Irreversible electroporation in prostate cancer: efficacy, tumor immune microenvironment remodeling, and combination immunotherapy—a narrative review

Introduction

Prostate cancer (PCa) is a major threat to global male health, ranking second in cancer-related deaths in men in the United States. Currently, there are over 1.5 million diagnosed PCa cases worldwide, and projections indicate that the number of new cases will reach 2.9 million by 2040 (1,2). Conventional PCa treatment modalities, however, are associated with significant limitations: for early-stage PCa, active surveillance avoids overtreatment but is accompanied by progression anxiety, economic burdens from frequent follow-up monitoring, and risks of unpredictable disease progression or delayed intervention (3); radical prostatectomy is associated with a 5–15% incidence of urinary incontinence and a 30–70% risk of erectile dysfunction; external beam radiation therapy (EBRT) results in a local recurrence rate of approximately 30% in patients with low-to-intermediate-risk PCa (4); long-term androgen deprivation therapy (ADT) often induces drug resistance, with median survival times of 33 months for non-metastatic disease and 15 months for metastatic disease (5); for metastatic castration-resistant PCa (mCRPC), the response rate to systemic therapy is less than 30%, and the median survival is only 2.8 years (6,7). Given these limitations, there remains a clear need for safer and more effective therapeutic strategies for PCa.

Irreversible electroporation (IRE), an emerging non-thermal ablation technique, has been increasingly explored as a minimally invasive treatment option for selected patients with PCa, particularly in focal or salvage settings. It delivers high-frequency, short-duration electrical pulses (1–3 kV/cm, 100–300 µs) to create irreversible nanoscale pores in the cell membranes of tumor cells, disrupting cellular homeostasis and triggering apoptosis or autophagy (8). The key advantages of IRE include precise image-guided [ultrasound, computed tomography (CT), magnetic resonance imaging (MRI)] ablation, preservation of critical adjacent structures due to its non-thermal mechanism, and the potential to induce transient immune modulation through tumor antigen release (9). Recent studies have further demonstrated that IRE-based combination immunotherapies [e.g., in conjunction with immune checkpoint inhibitors (ICIs), oncolytic viruses (OVs), or cancer vaccines] can reverse the immunosuppressive microenvironment of PCa by reducing the number of regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs), while upregulating T helper 1 (Th1) cytokines.

This review summarizes the immunomodulatory mechanisms of IRE, its clinical progress across different stages of PCa, and its combination therapeutic strategies, with the aim of guiding the precise clinical application of IRE. Clarifying the clinical value of IRE, its immunomodulatory mechanisms, and the efficacy of IRE-based combination therapies is crucial for advancing the translation of IRE into routine PCa clinical practice. We present this article in accordance with the Narrative Review reporting checklist (available at https://tau.amegroups.com/article/view/10.21037/tau-2025-aw-871/rc).

Methods

To compile evidence for this narrative review, we conducted a comprehensive literature search across three authoritative electronic databases: PubMed/MEDLINE, the Cochrane Library, and Scopus. The search period was limited to January 2015–August 2025 to focus on recent advancements in the field. The search strategy combined the keywords “irreversible electroporation” or “NanoKnife” with “prostate cancer”; to ensure comprehensiveness and accuracy, relevant Medical Subject Headings terms were integrated, and Boolean operators (AND, OR) were used to refine the search results.

Literature screening had two stages: two independent reviewers first excluded irrelevant studies via title/abstract, then assessed full texts against criteria. Inclusion criteria comprised high-quality clinical studies, including prospective cohorts and randomized controlled trials, evaluating oncological outcomes or immune-related effects of IRE in PCa. And representative preclinical and animal studies were included to elucidate immunological mechanisms and the biological rationale for combination strategies (English-only to reduce translation bias). Exclusion: reviews, editorials, case reports, conference abstracts, and meta-analyses. Discrepancies were resolved by a third reviewer (Table 1).

We extracted core data (authors, year, sample size, design, oncological/functional outcomes, complications) and categorized results by IRE’s PCa-stage application, TIME-remodeling mechanisms, and combination efficacy. We also evaluated study limitations (biases, design heterogeneity, population differences) to objectively assess current IRE research in PCa (Figure 1).

