The fight against cancer has traditionally been described through three major pillars: surgery, chemotherapy, and radiotherapy. More recently, immunotherapy and targeted therapies have transformed the way we understand cancer treatment. However, there is a line of research that, although less known to the general public, is gaining increasing relevance: the use of pulsed electric fields as a tool to attack tumors and, in some cases, stimulate an immune response against cancer.
The idea may sound futuristic: applying controlled electrical pulses to a tumor to alter its cells, facilitate drug entry, destroy tumor tissue, or even help the immune system recognize cancer more effectively. But this strategy does not belong to science fiction. It is part of a field called bioelectricity, which studies how electrical signals influence cells and how we can use external electrical stimuli to modify their behavior. In cancer, these electrical pulses have been explored in several therapeutic modalities, including electrochemotherapy, irreversible electroporation, and nanosecond pulsed electric fields.
Why can electricity affect a cancer cell?
Every cell is surrounded by a membrane, a structure mainly composed of lipids that acts as a selective barrier. This membrane protects the interior of the cell and regulates which molecules can enter or leave. However, when a sufficiently intense electric field is applied, that membrane can become temporarily permeable. This phenomenon is known as electroporation.
Electroporation occurs when the electric field induces small defects or pores in the cell membrane. Depending on the intensity, duration, and number of pulses, these pores can be temporary or permanent. If they are temporary, the cell can survive, and that window can be used to introduce drugs, genes, or other molecules. If the damage is irreversible, the cell loses its ability to maintain internal balance and may die.
This principle is key: the goal is to apply pulses with very specific parameters to produce concrete biological effects. Pulse duration matters greatly. Pulsed electric fields can generally be classified into three domains: millisecond pulses, microsecond pulses, and nanosecond pulses. Each has different applications in oncology.
Millisecond Pulses: Opening the door to therapeutic gene delivery
Longer pulses, in the millisecond range, are often used to promote the entry of genetic material into cells. This technique is known as gene electrotransfer, or electroporation-mediated gene transfer.
In this approach, a plasmid—a small circular DNA molecule—is introduced near the tumor. Then, electrical pulses are applied to facilitate its entry into the cells. The objective is not to destroy them, but rather to make them express a therapeutic molecule.
An important example is the use of plasmids encoding interleukin-12, a cytokine that can promote immune responses, stimulate interferon-gamma production, and support antitumor mechanisms. In clinical studies of melanoma, IL-12 gene transfer through electroporation showed promising results, including effects on treated tumors and also on some nearby lesions that were not directly treated.
Electrochemotherapy: Helping drugs enter where they could not before
One of the most developed applications of electroporation in cancer is electrochemotherapy. This technique combines electrical pulses with anticancer drugs, especially drugs that have difficulty crossing the cell membrane on their own.
The classic example is bleomycin, a molecule with potent cytotoxic activity but limited ability to enter certain cells. When electrical pulses are applied, the tumor membrane becomes transiently permeable, allowing bleomycin to reach the inside of the cell. Once inside, it can induce DNA damage and trigger cell death.
Electrochemotherapy has been studied especially in cutaneous tumors and superficial lesions, including melanoma, basal cell carcinoma, breast cancer with cutaneous metastases, and Kaposi’s sarcoma. In different studies, this technique has shown relevant efficacy in superficial lesions, with important rates of local response. In addition, in Europe it has been incorporated into certain clinical contexts, although its approval and availability vary by country.
What makes electrochemotherapy particularly interesting is that it does not only act as a way to improve drug delivery. It can also induce cellular damage signals that attract immune cells, such as dendritic cells. These cells can capture tumor antigens and present them to the immune system, initiating an adaptive response. This process is known as immunogenic cell death.
Immunogenic cell death is different from silent cell death. Instead of going unnoticed, the tumor cell dies while releasing alarm signals. These signals may include molecules known as DAMPs, or damage-associated molecular patterns, which function as a kind of biological alert for the immune system.
Irreversible Electroporation: Destroying the tumor without relying on heat
Another important modality is irreversible electroporation, or IRE. Unlike reversible electroporation used to facilitate drug entry, IRE applies higher-intensity electric fields that create permanent pores in the cell membrane. The cell can no longer restore its internal balance and eventually dies.
A relevant advantage of IRE is that it is considered a primarily non-thermal technique. This means that its destructive effect does not depend on heat, unlike other forms of ablation. This characteristic can be useful in tumors located near large blood vessels, where thermal therapies may lose effectiveness due to the so-called heat sink effect, meaning heat dissipation caused by blood flow.
