When we think of cancer, we usually imagine an enemy growing inside the body, expanding uncontrollably. But we rarely consider the environment that surrounds it: a complex and dynamic ecosystem known as the tumor microenvironment (TME). This space is not composed only of malignant cells, but also of blood vessels, fibroblasts, extracellular matrix, and, above all, immune cells. Among them, one group stands out for its paradoxical role: regulatory T cells, or Tregs.
These cells, normally guardians of immune balance, become decisive actors within cancer. Their function can be to protect the body from autoimmune responses or, ironically, to protect the tumor from the immune system. The article published by Sato (2025) in Biomedicines explores this duality in depth and how understanding it could transform the way we treat cancer.
An ecosystem that determines the tumor’s fate
The tumor microenvironment functions as a “habitat” that cancer cells manipulate to survive. Within it, Tregs act as moderators of the immune system: their usual task is to prevent exaggerated immune responses that could harm the body itself. However, in the context of cancer, these cells can silence antitumor defenses, allowing malignant cells to grow without obstacles.
Tregs are identified by the presence of the FOXP3 gene, which regulates their development and function; when this gene fails, severe autoimmune diseases can appear, demonstrating its importance in maintaining immune harmony. Yet within a tumor, a high number of Tregs is often associated with a worse prognosis, as they suppress the activity of lymphocytes that could attack cancer cells.
Nevertheless, the picture is not so simple. Not all Tregs are the same or act in the same way in all cancer types. Their behavior depends on the tissue, metabolic environment, and tumor type, making them a complex and fascinating therapeutic target.
Flexible and diverse cells
One of the most interesting findings about Tregs is their plasticity, these cells can adapt according to environmental signals. For example, in the presence of inflammatory cytokines such as IL-1 or IL-6, they can lose their identity and transform into proinflammatory cells. This change can be beneficial or harmful depending on the context, since inflammation implies an immune activation that, if uncontrolled, could become deadly.
In cancer, this ability to transform plays a crucial role: when Tregs lose their regulatory function, they may favor a more active immune response against tumor cells, aiding their elimination. However, in many tumors, the microenvironment produces signals that reinforce their suppressive nature, turning Tregs into allies of cancer by blocking cytotoxic lymphocytes and allowing the tumor to hide from the immune system. Thus, their plasticity represents a double-edged sword, it can be the key to destroying the tumor or the shield that protects it.
Moreover, there are subpopulations of Tregs with different characteristics, reflecting their heterogeneity. Some are more stable, others more adaptable; this diversity explains why, in certain cancer types, their presence can even be associated with a better prognosis.
Tissue-resident Tregs have also been identified, living permanently in organs such as the skin, lungs, or intestine. Their local role is to maintain tolerance and repair tissues, but in cancer, they might participate in creating an environment that favors tumor growth.
Figure 1. Tregs are immune cells that normally keep inflammation under control, but inside tumors they can play two opposite roles. Sometimes they protect the cancer by silencing other immune cells, and other times they help the body fight back by reducing harmful inflammation and supporting antitumor activity.
Tregs: villains or allies, depending on the cancer type
The study details how Tregs’ influence varies according to tumor type:
Colorectal cancer: surprisingly, a higher presence of Tregs can be linked to better survival, possibly because some lose their suppressive capacity and help control chronic inflammation that favors the tumor.
Lung and breast cancer: in contrast, Tregs expressing receptors like CCR8 are associated with poor prognosis; their removal in animal models improves immune response and the effectiveness of radiotherapy or immunotherapy.
Pancreatic cancer: although the pancreas is not a typical immune organ, Tregs are intriguingly present; their removal can be harmful, suggesting they play a more regulatory than tumor-promoting role in this type of cancer.
Brain cancer: in tumors such as glioblastoma, Tregs contribute to a highly immunosuppressive environment; inhibiting molecules like GITR or PD-1 has improved immune responses in experimental models.
Melanoma: this type of skin cancer, a pioneer in immunotherapy treatments, shows how Tregs can interfere with the response to immune checkpoint inhibitors. Understanding their interaction with CD8+ T cells is key to overcoming treatment resistance.
The effect of Tregs depends on the balance between their protective function and their potential to block antitumor immunity. This delicate equilibrium defines whether they are allies or enemies of the patient.
Therapies targeting the heart of the tumor microenvironment
Due to their central role, Tregs have become a promising therapeutic target. Sato describes three main approaches:
Antibody–drug conjugates: these are antibodies directed against CD25, a Treg marker, bound to cytotoxic compounds. Such conjugates can selectively eliminate tumor Tregs, enhancing the response of effector cells (which destroy tumor cells). More than a dozen similar products have already been approved by the FDA, and several are in clinical trials for cancer.
Immunotoxins: before modern conjugates, toxins linked to molecules such as IL-2 or CD25 were used to eliminate Tregs in animal models, increasing antitumor immunity.
Inhibitory peptides: a more recent strategy employs small protein fragments (like peptide P60) that block FOXP3 function without destroying the entire cell. This method could have fewer side effects by reducing suppressive function without fully eliminating Tregs.
The challenge ahead: removing without harming
Although strategies to target Tregs show promise, the challenge is to do so without causing autoimmunity. In humans, completely eliminating these cells can trigger dangerous immune reactions. For this reason, researchers seek more selective approaches: instead of removing all Tregs, blocking their migration to the tumor through receptors such as CCR4 or CXCR4, or temporarily modulating their function.
Furthermore, emerging technologies such as single-cell sequencing (scRNA-seq) and spatial transcriptomics are helping map, with precision, the interactions among Tregs, lymphocytes, macrophages, and tumor cells. This knowledge could guide more personalized and effective therapies.
A recognition for scientific progress: the Nobel Prize
In this regard, the 2025 Nobel Prize in Physiology or Medicine was awarded to Shimon Sakaguchi, Mary E. Brunkow, and Fred Ramsdell for their key discoveries on regulatory T cells (Tregs) and peripheral immune tolerance, which laid the foundation for understanding how the immune system can both protect and harm the body.
This recognition underscores the relevance of studies like Sato’s, as manipulating Tregs is emerging as one of the frontiers of cancer immunotherapy.
Main reference:
Sato Y. (2025). The Role of Tregs in the Tumor Microenvironment. Biomedicines, 13(5), 1173. https://doi.org/10.3390/biomedicines13051173
Other references:
Mayer, S., Milo, T., Isaacson, A., Halperin, C., Miyara, S., Stein, Y., Lior, C., Pevsner-Fischer, M., Tzahor, E., Mayo, A., Alon, U., & Scherz-Shouval, R. (2023). The tumor microenvironment shows a hierarchy of cell-cell interactions dominated by fibroblasts. Nature communications, 14(1), 5810. https://doi.org/10.1038/s41467-023-41518-w
Giraldo, N. A., Sanchez-Salas, R., Peske, J. D., Vano, Y., Becht, E., Petitprez, F., Validire, P., Ingels, A., Cathelineau, X., Fridman, W. H., & Sautès-Fridman, C. (2019). The clinical role of the TME in solid cancer. British journal of cancer, 120(1), 45–53. https://doi.org/10.1038/s41416-018-0327-z
Anderson, N. M., & Simon, M. C. (2020). The tumor microenvironment. Current biology : CB, 30(16), R921–R925. https://doi.org/10.1016/j.cub.2020.06.081