Figure 1 Overview of literature identification and study selection for this narrative review.

Results

Application of IRE in different stages of PCa treatment

Low-to-intermediate-risk focal PCa: an effective alternative

Low-to-intermediate-risk focal PCa has become a major area of interest for focal therapies, and IRE has emerged as a potential alternative local treatment option for carefully selected patients, rather than a replacement for standard radical approaches. A study of 41 patients (ISUP grade 1–2, cT2b) showed IRE alone was associated with effective local lesion control and preserved urinary continence in the reported cohort, >90% erectile function preservation, mild urinary frequency/urgency in a few cases, low overall complications, and better quality of life vs. traditional treatments (10). A multicenter study of 411 untreated patients (median follow-up 24 months) found >70% recurrence-free rate at 12–18 months (biochemical recurrence: 9.5%); International Prostate Symptom Score (IPSS) (7.1→ 8.2 at 3 months → 6.1 at 6 months) and International Index of Erectile Function (IIEF) (16→12.1 at 3 months, then stabilized) only had short-term fluctuations (11). When compared indirectly with outcomes reported for other focal therapies such as cryoablation and high-intensity focused ultrasound (HIFU), IRE has demonstrated favorable functional preservation and acceptable short-term oncological control in selected clinical scenarios, particularly in patients with single or anterior prostate lesions (4). However, it should be emphasized that these observations are derived from separate single-arm studies rather than head-to-head comparative trials, and therefore do not allow definitive conclusions regarding superiority among focal treatment modalities. Overall, available data support the feasibility of IRE as a focal therapeutic option and provide preliminary evidence to justify further comparative and randomized investigations.

Locally recurrent PCa: a promising salvage option

For PCa patients with local recurrence after localized treatment, IRE has emerged as a promising salvage treatment option. A multicenter prospective trial of 37 radiotherapy-recurrent, non-metastatic patients showed IRE achieved a median prostate-specific antigen (PSA) of 0.12 ng/L, 78% local control (outperforming traditional salvage therapies), mild urgency/frequency/hematuria in a few, 93% good urinary control at 12 months, and symptom relief within 3–6 months (12). A 5-year follow-up of 229 patients found 82% complete tumor ablation (MRI), 91% 3-year progression-free survival (PFS), 84% 5-year PFS, 99% incontinence-free at 12 months, 58% sufficient erectile function; subgroup analyses confirmed benefits across ages and stages (13). In addition, owing to its non-thermal mechanism and preservation of tissue architecture, IRE is considered one of the most surgically salvageable focal therapies, allowing radical prostatectomy to remain feasible in the event of treatment failure. Prospective studies in relatively small cohorts suggest that IRE may represent a feasible salvage treatment option for selected patients with locally recurrent PCa.

Comprehensive efficacy and safety

IRE has been associated with acceptable short-term oncological outcomes in selected patients: post-treatment, patients typically exhibit significant PSA reductions, with representative cases showing declines from 7.75 to 1.71 ng/mL and from 9.46 to 0.78 ng/mL—providing preliminary signals of local tumor response (5,14). Interpretation of recurrence after focal IRE requires clear distinction between in-field and out-of-field events. Frequently cited early recurrence rates of up to 28% reflect global disease recurrence rather than true local treatment failure. Detailed analyses indicate that only a minority of recurrences (approximately 16%) occur within the ablation zone, whereas most represent out-of-field disease related to tumor multifocality, baseline biopsy limitations, or progression of untreated lesions (15). These observations suggest that local tumor control within the treated field is generally achieved, while recurrence more often reflects inherent limitations of focal therapy rather than inadequate ablation efficacy.

In contemporary practice, multiparametric MRI and prostate-specific membrane antigen (PSMA) positron emission tomography (PET) imaging are increasingly used for lesion localization, assessment of tumor extent, and exclusion of clinically significant multifocal or metastatic disease, thereby mitigating the risk of out-of-field recurrence.

Functionally, IRE is associated with favorable preservation of urinary continence and erectile function in a substantial proportion of patients. Across heterogeneous cohorts, erectile function is maintained or recovered in approximately 56–92% of patients at 6–12 months. Although these outcomes are not directly comparable due to differences in study assessments and follow-up protocols, their consistent direction supports a favorable functional profile in appropriately selected patients.

