Approximately half of all patients worldwide diagnosed with cancer receive radiotherapy as part of their treatment, whether with curative intent, palliative intent, or combined with other therapies.

Traditionally, it has been understood as a tool whose purpose is to destroy tumor cells through direct DNA damage. However, there is a phenomenon reported in some patients in which these effects go far beyond the site where radiation is applied, and which Robert Mole termed the “abscopal effect”.

The abscopal effect describes the ability of localized radiotherapy to generate systemic antitumor responses, reducing and inhibiting the growth of non-irradiated tumors in other parts of the body.

The term was introduced more than 70 years ago, but for a long time it was considered an anecdotal event due to its rarity. However, with the emergence and current advances in immunotherapy, and a better understanding of the immune system, this phenomenon began to acquire new meaning.

Today we know that not only is there a solid biological basis that explains it, but it can also be enhanced through combined therapeutic strategies such as immuno-radiotherapy (iRT), which is transforming cancer treatment, especially for patients with advanced or metastatic disease.

To understand how the abscopal effect occurs, it is important to recognize that radiotherapy not only destroys tumor cells, but also induces a series of immunological events that turn the tumor into a source of signals that stimulate the immune system:

When a tumor cell receives radiation, its DNA fragments and triggers the release of danger-associated molecular patterns (DAMPs), which act as an alarm that draws the attention of the immune system.

In addition, these DNA fragments that leak into the cytoplasm activate the cGAS–STING pathway, a route that promotes the release of type I interferon, which in turn stimulates dendritic cells (the “presenters” of the immune system) to capture tumor antigens and activate T lymphocytes capable of attacking not only the irradiated tumor but also other tumors in the body.

This mechanism explains why cytotoxic T lymphocytes (CD8+) are indispensable for an abscopal response to occur, since in preclinical studies, when these cells are removed, the abscopal effect disappears, even if radiotherapy is locally effective.

Dendritic cells also play a key role, as they are the ones that take the antigens released by the irradiated tumor and present them to T lymphocytes. Without this step, the immune system never receives the proper “message” to recognize other tumors as targets.

But the tumor microenvironment (TME) also has a decisive influence. This microenvironment is a complex ecosystem made up of immune cells, blood vessels, fibroblasts, connective tissue, and molecules secreted by the tumor.

Radiotherapy profoundly modifies this ecosystem. At the level of tumor cells, it increases their ability to be recognized by the immune system by upregulating MHC-I expression, which facilitates detection by T lymphocytes. It also generates local inflammation, which attracts immune cells, converting a “cold” microenvironment (poor in immune cells) into a “hot”, highly immunogenic one.

In the case of fibroblasts and the stroma, radiotherapy can activate pathways such as TGF-β, known for promoting scarring and fibrosis. Although this activation can favor invasive characteristics of the tumor, when combined with immunotherapy these negative effects can be counteracted and redirected toward an antitumor response.

Blood vessels are also affected, as radiation damages the endothelium and increases vascular permeability, allowing better entry of immune cells into the tumor.

Macrophages, which are abundant cells within the tumor microenvironment, undergo important reprogramming after radiotherapy. Tumor-associated macrophages (TAMs) normally act in an immunosuppressive manner, promoting tumor growth.

However, radiation can induce a shift toward a more inflammatory (M1) phenotype, capable of producing molecules that help destroy tumor cells. This reduces the presence of immunosuppressive molecules such as IL-10 and TGF-β and contributes to greater efficiency of the immune response.

Fig. 1. Radiation-treated tumors release signals that alert the immune system, helping activated T cells target cancer throughout the body.

Another key aspect is the impact of radiotherapy on immune suppressor cells, such as regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs). Although radiotherapy can temporarily increase some of these populations, immunotherapy blocks their escape pathways, creating a more favorable environment for cytotoxic T lymphocytes.

For this reason, radiotherapy alone rarely produces a strong abscopal effect; it needs the support of immunotherapy to fully unlock the immune response.

This is where immune checkpoint inhibitors, such as anti-PD-1, anti-PD–L1, and anti-CTLA-4 antibodies, play their role. These treatments release the brakes on the immune system, allowing T lymphocytes activated by radiotherapy to act more aggressively against tumors.

Studies have shown that this combination significantly improves survival and increases durable response rates in several types of cancer, including melanoma, lung cancer, renal cancer, and breast cancer. In fact, strong evidence has emerged that radiotherapy can make tumors resistant to immunotherapy respond by making them more visible to the immune system.

One of the most important questions today is how to optimize this combination therapy. Recent research suggests that the dose and fractionation of radiotherapy have a huge influence on the magnitude of the immune effect. Moderate, fractionated doses seem to generate an ideal balance (enough tumor damage to release antigens, but without activating resistance mechanisms).

In addition, treatment sequencing matters. Evidence indicates that administering immunotherapy during or immediately after radiotherapy produces better outcomes than doing so long before or long after.

Although the benefits are promising, risks also exist, such as increased immune-related toxicities, with pneumonitis being one of the most relevant adverse events when both therapies are combined. Even so, the results have been encouraging enough for this combination to be considered one of the most innovative and hopeful strategies in contemporary oncology.

The combination of radiotherapy with immunotherapy marks a new era in which the immune system itself becomes a fundamental ally in the fight against cancer, with the potential to generate profound responses even in patients with metastatic disease.

Although much remains to be understood and optimized, the future of this strategy is promising and represents real hope for thousands of patients worldwide.

 

Main reference:

Wang, X., Zhang, H., XinZhang, & Liu, Y. (2024). Abscopal effect: from a rare phenomenon to a new frontier in cancer therapy. Biomarker research, 12(1), 98. https://doi.org/10.1186/s40364-024-00628-3 

 

Other references:

Wu, Y., Zhu, K., Zhang, X., Du, W., Song, J., & Yang, H. (2023). Emerging plasmonic nanoparticles and their assemblies for cancer radiotherapy. Advanced drug delivery reviews, 194, 114710. https://doi.org/10.1016/j.addr.2023.114710 

Guipaud, O., Jaillet, C., Clément-Colmou, K., François, A., Supiot, S., & Milliat, F. (2018). The importance of the vascular endothelial barrier in the immune-inflammatory response induced by radiotherapy. The British journal of radiology, 91(1089), 20170762. https://doi.org/10.1259/bjr.20170762 

Herrera, F. G., Ronet, C., Ochoa de Olza, M., Barras, D., Crespo, I., Andreatta, M., Corria-Osorio, J., Spill, A., Benedetti, F., Genolet, R., Orcurto, A., Imbimbo, M., Ghisoni, E., Navarro Rodrigo, B., Berthold, D. R., Sarivalasis, A., Zaman, K., Duran, R., Dromain, C., Prior, J., … Coukos, G. (2022). Low-Dose Radiotherapy Reverses Tumor Immune Desertification and Resistance to Immunotherapy. Cancer discovery, 12(1), 108–133. https://doi.org/10.1158/2159-8290.CD-21-0003