Pulsed electric field ablation as a candidate to enhance the anti-tumor immune response to immune checkpoint inhibitors.

Cancer ablation with pulsed electric fields (PEFs) involves the delivery of high-voltage, short-duration electrical pulses that destabilize tumor cells, leading to cellular death. Unlike most conventional ablation technologies, PEF ablation is non-thermal, allowing for safe and targeted energy delivery to the tumor without damaging surrounding tissue and critical structures. PEFs allow for specific dosing, predictable treatment zones, and preservation of the extracellular matrix and adjacent vascular tissues. Preclinical and preliminary clinical data suggest that PEF ablation may induce inflammatory changes in the tumor microenvironment (TME) that engage host innate and adaptive immune cells, stimulating an anti-tumor response. Specifically, PEF promotes local and systemic anti-tumor immune activation through immunogenic cell death and the release of damage-associated molecular patterns (DAMPs) and tumor antigens. This tumor-specific immune activation could potentially enhance response to immune checkpoint inhibitor (ICI) therapies. Furthermore, PEF ablation induces the formation of tertiary lymphoid structures (TLSs) in the TME, which are predictive biomarkers for responsiveness to ICI across several solid tumors. This combination of effects activates antigen-presenting cells and stimulates the effector T cell response, which is often inhibited in ICI-resistant cancer patients. In this review, the onco-immunological characteristics of PEF ablation are discussed, with special emphasis placed on the clinical potential of PEF ablation to induce anti-cancer immune responses and enhance responsiveness to ICI therapy in ablated and non-ablated (abscopal) tumors.