The immune system requires the ability to defend against pathogens (‘non-self’) while sparing the body’s own cells (‘self’) from immune attack. Autoimmunity occurs when immune cells fail to correctly make this distinction. The Nobel Prize in Physiology or Medicine in 2025 was awarded to Shimon Sakaguchi, Fred Ramsdell and Mary E. Brunkow for the discovery of regulatory T cells (Tregs), a subset of T cells that are key regulators in this process. Tregs function as ‘security guards’, suppressing overactive peripheral immune cell activity and preventing autoimmunity. As engineered immune cell therapies using T cells, natural killer cells and macrophages are emerging in clinical trials, it is natural to think that engineering of Tregs could also prove beneficial, particularly for treatment of autoimmune diseases characterized by impaired Treg function or number. However, these cells are fundamentally different from other immune cell types, and adapting them for immunotherapies is not straightforward.

Previous research has elucidated key differences between Tregs and other T cell subsets. Tregs share fundamental characteristics with other T cells, such as thymic development and the expression of CD3 and T cell receptors (TCRs) for antigen recognition. However, effector T cells, B cells and macrophages activate immune responses and directly eliminate antigen-expressing cells, while Tregs suppress immune responses to maintain the body’s sense of self. They also have a unique molecular signature, such as the expression of FOXP3, which is required for their differentiation and function1,2,3, and high levels of the interleukin (IL)-2 receptor, which maintains their fitness and activates suppressive functions after binding to extracellular IL-2 (refs. 4,5). Effector T cells typically function through cell-contact-dependent mechanisms directed against antigen-expressing cells, but non-engineered Tregs are a polyclonal cell population capable of recognizing diverse antigens, giving them broad suppressive activity.

Consequently, the expansion of Treg cell populations in a patient with autoimmune disease or diseases characterized by excessive inflammation would restore the balance of immune cells (called tolerance). This has been shown in situ and evaluated in recent clinical trials. Given that IL-2 is indispensable for Treg function and survival, Nektar Therapeutics developed an IL-2-receptor agonist for use in patients with atopic dermatitis, a subset of whom also had asthma. They saw positive phase 2 results for both conditions and are now evaluating the drug for treating alopecia areata and type 1 diabetes, two other diseases characterized by immune-mediated chronic inflammation. Tregs can also be activated using an agonist to tumor necrosis factor receptor 2 (TNFR2), which is highly expressed on Tregs, and TRexBio is evaluating this strategy in a phase 1 study to alleviate inflammation in atopic dermatitis. IL-2 has also been used to expand Tregs ex vivo for controlling graft-versus-host disease6 and type 1 diabetes7, reducing prolonged immunosuppression caused by alternative small molecule immunosuppressants.

While Tregs have clinical potential, their adaptation is limited by restricted antigen specificity, possible in vivo instability, variable purity and limited persistence. Consequently, Treg-based therapies have been developed with three main strategies to get around these issues: engineering TCRs or chimeric antigen receptors (CARs) to target specific antigens; using gene editing to generate more potent and stable Treg cells; and converting other T cells into Tregs by inducing expression of FOXP3.

The success of CAR and TCR engineering technology in T cells, natural killer cells and myeloid cells has allowed researchers to engineer Tregs with enhanced specificity and efficacy. Unlike other CAR- or TCR-engineered immune cells, which eliminate disease cells through direct cytotoxicity, TCR-Tregs or CAR-Tregs activate suppressive pathways to control autoimmune responses and inflammation. For example, TCR-engineered Tregs have been designed to specifically recognize a fragment of the pancreatic islet-specific antigen glucose-6-phosphatase catalytic subunit-related protein (IGRP), an antigen associated with type 1 diabetes8. CAR-Tregs have been developed to induce and maintain immunological tolerance in patients with renal and liver transplant rejection and are also being developed for use in the autoimmune diseases refractory rheumatoid arthritis and hidradenitis suppurativa. Clinical trials are still in early stages.

Engineering Tregs with high antigen specificity is critical, and notable challenges exist. Tregs have a low in vivo frequency and are difficult to expand ex vivo, so engineering CAR-Tregs is considerably more challenging than engineering CAR-T cells. More strategies are needed to generate abundant, long-lasting Tregs for clinical use. A recent method has shown that conventional CD4+ T cells can be converted into stable and functional induced Treg cells (S/F-iTregs), which can suppress inflammatory bowel disease and graft-versus-host disease in mice9. Notably, S/F-iTregs with similar functional properties could be generated from patients with autoimmune disease using peripheral blood T cells10.

Engineering patient-specific Tregs for clinical application is further constrained by limitations in manufacturability, cost and scalability. Like other immunotherapies, ‘off-the-shelf’ Treg products can provide additional benefits, and some early efforts to produce Treg cell products from healthy donor-derived CD4+ T cells11, umbilical cord blood12 or human induced pluripotent stem cells13 look promising. Further research to enhance the expression and maintenance of FOXP3 in CD4⁺ T cells and to better understand the dominant immunosuppressive mechanisms in vivo will help advance Treg manufacturing.

Tackling Treg activity in cancer requires a different approach. In most scenarios, tumors actively recruit and expand Tregs to create an immunosuppressive tumor microenvironment that facilitates tumor immune escape, so the use of Treg agonists would be ineffective and detrimental. High numbers of Tregs in cancer are generally associated with worse treatment outcomes. Increased CAR-Tregs have been detected in patients resistant to CD19 CAR-T treatment, possibly as an inadvertent side product of the CAR-T manufacturing process14,15. These CAR-Tregs can suppress conventional CAR-T cell expansion and drive late relapses in preclinical models. Therefore, strategies that selectively deplete Tregs are needed for effective cancer immunotherapy.

Conventional IL-2 receptor-α subunit (CD25) monoclonal antibodies designed to disable and deplete Tregs in human tumors have failed to deliver clinical responses against solid tumors, mainly because IL-2 receptor signaling is also critical for effector T cell antitumor activity. Antibodies that specifically target Tregs can be used in combination with checkpoint inhibitors in selected tumor types where tumor-infiltrating Tregs mediate resistance to immune checkpoint blockade, such as those against CCR8 (refs. 16,17,18,19,20). As another example, an IL-2 mutant protein was fused to an antibody against CTLA-4, another Treg cell surface receptor, to selectively deplete Tregs from the tumor microenvironment; it is currently in clinical trials21. In addition, an optimized CD25 antibody selectively depletes tumor-infiltrating Tregs while preserving IL-2–STAT5 signaling in effector T cells, enhancing tumor control when combined with programmed cell death-1 (PD-1) blockade22. More research is needed to determine how these immune signaling pathways interact with each other and with current therapies.

The Nobel Prize celebrated the importance of understanding how the immune system is regulated and kept in check by Tregs, and now, over 20 years after the original basic research was conducted, there are clear therapeutic applications. Looking forward, the critical challenge lies in determining how to modulate Tregs to enhance their therapeutic efficacy without disturbing the delicate immune system equilibrium that they help maintain. To achieve this goal, advances in technology or new therapeutic strategies alone will not suffice — further unraveling the underlying mechanisms of Treg function in diverse physiological and pathological contexts will be equally essential. And it will continue to be even more important to invest in these basic biological research questions that make therapeutics with great impact.