Gallic acid enhances GVL effects of T cells without exacerbating GVHD after haematopoietic stem cell transplantation

Summary Allogeneic haematopoietic stem cell transplantation (allo‐HSCT) is an effective therapy for acute myeloid leukaemia (AML), predominantly due to its potent graft‐versus‐leukaemia (GVL) effect. However, leukaemia relapse remains a major obstacle to the success of allo‐HSCT. In this study, we demonstrated that gallic acid (GA), a natural dietary compound, can enhance T‐cell‐mediated GVL effects both in vitro and in vivo. GA‐treated T cells exhibited increased activation and elevated secretion of cytotoxic cytokines, leading to the apoptosis of AML cells in co‐culture systems in vitro. In a non‐irradiated leukaemia mouse model, we showed that GA treatment prolonged the survival of leukaemic mice and reduced leukaemia cell infiltration. Further analysis revealed that GA treatment increased T‐cell activation and tumour necrosis factor‐α secretion. Moreover, integrated transcriptomic and proteomic analyses indicated that GA augments T‐cell‐mediated GVL effects through the activation of the MAPK and NF‐κB pathways. Blocking these pathways individually diminished the protective effect of GA in AML model mice. Importantly, GA administration did not accelerate graft‐versus‐host disease (GVHD) progression in a mouse model. In conclusion, our study revealed that GA can enhance the GVL effects of T cells without exacerbating GVHD, offering insights into its potential to improve outcomes for patients after HSCT.