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Regulation of the immune system by Tregs
Regulatory T cells (Tregs) act as “Brakes” of the immune system. They ensure that immune cells do not mistakenly attack the body's own tissues, thus preventing autoimmune diseases. This crucial role of Tregs was discovered by the 2025 Nobel laureates (Shimon Sakaguchi, Mary Brunkow, and Fred Ramsdell) – they found that special T cells with the surface marker CD25 (and the key factor FOXP3), known as Tregs, suppress autoaggressive immune cells. Under normal conditions, this is vital, because without functioning Tregs, severe autoimmune reactions can occur even in childhood.
However, cancer cells exploit this “Peacekeepers” To their advantage: Tumors attract and activate Tregs, thus increasing the body's own immune response. Killer cells will be slowed down. Cancer cells literally hide behind Tregs.to evade the immune system. Modern therapies therefore attempt to release these brakes in the tumor environment. “For cancer treatment, the focus is on downregulating or destroying the Tregs so that the immune system can attack the malignant cells.”“This is what Karolinska Institute immunologist Marie Wahren-Herlenius explained upon receiving the Nobel Prize. While research is being conducted on medications to combat Tregs in cases of autoimmune diseases or after organ transplants,” she added. to promoteIn oncology, the opposite approach is pursued: Targeted weakening of Tregsso that the body's own defenses can be restored Full throttle can be given against the tumor.
Natural polyphenols as immunological aid
The findings about Tregs have triggered an intensive search for active substances that can influence these cells. In addition to monoclonal antibodies or genetic engineering approaches, natural substances are also coming into focus. Polyphenols – a group of plant-based ingredients, which include u.a. particular Antioxidants These include those derived from green tea, grapes, or fruit – namely, those that exhibit remarkable immunomodulatory effects. Three prominent examples are: EGCG, Resveratrol and QuercetinThese substances are not cures for cancer on their own, but they could be. accompanying in the Immuno-oncology be helpful. They seem to be able to to influence the balance of the immune system – sometimes inhibiting it, sometimes accelerating it – depending on the needIn the context of tumor control, it is particularly interesting that they are being used in laboratory and initial clinical studies. reduce the number or effect of Tregs and simultaneously strengthen tumor-fighting immune cells. The following explains how these polyphenols work and how they could be utilized – based on the new Nobel Prize findings.
EGCG – Green tea extract with anti-Treg effect
EGCG (epigallocatechin gallate) is the most important polyphenol in green tea. Green tea has long been considered healthy. u.a...because of its antioxidant and anti-inflammatory properties. Recent studies now show that EGCG also positively influences the immune system in the tumor environmentPut simply, EGCG can help to strengthen the immune system. less braked becomes.
In a clinical study with leukemia patients (chronic lymphocytic leukemia), it was observed that a green tea extract (rich in EGCG) significantly reduced the Treg number in the blood. reducedAt the same time, two key signals that Tregs normally use to suppress the immune response decreased: the Interleukin-10 (IL-10) and TGF-β[7]Similar results were shown in another study of patients with acute myeloid leukemia who took green tea polyphenols for several months: The frequency of Tregs decreased, while at the same time more active Killer T cells (CD8⁺) natural killer cells were demonstrably[8]This suggests that EGCG is a type of Unleashing The anti-tumor immune component does this by loosening the Treg-induced brake.
These effects are also observed in animal models. In a mouse model of skin cancer (melanoma), EGCG treatment led to tumor cells expressing less PD-L1 – PD-L1 is a “Clothes” protein with which the tumors hide from immune attacks. Furthermore The number of immunosuppressive Tregs in the tumor tissue decreased., which allowed the exhausted cytotoxic T cells to resume their tumor-killing function[9]Overall, these studies suggest that EGCG Targeted weakening of Tregs and can reduce their inhibiting influence[9][10].
Important effects of EGCG in tumors (examples from studies):
· A green tea extract (with a high EGCG content) reduced the number of circulating Tregs in leukemia patients and simultaneously lowered the levels of the inhibitory messenger substances IL-10 and TGF-β released by Tregs.[7].
· In another patient group (leukemia), EGCG led to fewer Tregs as well as more active killer cellsThe ratio of cytotoxic CD8 T cells to NK cells with an active profile increased.[8].
· In the mouse model (melanoma) EGCG blocked an important immune evasion mechanism. The tumor: Tumor cells produced less PD-L1, and significantly fewer Tregs infiltrated the tumor tissue. As a result, the body's own T killer cells were able to destroy tumor cells more effectively again.[9].
