Graft-versus-host disease (GVHD) is still a significant challenge for allogeneic hematopoietic stem cell transplantation (allo-HSCT), resulting in substantial non-relapse mortality. Regulatory T cells (Tregs) are essential for modulating immune responses and maintaining tolerance, resulting in a promising therapeutic approach for GVHD management. The purpose of this study is to explore the immunomodulatory effect of Tregs in preventing and managing GVHD without sacrificing the graft-versus-leukemia (GVL) effect. Preclinical and clinical studies demonstrate that ex vivo-expanded Tregs, derived from donor peripheral blood or umbilical cord blood, effectively reduce GVHD incidence when infused prophylactically. Combination therapies, including Tregs with tacrolimus or invariant natural killer T (iNKT) cell activation via α-galactosylceramide, enhance Treg's efficacy and reduce required cell doses. Improved Treg stability and in vivo expansion can be achieved through advanced strategies such as rapamycin-assisted expansion and orthogonal IL-2/IL-2Rβ systems. These findings highlight Tregs' potential to mitigate GVHD without compromising GVL, offering a biologically favorable alternative to traditional immunosuppression. Further randomized trials are needed to standardize protocols and confirm long-term efficacy in the face of challenges in Treg isolation, expansion, optimal dosing, and infusion timing, which will lead to improved transplant outcomes.

doi: 10.1016/j.jtct.2025.12.991.Online ahead of print.