For a long time, local cancer treatments have been understood in a fairly direct way: destroy the tumor where it is. Surgery seeks to remove it, radiotherapy damages it with radiation, and some forms of ablation eliminate it using extreme heat, intense cold, or other sources of energy. However, in recent years, a very interesting question has emerged: what if physically treating a tumor not only served to destroy cancer cells, but also to teach the immune system to recognize them better?
That is the central idea of a recent study published in Clinical Cancer Research. The work evaluated a specialized form of ablation with pulsed electric fields (PEF) in patients with early-stage non-small cell lung cancer. The researchers wanted to know whether, in addition to destroying cells, this type of energy could modify the tumor’s immune environment and favor a more active immune response.
Lung cancer and the challenge of activating immunity
Non-small cell lung cancer, known as NSCLC, accounts for more than 80% of lung cancer diagnoses. Although treatments such as surgery, radiotherapy, chemotherapy, targeted therapies, and immunotherapy exist, not all patients can receive the same options. Some tumors are difficult to operate on, others recur after treatment, and some do not respond well to immunological drugs.
Immunotherapy has changed the treatment of lung cancer, especially with immune checkpoint inhibitors. These drugs help T cells, a key part of the immune system, recognize and attack tumor cells. But there is a problem: for immunotherapy to work well, the tumor must have a microenvironment capable of attracting, organizing, and sustaining immune cells. In simple terms, the immune system needs to find the tumor, enter it, and receive clear signals about what it should attack.
Some tumors are “hot,” meaning they have many active immune cells inside them. Others are “cold,” with little immune infiltration and a lower probability of responding to immunotherapy. For this reason, one of the major current goals in oncology is to transform immunologically poor tumors into tumors that are more visible to the immune system.
What are pulsed electric fields?
PEF ablation uses very brief electrical pulses to alter the cells of the treated tissue. Unlike other ablations, such as radiofrequency or microwaves, which depend on heat, this technology does not seek to “burn” the tumor. Its effect is based on altering the electrical potentials of cell membranes, which can lead to loss of internal balance and cell death.
This difference is important. When a tumor is destroyed with extreme temperatures, some proteins and cellular structures can be intensely damaged or denatured. That can reduce the immune system’s ability to recognize tumor remnants as useful signals. In contrast, the study suggests that this specialized form of PEF can induce tumor death while better preserving tumor antigens, extracellular matrix, and components of the tissue environment. In other words, the tumor dies, but leaves behind biological signals that are more “legible” to the immune system.
Figure 1. Non-thermal PEF ablation disrupts tumor cell membranes, releasing tumor antigens and danger signals that may activate immune responses. This can increase immune infiltration, remodel the tumor microenvironment, and support TLS and germinal center formation.
The tumor as a source of immunological information
Each tumor contains unique information. Its cells express proteins, mutations, and signals that can serve as “clues” for the immune system. The problem is that many times those clues are hidden, poorly presented, or surrounded by signals that block the immune response.
When a local therapy causes immunogenic cell death, it can release tumor antigens and damage molecules known as damage-associated molecular patterns (DAMPs). These molecules function as alarm signals. They tell the immune system: “something abnormal is happening here.” If these signals appear in the right context, they can attract immune cells, activate antigen presentation, and help T cells learn to recognize the tumor.
Tertiary lymphoid structures: small immune centers inside the tumor
One of the most important concepts in the study is tertiary lymphoid structures, or TLS. Although the name sounds technical, the idea can be explained simply. Normally, the immune system organizes many of its responses in organs such as lymph nodes, the spleen, and tonsils. There, immune cells meet, exchange information, and learn to recognize threats.
TLS are structures similar to small “immune neighborhoods” that can form within or around inflamed tissues, including some tumors. When they appear in cancer, they are often associated with a more organized and active microenvironment. They can bring together B cells, T cells, antigen-presenting cells, and chemical signals that favor a more coordinated response.