Regarding safety, while IRE is generally well-tolerated, it is associated with specific complications: Grade I events (e.g., hematuria, dysuria) are the most common, affecting approximately 22% of patients within 30 days post-treatment (16), alongside occasional urinary retention or persistent urinary debris. Grade II complications (e.g., epididymitis) occur in about 4% of cases (17), and severe Grade III events (e.g., cardiac dysrhythmias) are rare but require vigilant monitoring.

Despite favorable functional and safety outcomes, oncological evidence for IRE remains preliminary. Most studies are single-arm, non-randomized, and heterogeneous, with early recurrence rates of 20–30% reported in some series, particularly among patients with multifocal disease. Therefore, while IRE appears to be a promising focal and salvage option, its long-term oncological efficacy relative to established radical therapies requires confirmation in well-designed prospective studies.

IRE remodels the PCa tumor immune microenvironment (TIME)

The PCa’s TIME is a dynamic, intricate network encompassing tumor cells, immune cells, cytokines, and stromal components—all of which collectively govern tumorigenesis, immune escape, and therapeutic resistance (18). Distinct from the TIME of other solid tumors, the PCa TIME exhibits unique immunobiological traits, fostering a profoundly immunosuppressive niche that severely constrains the efficacy of immunotherapeutic strategies.

Immunosuppressive features of PCa TIME

The PCa’s TIME features profound immune dysregulation: it has a striking paucity of tumor-infiltrating lymphocytes (TILs)—especially CD8⁺ cytotoxic T lymphocytes (CTLs) and CD4⁺ helper T cells, which are essential for effective antitumor immunity—reinforcing PCa’s status as an immunologically “cold” tumor (19). In contrast, immunosuppressive cell subsets dominate: Tregs secrete transforming growth factor-β (TGF-β) and interleukin-10 (IL-10) to suppress effector T cells, natural killer (NK) cells, and dendritic cells (DCs), with higher Treg density at the tumor margin consistently linked to worse progression-free and overall survival; tumor-associated macrophages (TAMs), mainly M2-polarized, release TGF-β2 and IL-6 to promote PCa proliferation, invasion, metastasis, and further consolidate immunosuppression (20). At the molecular level, the cytokine milieu is skewed toward suppression: TGF-β inhibits T/NK cell effector function while driving Treg differentiation, and tumor-secreted vascular endothelial growth factor (VEGF) sustains tumor growth via angiogenesis and recruits TAMs/MDSCs to amplify immune evasion. Collectively, these cellular and molecular interactions form a dense, resilient immunosuppressive network that acts as a major barrier to conventional immunotherapies.

Immune checkpoint-mediated escape

Aberrant activation of immune checkpoints is a pivotal mechanism for immune escape in PCa, with the programmed death-1 (PD-1)/programmed death-ligand 1 (PD-L1) axis and cytotoxic T lymphocyte antigen 4 (CTLA-4) pathway serving as core immunosuppressive regulators (21). Tumor cells and immunosuppressive subsets expressing PD-L1 engage PD-1 on T cells, directly suppressing T cell activation, proliferation, and cytotoxicity to sustain immune evasion; similarly, CTLA-4 competitively binds B7 molecules on antigen-presenting cells (APCs), disrupting costimulatory signaling and “braking” T cell activation. Together, these pathways weaken effector T cell responses and drive immune exhaustion characteristic of the PCa TIME (19). Notably, IRE further upregulates PD-L1 in PCa cells (likely a cellular stress response)—though this may blunt IRE’s immune-stimulatory effects, it also reveals a therapeutic vulnerability, providing a compelling rationale for combining IRE with immune checkpoint blockade to enhance efficacy.

