophysiological abnormalities drive malignant progression through membrane potential dysregulation, ion channel fingerprint remodeling, and microenvironmental electrical signal interactions. Precision intervention strategies—such as ion channel targeting, electric field therapy, and nanodelivery systems—show promising potential in overcoming drug resistance and remodeling the immunosuppressive tumor microenvironment. However, challenges remain, including treatment-related complications and insufficient validation of long-term efficacy. The development of intelligent delivery platforms and the integration of multi-omics strategies are expected to drive multidimensional breakthroughs in future precision oncology. Kailai Li: writing – review and editing, writing – original draft, visualization. Yasi Zhang: writing – original draft, writing – review and editing, visualization. Yue Qian: validation, writing – review and editing. Hu Qin: supervision. Hongtian Zhang: supervision. Chaoqun Li: supervision. Changmin Peng: supervision. Jian Zhang: project administration, supervision. Suyin Feng: project administration, supervision. The authors have nothing to report. The authors have nothing to report. Jian Zhang serves as a member of the Editorial Board for iMetaMed. He was excluded from editorial decision-making related to the acceptance of this article for publication in the journal. All other authors declare no conflicts of interest. The authors have nothing to report.
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