A recent Cell Perspective illustrates how decades of progress in regulatory T cell (Treg) biology are now converging with clinical innovation to enable immune tolerance–based treatments. Led by Profs. YUAN Junying and ZOU Chengyu at the Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, together with Profs.LI Peiying and LI Bin at Shanghai Jiao Tong University School of Medicine, and Prof. Tim Sparwasser at the University Medical Center Mainz, the work outlines major advances that are rapidly transforming Tregs from a foundational concept in immunology into a promising therapeutic platform. The article identifies key research priorities and translational challenges and sets forth a roadmap integrating basic and clinical insights to guide the development of next-generation precision tolerance therapies.
The central importance of Tregs in immune tolerance was formally recognized with the 2025 Nobel Prize in Physiology or Medicine, awarded for the discovery of regulatory T cells and their fundamental role in preventing autoimmunity. Building on this landmark achievement, the Perspective highlights how long-standing basic discoveries are now being translated into clinically actionable strategies, positioning Treg-based therapies to move steadily toward real-world application.
Rather than broadly suppressing immune responses, Tregs act as the immune system’s intrinsic regulators, restraining excessive inflammation while preserving protective immunity. This unique biology distinguishes Tregs from conventional immunosuppressive approaches and underpins their emergence as a new generation of “living drugs” capable of restoring immune balance while simultaneously promoting tissue repair.
The Perspective synthesizes key breakthroughs in Treg biology, including refined molecular and epigenetic markers that distinguish stable Tregs from transiently activated T cells, and emerging insights into how the transcription factor FOXP3 safeguards Treg stability in inflammatory environments. Beyond classical immune suppression, Tregs are shown to orchestrate tolerance through coordinated mechanisms involving direct cell–cell interactions, modulation of cytokine availability, and precise spatial positioning within tissues.
A major focus of the article is the metabolic specialization of Tregs. Unlike effector T cells that rely heavily on glycolysis, Tregs exhibit flexible metabolic programs that enable them to function in low-glucose, inflamed tissues. This metabolic adaptability not only supports suppressive function but also links lineage identity to cell survival and stability, revealing new opportunities for therapeutic intervention.
Importantly, the authors emphasize the expanding role of Tregs in tissue repair and regeneration. Tissue-resident Tregs actively contribute to healing processes in organs such as the heart, skeletal muscle, and central nervous system by secreting growth factors and coordinating local immune responses. These findings broaden the therapeutic relevance of Tregs beyond autoimmune diseases to include neurodegenerative disorders such as multiple sclerosis, amyotrophic lateral sclerosis, and Alzheimer’s disease.
On the translational front, the Perspective reviews key clinical milestones validating Treg-based therapies in humans. Low-dose interleukin-2 therapy has demonstrated the ability to selectively expand Tregs in patients, with encouraging results in both autoimmune and neurodegenerative disease trials. Adoptive transfer of ex vivo–expanded Tregs has shown safety and efficacy in preventing graft-versus-host disease, while early-stage studies of antigen-specific and CAR-engineered Tregs mark a significant step toward precision tolerance therapy.
The article also highlights emerging strategies to enhance Treg stability and persistence, including targeting the balance between proliferation and programmed cell death pathways, optimizing metabolic fitness, and engineering homing receptors to direct Tregs to inflamed tissues. At the same time, the authors candidly discuss remaining bottlenecks, such as scalable cell manufacturing, long-term stability in inflammatory environments, and the need for predictive biomarkers to guide patient selection.
By integrating basic immunology with clinical insights, this Perspective provides a forward-looking roadmap for Treg-based therapies. It underscores a paradigm shift from nonspecific immunosuppression toward deliberate immune reprogramming, with Tregs at the center of next-generation treatments for immune-mediated and neurodegenerative diseases.
YUAN Junying, Ph.D, Professor
Interdisciplinary Research Center on Biology and Chemistry (IRCBC)
Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences
Haike Road 100 Shanghai 201204 China
Email: junying_yuan@sioc.ac.cn
ZOU Chengyu, Ph.D, Professor
Interdisciplinary Research Center on Biology and Chemistry (IRCBC)
Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences
Haike Road 100 Shanghai 201204 China
Email: czou@mail.sioc.ac.cn