IRE-induced TIME remodeling

IRE-induced remodeling of the PCa TIME is driven by bioelectrical rather than thermal injury. High voltage pulsed electric fields generate irreversible nanopores in tumor cell membranes, causing ionic disequilibrium (Ca2⁺ influx and K⁺ efflux), mitochondrial depolarization, and endoplasmic reticulum stress (22). This triggers immunogenic cell death (ICD), releasing damage-associated molecular patterns (DAMPs) and tumor-associated antigens (TAAs), such as extracellular adenosine triphosphate (ATP) and HMGB1, which activate pattern recognition receptors (PRR) including P2X7 and TLR4 on APCs (23). Downstream signaling through NF-κB and IRF3 enhances proinflammatory cytokines (IL-1β, IL-12, TNF-α) and antigen cross-presentation, facilitating priming of tumor-specific CD8⁺ T cells (24,25). Unlike thermal ablation, IRE preserves microvasculature to facilitate immune cell trafficking into the ablated region. Activated DCs upregulate costimulatory molecules (CD80, CD86) and CCR7, enabling migration toward draining lymph nodes, where cross-presentation of IRE-released TAAs via major histocompatibility complex class I (MHC-I) drives the clonal expansion of tumor-specific CTLs (26). At the same time, IRE induced local inflammation boosts chemokine (IL-6, IL-8) release to recruit TILs and reshape TIME cellular composition. Recruited CD8⁺ cytotoxic T cells directly interact with damaged tumor cells and mediate granzyme B (GZMB)-dependent cytotoxicity, enhancing local tumor clearance at the ablation margin (27,28). Beyond local effects, IRE-induced ICD drives systemic antitumor responses (e.g., the “abscopal effect”, where activated CD8⁺ T cells target distant metastases and build durable immune memory) and modulates immune suppression by enhancing IL-2 production, inhibiting Treg expansion, and strengthening CD8⁺ T cell function—partially reversing PCa TIME’s immunosuppressive cycle (29). In parallel, interferon-γ released by activated T cells enhances antigen presentation while also driving adaptive immune resistance via stress-induced PD-L1 upregulation (Figure 2).

Figure 2 Remodeling effects of IRE on the TIME of PCa. IRE-induced tumor cell death releases DAMPs and antigens, promotes antigen presentation, activates cytotoxic T cells, and shifts the prostate cancer tumor immune microenvironment toward an immune-responsive state. APCs, antigen-presenting cells; ATP, adenosine triphosphate; CTLA-4, cytotoxic T lymphocyte antigen 4; CTLs, cytotoxic T lymphocytes; DAMPs, damage-associated molecular patterns; GZMB, granzyme B; IRE, irreversible electroporation; PCa, prostate cancer; PD-1, programmed death-1; PD-L1, programmed death-ligand 1; PRR, pattern recognition receptor; TAAs, tumor-associated antigens; TAMs, tumor-associated macrophages; TIME, tumor immune microenvironment; Tregs, regulatory T cells.

Collectively, these molecular events illustrate how IRE transiently converts an immune-excluded prostate tumor microenvironment into a locally inflamed, immune-permissive state, while also highlighting the intrinsic limitations of sustaining systemic immunity.

IRE-based combination immunotherapy

Evidence supporting IRE-based combination immunotherapy is derived predominantly from preclinical models and is discussed here as mechanistic and translational rationale rather than proof of clinical efficacy (30).

Given the intrinsically immunosuppressive nature of PCa, IRE alone is unlikely to generate durable antitumor immunity; however, it may create a narrow therapeutic window for rational combination strategies aimed at amplifying or sustaining immune responses.

IRE + ICIs

Immune checkpoint molecules act as “regulatory switches” on T cells to balance immune responses and prevent autoimmunity; their inhibitors are approved for PCa patients with high-risk microsatellite instability (MSI-H) or mismatch repair defects (dMMR), and offer a new option for mCRPC with DNA repair defects (31). CTLA-4 blockers promote T-cell activation by inhibiting CTLA-4/B7 binding on antigen-presenting cells, and their combination with ADT significantly reduces PSA levels in mCRPC, yet single-agent ICIs have limited efficacy in PCa (30). IRE’s unique immune-activating properties enable synergy with ICIs: the IRE-IMMUNO study found IRE for focal PCa increased peripheral blood CD4⁺/CD8⁺ T cells, reduced Tregs, and upregulated CTLA-4 on T cells in a tumor volume-dependent manner (reflecting T-cell activation with immune “braking”) (32); animal studies showed the combination of IRE and CTLA-4 blockade was associated with enhanced tumor-specific CD8⁺ T-cell responses and delayed tumor progression, supporting immune synergy at the mechanistic level, and prolonged mouse survival by nearly 30%, while preclinical studies confirmed IRE + anti-PD-1 antibodies downregulated tumor PD-L1, lifted immunosuppression, and enhanced CD8⁺ T-cell cytotoxicity. These findings suggest a potential strategy to mechanistically address immune escape in PCa, warranting further clinical investigation.