These results suggest that EGCG as natural “immune booster” adjuvant It could be used. It would then be administered alongside conventional cancer therapies to support the immune system – by releasing the tumor-related immune brake (Tregs) and enhancing the attack of immune cells.[10]Importantly, green tea and EGCG are generally well tolerated and have few known serious side effects, which facilitates their use in clinical trials.
Resveratrol – a polyphenol from red grapes
Resveratrol is a plant polyphenol found primarily in the skin of red grapes (and therefore in red wine). It gained prominence as “Health-promoting” substance in red wine, among other things, due to the discussed benefits for the cardiovascular system and aging processes. Meanwhile, it is becoming clear that resveratrol also antitumor and immunomodulatory properties possesses. In the context of Tregs, this means: Resveratrol can restore the tumor immune balance in favor of the Attacker cells move.
In various preclinical studies (tumor models), it was observed that resveratrol specifically the number of Tregs decreased and simultaneously strengthens the effector immune cells. For example, in mouse models of liver cancer, resveratrol led to both CD4⁺FOXP3⁺-Tregs as well as CD8⁺CD122⁺-Tregs (a specific Treg variant) were significantly reduced[11]Interestingly, this also reduced the proportion of so-called M2 macrophages These are tumor-associated phagocytic cells that tend to promote tumor growth. In parallel, more CD8⁺ T cells with interferon-γ (IFN-γ) – an important cancer-fighting signaling molecule – found in the tumor[11]Resveratrol therefore turned the Immune profile in the tumor towards “anti-cancer”: fewer braking cells, but more attack cells.
This change was accompanied by significant shifts in immune messenger substances.In the treated tumors, the levels of inhibitory cytokines decreased. TGF-β1 and IL-10, while pro-inflammatory, anti-tumor mediators such as TNF-α and IFN-γ increased[12]This shows that resveratrol's effect has two levels – quantitatively (fewer Tregs) and functional (fewer inhibitors, more attack signals).
Similar results were achieved in a melanoma model (skin cancer in mice): Resveratrol administration loosened the tumor “brakes” – as measured by a significant decrease in TGF-β – and The number of Tregs (identified as CD4⁺CD25⁺ cells) was reduced.[13]Even under difficult conditions, z.BDuring radiation therapy, a resveratrol derivative (HS-1793) was shown to have an effect in a breast cancer model. further reduce the number of Tregs and was able to suppress the production of IL-10 and TGF-β (i.e., the immunosuppressive factors).[14].
Research highlights on resveratrol's immunological effects:
· In mouse models of liver cancer Resveratrol significantly reduced the Treg population.At the same time, the number of M2 tumor macrophages (which promote tumor growth), while active CD8⁺ T killer cells produced increased amounts of IFN-γ – an indication of enhanced anti-tumor immunity.[11]Furthermore, inhibitory cytokines in the tumor (TGF-β1, IL-10) were significantly reduced, while inflammatory mediators such as TNF-α increased.[12].
· In a melanoma mouse model, resveratrol led to fewer immunosuppressive signalsThe tumor tissue showed lower TGF-β levels, and the population of Tregs (CD4⁺CD25⁺) decreased.[13].
· A resveratrol analogue (HS-1793) was found to be effective in combination with radiotherapy. further reduce Tregs and inhibit the release of IL-10 and TGF-β.This partially reversed the radiation-induced immunosuppression in a breast tumor model.[14].
Resveratrol thus exhibits a great potential as an immunomodulator in the tumor context. By suppressing Tregs and other immunosuppressive cells (such as M2 macrophages) It reverses the immunological “microclimate” of the tumor. – away from tolerance, towards attack[15]It is noteworthy that these effects have been observed similarly in different types of tumors (liver cancer, skin cancer, breast cancer), suggesting a general mechanism. Although most of the data comes from animal models, they provide a clear biological basis. Rationale: Resveratrol could serve as an adjunctive agent in cancer therapy., to boost the immune system. Due to its natural origin and low toxicity, it would be ideal as a complement to existing therapies – especially since it has diverse targets (signaling pathways such as STAT3, immune cell types such as Tregs and macrophages) Killing several birds with one stone could.
Quercetin – a plant flavonoid with dual action
Quercetin is a widespread polyphenol (a flavonoid) found in many fruits and vegetables (z.B(Apples, onions, berries). It is known for its antioxidant and anti-inflammatory effects. In immuno-oncology, quercetin is attracting attention because it It has a double effectIt can weaken immunosuppressive mechanisms (such as Tregs) on the one hand and strengthen the direct defenses against the tumor on the other.