But there is an even more interesting level: TLS with germinal centers. Germinal centers are areas where B cells mature, improve the quality of their antibodies, and can become memory B cells or antibody-producing plasma cells. In many cancers, the presence of TLS with germinal centers has been linked to better prognosis and better responses to immunotherapies. The challenge is that, until now, there are no commercial therapies specifically designed to reliably induce the formation of these structures inside the tumor.
What did the study do?
The study was designed as a “treat-and-resect” clinical trial. This means that patients received an intervention before surgery and then the tumor was removed to analyze what had changed inside the tissue.
The patients had early-stage non-small cell lung cancer and were candidates for surgery. One group received diagnostic biopsy followed by PEF ablation; another group received biopsy and standard surgery without ablation. Afterward, the researchers compared blood and tumor tissue samples to observe immunological changes.
It is important to clarify that the goal was not to completely destroy the tumor with ablation. In fact, the researchers wanted to leave enough tumor tissue to study how the microenvironment had responded after the energy. This allows for a better understanding of the biological effect of the procedure.
The results were striking. In tumors treated with this specialized form of PEF, the researchers observed an increase in signals associated with immune cell recruitment and organization. One of them was CXCL13, an important molecule for attracting B cells and favoring lymphoid structures within the tissue.
They also found increases in populations related to germinal centers, such as class-switched memory B cells and plasma cells. These cells are relevant because they suggest that immune cells not only arrived at the tumor, but that some may have been entering processes of maturation and specialization.
In addition, tumors from the treated group showed a higher proportion of TLS with germinal centers: 47% compared with 24% in the control group. In blood, treated patients also showed signs of systemic activation, including increased serum HMGB1 and more circulating cytotoxic T cells.
Why does this matter?
The importance of these findings is not only that the tumor was locally damaged. What is relevant is that the procedure appears to modify the immunological context around the tumor. Instead of being only a physical destruction technique, it could act as a kind of “training signal” for the immune system.
This does not mean that PEF is a cancer vaccine or that it can replace established treatments. The study is exploratory, and larger studies are still needed. But it does suggest a very valuable possibility: that some local treatments could be combined with immunotherapy to improve the body’s ability to recognize the tumor.
Main reference:
Jimenez, M., Hatton, B. A., Moreno-Gonzalez, A., Iding, J. S., Flandes, J., van der Heijden, E. H. F. M., Ng, C. S. H., Prieto, C., Teodosio, C., Flores-Montero, J. A., Rodríguez-González, M., Cedeño Diaz, O. M., Vos, S., Lau, R. W. H., Kaiza, M. E., Moore, W. H., Orfao, A., & Bruno, T. C. (2026). Pulsed electric field ablation reprograms tumor immunity and stimulates germinal center formation in tertiary lymphoid structures in patients with non-small cell lung cancer. Clinical Cancer Research: An Official Journal of the American Association for Cancer Research. https://doi.org/10.1158/1078-0432.CCR-25-3847
Other references:
Pastori, C., Nafie, E. H. O., Wagh, M. S., Mammarappallil, J. G., & Neal, R. E., 2nd (2024). Pulsed Electric Field Ablation versus Radiofrequency Thermal Ablation in Murine Breast Cancer Models: Anticancer Immune Stimulation, Tumor Response, and Abscopal Effects. Journal of vascular and interventional radiology : JVIR, 35(3), 442–451.e7. https://doi.org/10.1016/j.jvir.2023.11.021
Ersching, J., Efeyan, A., Mesin, L., Jacobsen, J. T., Pasqual, G., Grabiner, B. C., Dominguez-Sola, D., Sabatini, D. M., & Victora, G. D. (2017). Germinal Center Selection and Affinity Maturation Require Dynamic Regulation of mTORC1 Kinase. Immunity, 46(6), 1045–1058.e6. https://doi.org/10.1016/j.immuni.2017.06.005
