Abstract

New therapeutic strategies and paradigms are direly needed for the treatment of cancer. While the surgical removal of tumors is favored in most cancer treatment plans, resection options are often limited based on tumor localization. Over the last two decades, multiple tumor ablation strategies have emerged as promising stand-alone or combination therapeutic options for patients. These strategies are often employed to treat tumors in areas where surgical resection is not possible or where chemotherapeutics have proven ineffective. The type of cell death induced by the ablation modality is a critical aspect of therapeutic success that can impact the efficacy of the treatment and systemic anti-tumor immune system responses. Electroporation-based ablation technologies include electrochemotherapy, irreversible electroporation, and other modalities that rely on pulsed electric fields to create pores in cell membranes. These pores can either be reversible or irreversible depending on the electric field parameters and can induce cell death either alone or in combination with a therapeutic agent. However, there have been many controversial findings among these technologies as to the cell death type initiated, from apoptosis to pyroptosis. As cell death mechanisms can impact treatment side effects and efficacy, we review the main types of cell death induced by electroporation-based treatments and summarize the impact of these mechanisms on treatment response. We also discuss potential reasons behind the variability of findings such as the similarities between cell death pathways, differences between cell-types, and the variation in electric field strength across the treatment area.

Highlights

  • Despite improvements in survival and quality of life provided by current therapeutic practices, cancer death rates remain unacceptably high [1]

  • As electroporation ablation modalities become more mainstream and progress from preclinical studies to clinical applications, characterization of specific cell death mechanisms associated with treatment will become more relevant

  • Conflicting reports on cell death mechanisms ranging from apoptosis to necrosis and pyroptosis has led to confusion in the field

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Summary

INTRODUCTION

Despite improvements in survival and quality of life provided by current therapeutic practices, cancer death rates remain unacceptably high [1]. In addition to IL-1β and IL-18, pyroptosis produces a significant amount of DAMPs, including HMGB1, ATP, and ROS to further stimulate the innate immune system [56, 59, 60] This high signaling state leads to rapid responses from the body with recruitment of immune cells to the local area as well as increased systemic signaling to enhance immunosurveillance and heighten antigen presentation potential that could be beneficial for cancer treatment [61]. In in vitro hydrogel studies, H-FIRE applied in calcium-rich media showed a significant shift toward necrotic cell death with higher lesion areas and fewer survival signals [113] These data suggest that HFIRE effects could be modified by injecting calcium or sucrose near the treatment site to allow for controlled applications in difficult-to-treat malignancies or tissue locations. Based on the inflammatory and immunomodulatory conditions, these studies reveal that nsPEFs may induce programmed necrosis or necroptotic cell death in breast, melanoma, and pancreatic cancers [118,119,120]

DISCUSSION
13. Methods
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