Schematic representation using quercetin as an example: Quercetin (green molecule) It influences the tumor immune environment by inhibitory signals blocked (blue lines) and Activating defense signals (red arrows). Firstly, quercetin inhibits pro-inflammatory cascades such as IL-6 → JAK2 → STAT3, which normally induce Tregs, IL-10 and PD-L1[16]. Through this Tumor cells produce less PD-L1 (a “camouflage signal”) and Tregs and IL-10 are reduced. – so the immune system's brakes loosen. Secondly promotes Quercetin via other pathways (z.B. by influencing CD47/PDK1 signals) the Transformation of macrophages into the M1 “wartime form” and stimulates CD8⁺ T cells. More tumor-fighting M1 macrophages, more cytotoxic T cells, and increased release of IL-2 and IFN-γ. are the result[16]In summary, quercetin shifts the balance in the tumor away from suppression and towards active immune defense.
Studies in model systems show that these mechanisms are not merely theoretical: In a breast cancer mouse model (triple-negative breast carcinoma, 4T1), quercetin caused the local immune system to become significantly more aggressive against the tumor. Measurements were taken elevated levels of IL-2 and IFN-γ – both messenger substances that activate T cells and NK cells – as well as a decrease in IL-10, the immunosuppressive cytokine of Tregs[17]. It was also found that more CD4⁺ and CD8⁺ T-cells in the tumor, specifically an increase in active killer cells, and at the same time fewer Tregs[17]. Also the natural killer cells (NK) infiltrated the tumor more extensively[18]This shift in favor of effector cells is consistent with the molecular effects of quercetin mentioned above.
Researchers were also able to identify the exact signaling pathway by which quercetin suppresses the formation of Tregs: It blocks the IL-6/JAK2/STAT3 path, which is chronically activated in many tumors and normally drives the formation of Tregs and the release of IL-10[19]This blockage also deprives the tumor cells of an important escape mechanism – the PD-L1 expression is reduced, which means that the tumor cells are less able to hide from the T-killer cells.[16]Additionally, quercetin influences the congenital Immune defense in the tumor: It inhibits the formation of tumor-promoting M2 macrophages (u.a. by inhibiting the messenger substance CXCL8) and supports the Recruitment or activation of M1 phagocytes, which attack the tumor[20][21]Overall, quercetin helps to make tumor tissue more accessible to the immune system. "hot" to make – from an immunological “cold”, hidden tumor becomes a visible target that can be recognized and fought by the immune cells.[21][16].
Key findings on quercetin in cancer immunology:
· In an aggressive breast cancer model, quercetin increased the concentration of immune-activating Messenger substances Interleukin-2 and Interferon-γ, while it immunosuppressive factor IL-10 lowered. This was accompanied by a Increase in active CD4⁺ and CD8⁺ T cells as well as NK cells in the tumor and a Decline in Treg cells[17]Mice treated with quercetin therefore had a significantly more resilient tumor immune system as untreated.
· Quercetin It specifically blocks the IL-6/JAK2/STAT3 signaling cascade., which often maintains an immunosuppressive environment in tumor cells. This leads to fewer Tregs and IL-10 formed and expressed by the tumor cells fewer PD-L1[16]In practical terms, this means that the tumor cells are more vulnerable to an immune attack, as the "protective bubble" of Tregs and PD-L1 shrinks.
· At the same time Quercetin promotes the anti-tumor immune responseIt facilitates the transition of phagocytes into the M1 mode (tumor-destroying) and supports the proliferation and activity of cytotoxic CD8 T cells (increased IL-2 and IFN-γ production)[16]Other inhibitory cells in the tumor (z.B. certain myeloid suppressor cells) are reduced, while the natural killer cells their tumor defense will be strengthened[16].
In summary Quercetin acts like an immune pacemaker.Quercetin, which readjusts the interplay within the tumor microenvironment: away from immune tolerance and towards active defense. This makes quercetin a promising candidate as a supportive measure in cancer therapy.
Sources: Shimon Sakaguchi, Mary Brunkow &Fred Ramsdell (Nobel Prize 2025, discovery of Tregs); Current research on EGCG[7][9], Resveratrol[11][14] and quercetin[17][16] in cancer immunology; as well as background information on the immunology of cancer.[6][4].
[1] [2] [3] [4] [5] [6] [22] Nobel prize in medicine awarded to scientists for immune system research | Nobel prizes | The Guardian
[7] [8] [9] [10] [24] [25] [26] Frontiers | The roles of epigallocatechin gallate in the tumor microenvironment, metabolic reprogramming, and immunotherapy
https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2024.1331641/full
[11] [12] [13] [14] [15] Recent Advancements on Immunomodulatory Mechanisms of Resveratrol in Tumor Microenvironment
https://www.mdpi.com/1420-3049/26/5/1343
[16] [17] [18] [19] [20] [21] [23] [27] Frontiers | Synergistic chemotherapy and immunomodulatory effects of quercetin in cancer: a review
https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2025.1547992/full