Irreversible Electroporation: An Emerging Immunomodulatory Therapy on Solid Tumors

Abstract

Irreversible electroporation (IRE), a novel non-thermal ablation technique, is utilized to ablate unresectable solid tumors and demonstrates favorable safety and efficacy in the clinic. IRE applies electric pulses to alter the cell transmembrane voltage and causes nanometer-sized membrane defects or pores in the cells, which leads to loss of cell homeostasis and ultimately results in cell death. The major drawbacks of IRE are incomplete ablation and susceptibility to recurrence, which limit its clinical application. Recent studies have shown that IRE promotes the massive release of intracellular concealed tumor antigens that become an “in-situ tumor vaccine,” inducing a potential antitumor immune response to kill residual tumor cells after ablation and inhibiting local recurrence and distant metastasis. Therefore, IRE can be regarded as a potential immunomodulatory therapy, and combined with immunotherapy, it can exhibit synergistic treatment effects on malignant tumors, which provides broad application prospects for tumor treatment. This work reviewed the current status of the clinical efficacy of IRE in tumor treatment, summarized the characteristics of local and systemic immune responses induced by IRE in tumor-bearing organisms, and analyzed the specific mechanisms of the IRE-induced immune response. Moreover, we reviewed the current research progress of IRE combined with immunotherapy in the treatment of solid tumors. Based on the findings, we present deficiencies of current preclinical studies of animal models and analyze possible reasons and solutions. We also propose possible demands for clinical research. This review aimed to provide theoretical and practical guidance for the combination of IRE with immunotherapy in the treatment of malignant tumors.

Electricity‐Assisted Cancer Therapy: From Traditional Clinic Applications to Emerging Methods Integrated with Nanotechnologies

“…Compared with other techniques such as thermal ablation, IRE has some unique advantages. [ 14,19 ] First, IRE‐induced tumor ablation is complete with clear margins and it does not cause thermal damage to the surrounding normal tissues, especially to some important and fragile blood vessels, nerves, and cavities. Second, it has no thermal deposition effect, avoiding incomplete tumor ablation due to the energy reduction by blood flow.…”

“…In addition to destroying local tumors, IRE has been discovered to be able to activate systemic immune responses and induce durable systemic protective responses. [ 19 ] The specific content will be introduced in detail as a separate part.…”

Pulse Parameters and Thresholds for (ir)Reversible Electroporation on Hepatocellular Carcinoma Cells in Vitro

“…Nonthermal EP-based therapies seem the most promising, mainly due to their possibility to induce apoptosis instead of necrosis, which can lead to a superior immune effect, and their avoidance of thermal side effects. 6 , 7 The latter makes it possible to operate in proximity to vulnerable structures such as blood vessels, nerves, and ducts. 6 , 8 , 9 In EP-based therapies, biological cell membranes are exposed to an external, sufficiently high, pulsed electric field (PEF), which can lead to a rapid and large increase in electric conductivity and permeability, creating so-called nanopores into the lipid bilayer of the cell membrane.…”

Real-Time Temperature Rise Estimation during Irreversible Electroporation Treatment through State-Space Modeling

“…Other factors to consider include that IRE performed in proximity to a metal stent has demonstrated higher temperatures surrounding the electrodes and viable tissue remnants [ 21 ]. Furthermore, current research shows that, even when thermal damage is improbable, lowering mild-to-moderate thermal impacts may encourage greater immune activation, which may improve long-term therapeutic effectiveness and patient outcomes [ 22 , 23 , 24 ]. As a result, strategies to reduce and/or manage thermal effects in the proximity of the electrodes are critical to improving IRE and other pulsed electric field (PEF)-based ablation modalities for wider clinical usage.…”