Advancing Electrochemotherapy in Melanoma and Non-Melanoma Skin Cancer: From Clinical Practice to Emerging Frontiers.

Electrochemotherapy (ECT) is a locoregional treatment that combines poorly permeable drugs, commonly bleomycin (BLM) or cisplatin (CDDP), with electric pulses that induce electroporation. By transiently increasing cell membrane permeability, ECT promotes intracellular drug accumulation, enhancing cytotoxic effects while minimizing undesirable systemic toxicity. Beyond its direct cytotoxic effects, ECT exerts additional antitumour mechanisms that contribute to tumour control. These include the induction of immunogenic cell death (ICD), leading to activation of innate and adaptive immune responses; the "abscopal effect", achieved with the combination of ECT and immune checkpoint inhibitors; and the "vascular lock" phenomenon, promoting a transient local blood flow reduction and enhancing intratumoural drug retention; and a "vascular disrupting effect" that contributes to tumour vascular damage and secondary tumour cell death. ECT has demonstrated high objective response rates (ORR) across a wide range of cutaneous malignancies, including melanoma and non-melanoma skin cancers (NMSCs) and cutaneous dissemination of other tumours. Although predictive biomarkers capable of identifying patients who benefit from treatment are still lacking, substantial preclinical and clinical evidence supports the efficacy, safety and tolerability of ECT. Several ongoing clinical trials are currently evaluating ECT, particularly in advanced or non-resecable melanoma, aiming to investigate further biological effects and optimize therapeutic strategies. Furthermore, innovative approaches integrating ECT with gene electrotransfer and nanomedicine represent a promising avenue to enhance its therapeutic efficacy and expand its role in precision oncology.