In addition, because it does not depend on heat, IRE may preserve certain tissue structures, such as blood vessels or components of the extracellular matrix. This does not mean it is harmless, but rather that its mechanism of action is different from classic thermal ablation.
IRE has been explored in pancreatic tumors, liver metastases, renal tumors, and other complex lesions. However, unlike other modalities such as nanosecond pulses, IRE does not appear to induce such a strong antitumor immune response.
Not all forms of tumor destruction are immunologically equivalent. Killing tumor cells does not always mean activating a powerful immune response. The way a cell dies can determine whether the immune system ignores it or recognizes it as a threat.
Nanosecond pulses: A deeper dimension
Nanosecond pulsed electric fields represent one of the most fascinating areas of bioelectricity applied to cancer. Unlike longer pulses, these ultrashort pulses can act not only on the plasma membrane, but also on internal cellular structures such as mitochondria, the endoplasmic reticulum, vesicles, and even the nucleus.
This happens because the pulses are so fast that they pass through the cell before internal charges have time to redistribute and neutralize the electric field. Put simply: the pulse enters before the cell can “electrically protect” itself. This property allows intracellular effects that are not observed in the same way with longer pulses.
Nanosecond pulses can create extremely small nanopores in cellular and organelle membranes. These pores allow ions to pass, especially calcium. Calcium is not only a mineral; inside the cell, it functions as a fundamental signal. Sudden changes in intracellular calcium can alter processes such as secretion, metabolism, cellular stress, cell death, and immune activation.
In preclinical models, nanosecond pulses have shown the ability to induce immunogenic cell death. The release of signals such as ATP, HMGB1, and calreticulin exposure has been described, all of which are associated with greater immunological visibility of the tumor. More importantly, some studies have found adaptive responses dependent on CD8+ T cells, which may be essential for attacking tumor cells beyond the treated site.
Figure 1. Controlled electric pulses can target tumor tissue to improve drug uptake, induce non-thermal ablation, damage intracellular structures, and potentially stimulate antitumor immune responses.
From local treatment to systemic response
One of the most promising concepts in this area is that a treatment applied locally to a tumor could generate systemic effects. In other words, treating one lesion could help the immune system recognize tumor cells in other parts of the body.
This idea is related to the concept of turning the tumor into a kind of in situ vaccine. When cancer cells die in an immunogenic way, they release tumor antigens along with alarm signals. Dendritic cells can capture those antigens, migrate to lymph nodes, and activate tumor-specific T cells. Those T cells could then circulate and attack metastatic lesions.
However, it is important to remain cautious. Although preclinical models are promising, translating these effects to human patients is complex. The tumor microenvironment can be immunosuppressive, metastases may have different characteristics from the primary tumor, and not all patients have the same ability to mount an effective immune response.
Even so, the potential is enormous. Bioelectric therapies could be combined with immunotherapy, checkpoint inhibitors, tumor microenvironment modulators, or intratumoral strategies to amplify the antitumor response.
Advantages and challenges
Therapies based on pulsed electric fields have several conceptual advantages. They can be precise, local, non-thermal in certain contexts, and, depending on the modality, may avoid the need for systemic drugs. Some techniques can preserve important anatomical structures and may be useful in tumors that are difficult to treat with conventional methods.
But there are also challenges. Their application requires specialized equipment, careful planning, appropriate electrodes, and strict control of physical parameters. In addition, not all tumors are accessible in the same way. Larger tumors may require multiple applications to cover the entire tumor volume. In the case of nanosecond pulses, the high intensities required may limit the size of the treated area.
More clinical evidence is also needed. Some modalities, such as electrochemotherapy, have a longer track record in certain contexts. Others, such as nanopulse stimulation, remain areas of research with great potential, but are still under development for many oncological indications.
Main reference:
Nuccitelli R. (2019). Application of Pulsed Electric Fields to Cancer Therapy. Bioelectricity, 1(1), 30–34. https://doi.org/10.1089/bioe.2018.0001
Other reference:
Gong, X., Chen, Z., Hu, J. J., & Liu, C. (2022). Advances of Electroporation-Related Therapies and the Synergy with Immunotherapy in Cancer Treatment. Vaccines, 10(11), 1942. https://doi.org/10.3390/vaccines10111942
Rao, X., Chen, S., Alfadhl, Y., Chen, X., Sun, L., Yu, L., & Zhou, J. (2022). Pulse width and intensity effects of pulsed electric fields on cancerous and normal skin cells. Scientific reports, 12(1), 18039. https://doi.org/10.1038/s41598-022-22874-x
