Age is one of the main risk factors for developing cancer. This is not only because cells accumulate genetic alterations over time, but also because aging profoundly changes the immune system, leading to poorer function and creating conditions that may favor tumor growth and resistance to certain treatments.
One of these changes is known as inflammaging, a term used to describe a persistent state of mild, systemic inflammation associated with age. Unlike acute inflammation, which appears during an infection or injury and then subsides, inflammaging can persist for years. This prolonged activation affects different organs, alters immune-cell function, and has been linked to cardiovascular, neurodegenerative, and metabolic diseases, as well as cancer.
A study published in Nature Communications identified a possible connection between aging of the thymus, inflammation produced by immune cells, and the response to immunotherapy. The researchers found that a small molecule called thymulin, which is produced by the thymus and gradually declines with age, was able to reduce inflammation, strengthen the activity of specialized immune cells such as T cells, and improve the response to immunotherapy in aged mice.
When inflammation stops being protective
Inflammation is part of the body’s normal defense mechanisms. It helps detect infections, eliminate damaged cells, and initiate tissue repair. However, when it remains continuously active, it can produce the opposite effect.
During aging, the levels of inflammatory cytokines increase. These molecules act as communication signals between immune cells, activating them and essentially telling them that something is wrong and that they should respond. In a controlled immune reaction, these signals are necessary. However, when they are produced persistently, they can disrupt immune balance and promote an environment that supports tumor development.
In cancer, chronic inflammation can stimulate cell proliferation, promote the formation of new blood vessels, alter nearby tissues, and contribute to treatment resistance. It can also encourage the accumulation of immune cells that, instead of attacking the tumor, ultimately help support its growth.
The authors observed that aged mice had a higher proportion of cells producing inflammatory cytokines. These cells mainly included monocytes, macrophages, granulocytes, and dendritic cells, all of which are immune cells. In addition, in breast cancer models, aged animals developed tumors more rapidly and had shorter survival than young mice.
Myeloid Cells: Defenders that can change their function
Myeloid cells are a broad family of immune cells. They include monocytes, macrophages, granulocytes, and certain dendritic cells. Under normal conditions, they help detect microorganisms, remove cellular debris, and activate other branches of the immune response.
Inside a tumor, however, these cells can adopt very different states. Some retain antitumor functions, while others produce cytokines and factors that promote chronic inflammation, block T-cell activity, or help the tumor adapt.
The researchers found that, in tumors from aged mice, myeloid cells producing pro-inflammatory cytokines were more frequent. The predominant subtype varied depending on the experimental model, showing that inflammaging does not depend on a single cell population and that the microenvironment of each tumor may influence which cells acquire a more inflammatory profile.
Does this also occur in humans?
The study was not limited to animal models. The researchers analyzed blood cells from healthy people of different ages and observed that the frequency of myeloid cells producing inflammatory cytokines increased with age.
They also reused a publicly available single-cell RNA sequencing dataset from human breast tumors.
In samples from older patients, a relatively higher proportion of myeloid cells was observed. These cells also showed increased expression of genes related to inflammatory cytokines. In contrast, myeloid cells from younger patients showed higher expression of genes associated with maturation and antigen presentation, processes that are necessary for activating T cells.
These results do not prove that age is the only cause of the differences observed in human tumors. Nevertheless, they support the existence of a more inflammatory myeloid profile in older individuals and provide an important link between the experiments in mice and human biology.
An experiment to study the effect of young circulation
One of the central questions was whether age-associated inflammation was permanently fixed within the cells or whether it could be modified by circulating signals.
To investigate this, the researchers used a technique called heterochronic parabiosis. In this procedure, a young mouse and an aged mouse are surgically joined so that they share part of their blood circulation. Same-age pairs were also used as controls.
When aged mice shared circulation with young animals, their myeloid cells produced fewer inflammatory cytokines. Their tumors also grew more slowly, and survival improved compared with aged mice paired with other aged animals.
The evidence indicated that the young systemic environment contained factors capable of reducing the inflammatory state of aged cells. Additional bone marrow transplantation experiments showed that these factors mainly came from sources outside the bone marrow itself. Even aged myeloid cells could behave in a less inflammatory way when they were placed within a young organism.
This led the researchers to investigate which organ might produce a regulatory signal with these characteristics.
