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Targeting the Pentose Phosphate Pathway Mitigates Graft-versus-host Disease by Rewiring Alloreactive T-cell Metabolism

Researchers at Roswell Park Comprehensive Cancer Center and the University of Minnesota have found that targeting the pentose phosphate pathway (PPP) in donor T cells can significantly reduce the severity of acute graft-versus-host disease (aGVHD) while preserving beneficial anti-tumor immunity. This collaborative study, published in JCI Insight in October 2025, shows that inhibiting the PPP by targeting the enzyme 6-phosphogluconate dehydrogenase (6PGD) rewires alloreactive T cell metabolism, limits their pathological expansion, and improves survival in multiple transplant models. Overall, selectively modulating T cell metabolism, rather than broadly suppressing immunity, can uncouple harmful graft-versus-host effects from the desired graft-versus-tumor response.

Acute GVHD remains a major cause of mortality after allogeneic hematopoietic cell transplantation and is driven by expansive proliferation of donor T cells that damage the gut, liver, and skin. Although pathogenic T cells are known to rely heavily on glycolysis, directly blocking glucose metabolism is not clinically feasible. The authors therefore focused on the PPP, a critical branch of glucose metabolism supporting nucleotide synthesis and redox balance. Single-cell and bulk transcriptional profiling showed that PPP pathway genes were among the most strongly upregulated metabolic programs in alloreactive T cells during GVHD. Genetic deletion of 6PGD did not affect T cell viability but reduced in vitro proliferation by approximately 40–60% based on CFSE dilution and Ki67 staining (p<0.01). In vivo, when equal numbers of wild-type and 6PGD-deficient T cells were co-transferred, 6PGD-deficient cells represented less than 30% of donor T cells in spleen and liver by day +7 (p<0.01), demonstrating a profound competitive disadvantage in expansion.

In fully mismatched C57BL/6 to BALB/c transplants, pharmacologic 6PGD inhibition with 6-aminonicotinamide (0.5 mg/kg daily) reduced clinical GVHD scores by more than 50% after day +40 and improved survival from 0% in controls to 35% at day +46 (p<0.01). In a minor-mismatch model, weight loss was reduced by approximately 15–20% and survival was significantly prolonged (p<0.05). In xenogeneic GVHD using human PBMCs, median survival increased from 23.5 to 29.5 days (p=0.008), with a 40–60% reduction in human CD4+ and CD8+ T cell numbers in target organs. Despite this, graft-versus-tumor activity was preserved, with granzyme B–high effector T cells remaining detectable and leukemia control maintained. Together, these data establish the pentose phosphate pathway as a quantitative metabolic bottleneck in GVHD and suggest 6PGD inhibition as a precision strategy to make transplantation safer without sacrificing cure.

Reference:

Daneshmandi S, Ko E, Yan Q, et al. Targeting the pentose phosphate pathway mitigates graft-versus-host disease by rewiring alloreactive T cell metabolism. JCI Insight. 2025;10(23):e192774. Published 2025 Dec 8.

http://doi.org/10.1172/jci.insight.192774