Regulatory T cell function and engineering for next generation cell therapies

Regulatory T cells (Tregs) are essential for immune tolerance and tissue homeostasis. Their dysfunction contributes to a broad range of autoimmune, inflammatory, and degenerative diseases, motivating interest in Treg-based therapies. Clinical translation has been constrained by limited stability, persistence, and functional specialization, particularly within inflammatory tissue environments. Emerging evidence reveals that Tregs are not a uniform suppressive lineage but comprise tissue-adapted populations with distinct transcriptional, metabolic, and functional programs. These cells support organ integrity through mechanisms extending beyond immune regulation, including roles in tissue repair, metabolic tuning, and stem cell niche maintenance that significantly broadens their therapeutic potential. Here, we review established Treg biology and key learnings from select clinical experiences using unmodified Tregs. From there, we discuss the mechanisms and challenges limiting efficacy of Tregs, and present how the state-of-the-art engineering aims to enhance Treg durability, stability, and specificity. Finally, we conclude with a forward-looking perspective on how the future of Tregs can expand beyond immune suppression by incorporating recently discovered tissue-specific functions for next-generation therapies targeting a broad range of indications.