Metabolic pathways as therapeutic target to improve allo-HSCT outcomes

Abstract Allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains the only curative option for many high-risk hematologic malignancies, yet its efficacy is limited by graft-versus-host disease (GVHD), relapse, and immune dysregulation. Emerging evidence identifies cellular metabolism as a central, underexplored determinant of transplant outcomes. Across transplant-relevant malignancies, including myelodysplastic neoplasms, acute myeloid and lymphoblastic leukemia, and high-risk lymphoma, disease-specific metabolic programs encompassing mitochondrial dysfunction, oxidative stress, lipid and fatty acid remodeling, and oncometabolite accumulation cooperate to sustain clonal persistence, suppress antitumor immunity, and confer resistance to cytotoxic and targeted therapies. Within the transplant itself, donor T-cell metabolic reprogramming fuels the dichotomy between GVHD and graft-versus-leukemia (GVL) activity, with alloreactive effector T cells depending on glycolysis and fatty acid oxidation in ways that are mechanistically separable from GVL-mediating responses. This review synthesizes current evidence on disease-specific and transplant-specific metabolic programs and evaluates pharmacological strategies that may be deployed peri-transplant to simultaneously reduce GVHD, prevent relapse, and preserve GVL.