Letter to the Editor: High-frequency irreversible electroporation as an immune primer in hepatocellular carcinoma

Abstract

We read with great interest the recent study by Huang et al published in the World Journal of Gastroenterology. High-frequency irreversible electroporation (H-FIRE) is an emerging non-thermal ablation method that has been shown to induce features consistent with immunogenic cell death in hepatocellular carcinoma (HCC). This process releases damage-associated molecular patterns that prime adaptive antitumor immunity. A recent preclinical study demonstrated that the triple combination of H-FIRE, the small-molecule programmed death-1 (PD-1)/PD-ligand 1 (PD-L1) interaction inhibitor BMS-1, and the TLR7/8 agonist resiquimod synergistically reprograms the immunosuppressive tumor microenvironment, suppresses primary and distant tumor growth, and produces a strong abscopal effect in a murine HCC model. While this work provides an important proof-of-concept, several methodological and translational limitations merit discussion. These include using a subcutaneous ectopic tumor model that does not replicate the native hepatic immune microenvironment, relying on a single, highly immunogenic cell line, conducting immune profiling at a single time point without longitudinal kinetic analysis, lacking tumor rechallenge data to confirm immune memory, and using a non-clinically approved small-molecule PD-1/PD-L1 inhibitor (BMS-1) rather than a clinically validated checkpoint inhibitor. This letter addresses the limitations, outlines the most effective methodological approaches to address them, and presents a prioritized translational research plan and advances toward a Phase I investigator-initiated clinical trial in unresectable HCC.

Keywords: High-frequency irreversible electroporation; Hepatocellular carcinoma; Immunogenic cell death; Tumor microenvironment; Programmed death-1; Programmed death-ligand 1; Abscopal effect; Tumor immunotherapy; Liver ablation; Translational oncology

Core Tip: High-frequency irreversible electroporation induces features consistent with immunogenic cell death in hepatocellular carcinoma tumors and, when combined with the small-molecule programmed death-1/programmed death-ligand 1 interaction inhibitor BMS-1 and TLR7/8 agonist resiquimod, reverses immunosuppression both locally and systemically. While this triple combination shows strong preclinical efficacy, including a robust abscopal effect, important limitations, such as dependence on a subcutaneous ectopic model, single-timepoint immune profiling, and lack of immune memory validation, need to be addressed before moving to clinical trials. Future research should focus on validating orthotopic models, conducting longitudinal immune studies, performing tumor rechallenge experiments, and optimizing nanoparticle drug delivery as important steps toward a Phase I trial in unresectable hepatocellular carcinoma.