IRE + OVs

OVs specifically infect and lyse tumor cells while activating the body’s anti-tumor immunity through multiple mechanisms, including cytokine secretion, enhanced antigen presentation, and modulation of the TIME. In PCa models, OVs such as the Newcastle disease virus (NDV) La Sota strain have demonstrated selective cytotoxicity and immunostimulatory potential (33,34).

The combination of IRE and OVs demonstrates complementary immunological effects in preclinical models, particularly in enhancing antigen release and immune cell recruitment. While immune activation following IRE may remain spatially restricted to peri-ablation regions, OVs can secrete chemokines such as CXCL9 and CXCL10 to promote deeper infiltration of CTLs into tumor parenchyma (35). In addition, IRE-induced alterations in tumor cell membrane permeability may facilitate viral entry and intratumoral spread.

Preclinically, OVs-loaded nanoparticles combined with IRE significantly reduced tumor volume and prolonged mouse survival in PCa models. This combination strategy may hold translational relevance. Nevertheless, evidence supporting IRE-OV combinations is currently limited to preclinical settings, and clinical feasibility and efficacy remain unknown.

IRE + nano immunomodulation

Nano-immunomodulation strategies employ engineered carriers to improve the delivery and local retention of immunostimulatory agents within tumors. When combined with IRE, these platforms may function primarily as immune amplifiers, enhancing the magnitude and persistence of immune signals initiated within the post-IRE tumor microenvironment (36). One study combined the nanocarrier (PPR@CM-PD-1) loaded with imiquimod (R837), a TLR7 receptor agonist, with IRE; by optimizing electric field distribution via nanosecond-microsecond pulse electric field (nµPEF), it significantly enhanced tumor cell ICD, remodeled TIME, and facilitated nanocarrier accumulation and immune cell infiltration in tumors, demonstrating enhanced immune activation and suppression of tumor growth in preclinical models (37). Another study developed immunoreactive nanoparticles (CMP) based on a metal-phenolic network (MPN), with surface-loaded cytosine-phospho-guanine oligodeoxynucleotide (CpG-ODN) that activates antigen-presenting cells, induces M1-type macrophage polarization, and promotes the secretion of type I interferon (IFN-I) and pro-inflammatory cytokines. Bipolar IRE combined with CMP nanoparticles exhibited potent anti-tumor effects in a mouse colon cancer model, and this strategy highlights a potential translational direction for augmenting IRE-induced immune responses in PCa—its core mechanism involves manganese ions in nanoparticles synergizing with IRE-induced ICD by activating the cyclic GMP-AMP synthase (cGAS)/STING pathway, thereby reinforcing innate and adaptive immune responses (38).

Limitations of IRE-mediated immune effects

IRE-mediated immune effects are constrained by multiple factors. Technically, its complex parameters (e.g., electric field strength, pulse frequency) lack standardization: tumor tissue’s electrical heterogeneity disrupts uniform pulsed field distribution, risking incomplete ablation and recurrence. There is no universal IRE protocol for PCa, with parameter selection relying on clinician experience; while strategies like nµPEF show potential, they need further clinical validation. In combination immunotherapy, ICIs have limited efficacy in PCa’s immunosuppressive microenvironment; the persistence/strength of IRE-induced immune responses, extent of systemic immune activation, and interactions between IRE and immunotherapeutics lack clinical evidence. Additionally, optimal combination strategies, therapeutic windows, and compounded adverse effects remain unclear. Critically, there are no reliable biomarkers to guide patient selection, stratify responsiveness, or monitor outcomes, restricting personalized therapy. Moreover, PCa’s heterogeneous “cold” TIME—characterized by sparse effector T cells and abundant immunosuppressive cells (Tregs, MDSCs, TAMs)—leads to variable IRE-induced immune activation, limiting synergy in highly suppressive TIME. These issues widen the preclinical-clinical translation gap, requiring biomarker-driven trials and stratified strategies to address.

