The discoveries awarded the Nobel Prizes in Physiology or Medicine in 2018 and 2025 are redefining the frontiers of modern medicine, highlighting how health is the result of a dynamic balance between immune defense and immune regulation. The keyword is precision: knowing when and how to activate -or suppress- the immune response is the new frontier of personalized medicine.
The 2025 Nobel Prize was awarded to Mary E. Brunkow, Fred Ramsdell, and Shimon Sakaguchi for their discovery of peripheral immune tolerance—an essential regulatory mechanism that prevents the immune system from attacking healthy tissues. In 2018, James P. Allison and Tasuku Honjo received the same award for their groundbreaking work on cancer immunotherapy, specifically for identifying immune checkpoint inhibitors.
These Nobel Prizes illustrate how immunological research has paved the way for innovative therapies to treat diseases that, until recently, were considered untreatable. The immune system is a highly complex and finely regulated army: it detects and neutralizes both external threats (viruses, bacteria, foreign agents) and internal ones (tumor cells). And it all revolves around one critical principle: balance. An overactive response may lead to autoimmunity; an underactive response enables the development of cancer and infection.
Immune tolerance: the central role of treg cells
What are treg cells, and why do they matter?
In 1995, Shimon Sakaguchi identified a new population of T lymphocytes-regulatory T cells (Tregs)-which prevent autoreactive lymphocytes from attacking the body. Characterized by CD25 and FOXP3 expression, Tregs are central to peripheral immune tolerance, acting as sentinels to safeguard healthy tissues.
From central to peripheral tolerance: FOXP3, CD25, and autoimmunity
This discovery expanded the classical theory of central tolerance (developed in the thymus), introducing a second layer of immune control in peripheral tissues: Tregs suppress excessive immune responses and prevent autoimmunity.
Treg deficiency or dysfunction is associated with autoimmune diseases such as:
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Type 1 diabetes
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Autoimmune thyroiditis
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Multiple sclerosis
When tregs promote cancer: the immunological paradox
In contrast, excessive or dysfunctional Treg activity may enable cancer progression by shielding tumor cells from immune attack. Within the tumor microenvironment, Tregs build an immunosuppressive barrier that blocks cytotoxic T cells from acting.
Immune checkpoints: releasing the brakes on cancer immunity
CTLA-4 and PD-1: Molecular Brakes on the Immune Response
Immunotherapy has deep historical roots. As early as the 19th century, William B. Coley had already grasped the immune system’s potential to fight cancer. But it was only with the studies of Allison and Honjo that the real breakthrough occurred: the identification of CTLA-4 and PD-1, true molecular brakes of the immune system. These molecules, expressed on the surface of T lymphocytes, bind to inhibitory ligands and shut down the immune response against neoplastic cells.
Checkpoint Inhibitors: How They Work and Why They Revolutionized Oncology
The use of monoclonal antibodies to block these molecules (checkpoint inhibitors) makes it possible to:
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reactivate T lymphocytes
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recognize tumor cells
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restore an effective immune response
Clinical applications: the future of immune-modulated medicine
The Nobel Prize discoveries in 2018 and 2025 are transforming modern medicine, based on a common principle: modulating the balance of the immune system to harness its extraordinary therapeutic potential. The Tregs identified by Sakaguchi, Brunkow, and Ramsdell embody the principle of control, while the CTLA-4 and PD-1 molecules discovered by Allison and Honjo represent activation. Two complementary mechanisms in constant equilibrium: Tregs maintain immune peace, while checkpoint inhibitors reactivate the immune response when needed.
The future of medicine lies in knowing when to brake and when to accelerate.
Autoimmunity: Treg- and IL-2-Based Therapies
In autoimmune diseases, the goal is to enhance or restore Treg function in order to re-establish immune tolerance and reduce chronic inflammation.
Some of the approaches under investigation include low-dose IL-2 administration, the use of autologous Tregs expanded ex vivo, and gene therapy based on engineered Tregs.
Clinical studies have shown promising results across several conditions:
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Type 1 diabetes: The infusion of autologous Tregs has shown safety, good tolerance, and in some cases, reduced insulin requirements and preservation of pancreatic β-cell function.
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Chronic intestinal diseases: Ex vivo expanded Tregs capable of producing IL-10 have reduced mucosal inflammation and promoted remission in animal models and early-phase trials.
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Systemic lupus erythematosus and multiple sclerosis: Preliminary studies indicate that Treg expansion improves peripheral tolerance and reduces the pro-inflammatory Th17 response.
Transplants: induced tolerance and reduced immunosuppressive therapy
In the field of organ transplantation, the goal is to expand regulatory T cells (Tregs) to prevent graft rejection and reduce the need for long-term immunosuppressive treatment. Clinical trials have shown that the infusion of ex vivo expanded autologous Tregs can promote transplant acceptance and mitigate graft-versus-host reactions.
These protocols, often involving IL-2, rapamycin, and retinoids have demonstrated safety and phenotypic stability of the infused cells, paving the way for personalized immunotolerance strategies in liver, kidney, and bone marrow transplants.
Oncology: targeting tumor tregs and combined immunotherapy
In oncology, the challenge is reversed: to inhibit or reprogram dysfunctional Tregs that establish an immunosuppressive tumor microenvironment.
Checkpoint inhibitor therapies (anti-PD-1, anti-PD-L1, anti-CTLA-4) have transformed the treatment landscape for various solid tumors, yielding durable responses and, in some cases, complete remission.
Current research is exploring targeted combination strategies:
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Checkpoint inhibitors paired with anti-CD25 or anti-CCR8 antibodies to selectively deplete tumor-infiltrating Tregs
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Metabolic inhibitors aimed at reducing Treg survival
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Engineered regulatory T cells (CAR-Tregs) designed to act selectively on specific tissues or tumor types
To learn more
- Zhang A, Fan T, Liu Y, Yu G, Li C, Jiang Z. Regulatory T cells in immune checkpoint blockade antitumor therapy. Mol Cancer. 2024 Nov 8;23(1):251.
- Goswami TK, Singh M, Dhawan M, Mitra S, Emran TB, Rabaan AA, Mutair AA, Alawi ZA, Alhumaid S, Dhama K. Regulatory T cells (Tregs) and their therapeutic potential against autoimmune disorders – Advances and challenges. Hum Vaccin Immunother. 2022 Dec 31;18(1):2035117.
- Tay C, Tanaka A, Sakaguchi S. Tumor-infiltrating regulatory T cells as targets of cancer immunotherapy. Cancer Cell. 2023 Mar 13;41(3):450-465.
- Iwai Y, Terawaki S, Honjo T. PD-1 blockade inhibits hematogenous spread of poorly immunogenic tumor cells by enhanced recruitment of effector T cells. Int Immunol. 2005 Feb;17(2):133-44
- Leach DR, Krummel MF, Allison JP. Enhancement of antitumor immunity by CTLA-4 blockade. Science. 1996 Mar 22;271(5256):1734-6
- Hori S, Nomura T, Sakaguchi S. Control of regulatory T cell development by the transcription factor Foxp3. Science. 2003 Feb 14;299(5609):1057-61.
- Dikiy S, Rudensky AY. Principles of regulatory T cell function. Immunity. 2023 Feb 14;56(2):240-255.