The Thymus: More than a school for T cells
The thymus is an organ located in the upper part of the chest. Its best-known function is to support the maturation and selection of T cells. It is highly active during childhood, but after adolescence it begins to decrease in size and function, a process known as thymic involution.
Traditionally, the impact of this decline has been explained by a reduced production of new T cells and a decrease in the diversity of the immune-cell repertoire. The new study proposes an additional function: the thymus may also indirectly regulate inflammation produced by myeloid cells through factors released into the circulation.
Using computational analyses and previous evidence, the researchers identified several molecules produced by thymic epithelial cells. One of them was thymulin, a small protein whose circulating activity declines with age.
Thymulin had already been associated with immune regulation and reduced production of inflammatory cytokines. The researchers therefore tested whether it could be one of the signals responsible for the effects observed in young animals.
How thymulin works
When human blood cells were treated with thymulin for 24 hours, the proportion of myeloid cells producing inflammatory cytokines decreased. The effect was more evident in samples from older individuals.
In aged mice, one week of treatment reduced the number of inflammatory myeloid cells in the blood. In young animals, by contrast, the effect was minimal. A similar pattern was observed in bone marrow-derived macrophages: thymulin mainly reduced cytokine production in cells obtained from aged animals.
The researchers linked this effect to the NF-κB pathway, one of the major molecular systems that controls the expression of inflammatory genes. When NF-κB is activated, it enters the cell nucleus and promotes cytokine production.
Thymulin reduced the ability of NF-κB to bind to DNA and inhibited a step required for activation of the pathway. Put simply, thymulin does not appear to completely shut down the immune system. Its effect is more similar to lowering an inflammatory alarm that remains excessively active during aging.
Figure 1. Age-related thymic involution promotes inflammaging, increasing pro-inflammatory myeloid activity and cytokine production, which weakens antitumor immunity and contributes to a suppressive tumor microenvironment with reduced response to anti-PD-L1 therapy.
What happened to the tumors?
In breast cancer models, thymulin delayed tumor growth and improved survival in aged mice. Inside the tumors, the number of myeloid cells producing inflammatory cytokines decreased. At the same time, production of interferon gamma increased in CD4 and CD8 T cells. Interferon gamma is an important cytokine that strengthens immune responses against malignant cells.
The T cells also showed a greater ability to destroy tumor cells in experimental assays. This suggests that reducing chronic myeloid inflammation allowed part of the antitumor activity of T cells to recover.
Thymulin and anti-PD-L1 immunotherapy
PD-L1 is a protein that can be expressed by tumor cells and other components of the tumor microenvironment. When it binds to PD-1 on T cells, it sends an inhibitory signal that reduces their activity.
Anti-PD-L1 antibodies are designed to block this immune brake. However, their effectiveness depends on the presence of a functional immune response that can be reactivated. In an environment dominated by chronic inflammation, altered myeloid cells, and weakened lymphocytes, simply removing the brake may not be enough.
In the study, anti-PD-L1 therapy alone did not control tumors in aged mice. When it was combined with thymulin, however, the tumors became sensitive to treatment, tumor growth was delayed, and survival increased.
What the study does not yet demonstrate
Although the results are promising, most of the therapeutic evidence comes from animal models of breast cancer. This study did not demonstrate that thymulin improves the response to immunotherapy in patients.
Further research is also needed in other cancer types, additional animal models, and larger human populations. The analysis of human tumors was observational and based on public datasets, whereas the direct treatment effects were tested mainly in isolated cells and mice.
The appropriate dose, administration schedule, long-term safety, and best therapeutic combination in humans are also still unknown. Reducing certain inflammatory signals may be beneficial in one context, but excessive interference with them could also impair defenses against infections or tissue repair.
The authors emphasize that differences between species and experimental models must be interpreted cautiously. In addition, the preclinical studies focused mainly on breast cancer, so it remains uncertain whether the mechanism can be generalized to other malignancies.
Thymulin is still far from becoming an established cancer therapy. However, the study opens an interesting direction: understanding how aging reshapes immunity and using that knowledge to develop treatments better adapted to the biological characteristics of older patients.
Main reference:
Kanemaru, H., Luong, S., Yamamoto, Y., Mizukami, Y., & Ito, F. (2026). Thymulin restrains age-associated myeloid inflammation and enhances cancer immunotherapy. Nature Communications, 17(1). https://doi.org/10.1038/s41467-026-75383-0