Importantly, most clinical evidence discussed above is derived from small, non-randomized studies and should therefore be interpreted as preliminary rather than confirmatory.

Discussion

IRE has emerged as a minimally invasive focal ablation technique that has been increasingly explored in selected PCa settings, owing to its potential to achieve local tumor control while preserving urinary continence and sexual function (39). Nevertheless, the available evidence remains heterogeneous, and both the clinical and immunological implications of IRE warrant cautious interpretation.

From an oncological perspective, existing studies suggest that IRE can provide acceptable short- to mid-term local control in carefully selected patients, particularly those with low- to intermediate-risk unifocal disease or locally recurrent tumors following radiotherapy (40). Outcomes, however, vary substantially across studies owing to differences in patient selection, tumor characteristics, imaging guidance, and ablation parameters. Recurrence rates of up to 20–30% within the first year have been reported, especially among patients with multifocal disease (13). In addition, the predominance of single-arm, non-randomized studies from specialized centers limits generalizability and precludes meaningful comparison with established radical therapies.

Functional preservation is frequently reported as a major advantage of IRE. High rates of urinary continence and relatively favorable erectile function outcomes have been described (8); however, these findings depend strongly on lesion location, treatment extent, and strict patient selection. Short follow-up durations and heterogeneous assessment methods further limit conclusions regarding long-term functional benefit.

Interest has increasingly focused on the immunomodulatory effects of IRE. Preclinical studies suggest that IRE can induce ICD and transient immune activation, but the clinical relevance of these effects in PCa remains uncertain (32). The profoundly immunosuppressive TIME characteristic of PCa is likely to restrict both the magnitude and durability of IRE-induced immune responses.

Immune effects following IRE appear context-dependent. Stress-induced upregulation of immune checkpoint molecules, such as PD-L1, may reflect adaptive immune resistance rather than sustained antitumor immunity (41). To date, there is no convincing clinical evidence demonstrating durable systemic immune responses or reproducible abscopal effects after IRE in PCa.

The rationale for combining IRE with immunotherapeutic strategies—including ICIs, OVs, and nano-immunomodulatory platforms—derives largely from preclinical models. Although enhanced immune activation has been observed in experimental systems, translational relevance remains uncertain, as these models do not fully recapitulate the immune tolerance and stromal complexity of human PCa.

Additional challenges include the lack of standardized IRE protocols, variability in electric field distribution due to tissue heterogeneity, and the absence of validated biomarkers for patient selection or immune responsiveness. Above all, these factors limit the current clinical applicability of IRE.

In summary, IRE represents a promising investigational focal therapy with favorable functional outcomes in selected PCa patients. However, its long-term oncological efficacy, reproducibility, and ability to meaningfully enhance antitumor immunity remain unproven and require confirmation in well-designed prospective studies.

Conclusions

IRE appears to be a feasible focal or salvage treatment option for carefully selected patients with PCa, with acceptable short- to mid-term local tumor control and favorable preservation of urinary continence and sexual function. Nevertheless, the current clinical evidence is heterogeneous and predominantly derived from non-randomized, single-arm studies with limited follow-up, which precludes definitive conclusions regarding long-term oncological efficacy.

Preclinical and limited exploratory clinical data suggest that IRE may transiently modulate the TIME, providing a biological rationale for combination strategies with immunotherapy. However, such approaches remain investigational, and their clinical relevance has not yet been established. Well-designed prospective studies incorporating standardized IRE protocols, biomarker-driven patient selection, and immune-correlative endpoints are required to determine whether IRE-induced immune modulation can be translated into durable clinical benefit for patients with PCa.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the Narrative Review reporting checklist. Available at https://tau.amegroups.com/article/view/10.21037/tau-2025-aw-871/rc

Peer Review File: Available at https://tau.amegroups.com/article/view/10.21037/tau-2025-aw-871/prf

Funding: This work was supported by the Tianjin Science and Technology Project (Nos. 21ZXJBY00090, KJ20169 and 24JCYBJC01040), and The Second Hospital of Tianjin Medical University (No. MYSRC202306).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tau.amegroups.com/article/view/10.21037/tau-2025-aw-871/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

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