Changes in the intestinal microbiome and microbiota-derived metabolites predict clinical outcomes after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Here, we report that desaminotyrosine (DAT), a product of bacterial flavonoid metabolism, correlates with improved overall survival and reduced relapse rates in patients receiving allo-HSCT. In preclinical mouse models, treatment with synthetic DAT prevents graft-versus-host disease by protecting the intestinal barrier and promoting intestinal regeneration and contributes to graft-vs.-leukemia responses. DAT´s beneficial effects on intestinal regeneration remain effective despite broad-spectrum antibiotics-induced dysbiosis, also when administered by fecal microbiota transfer with flavonoid-degrading F. plautii. Mechanistically, DAT promotes mTORC1-dependent activation and proliferation of intestinal stem cells, with concomitant engagement of the innate immune receptor STING required to mitigate metabolic stress and maintain an undifferentiated stem cell state independently of type-I interferon responses. Additionally, DAT can skew T cells towards an effector phenotype to modulate graft-versus-leukemia responses. Our data uncover DAT’s dual, tissue- and immune-modulating properties and underscore its potential in precision microbiome-based therapies to improve tissue regeneration and minimize immune-mediated side effects.

Paradoxically, immune cell infiltration correlates with worse prognosis in renal cell carcinoma (RCC) patients, with tumor-associated myeloid cells playing a key role in tumor progression. However, little is known about factors driving their polarization. Here, we investigated the link between RCC-related glycolysis, hypoxia-inducible factor (HIF)1α-associated myeloid inflammation, and patient prognosis. TCGA data revealed a strong correlation between the expression of monocarboxylate transporter 4 (MCT4), the myeloid marker CD14 and patient survival in ccRCC patients. scRNAseq data confirmed high MCT4 expression in both tumor and myeloid cells, suggesting lactate transport. In vitro analyses proved lactate uptake by CD14⁺ monocytes, which stabilized HIF1α and induced an MDSC-like, HLA-DR low phenotype. In line, the HIF1α-stabilizing drug Roxadustat increased the number of CD14⁺ HLA-DR low cells. Lactate uptake also increased protein lactylation. To further investigate the interplay between RCC tumor and myeloid cells, we established a 3D spheroid co-culture model and analyzed the effects of MCT inhibitors. This 3D model reflected tumor-myeloid cell interactions, as spheroid-infiltrating myeloid cells exhibited spontaneous IL-6 secretion comparable to patient-derived RCC cultures. Inhibition of lactate secretion reduced lactate and IL-6 secretion while increasing CD14⁺ HLA-DR⁺ cells. These findings were validated in patient-derived RCC cultures treated with anti-glycolytic drugs. Our data dissect the intratumoral network of RCC and show that tumor-derived lactate promotes a pro-tumorigenic myeloid phenotype with low MHC-II but high immune-checkpoint, LOX-1 and S100A8/9 expression. Blocking MCT disrupts this interplay, offering a promising strategy to re-educate tumor-associated myeloid cells and enhance tumor immune surveillance.

We previously described that elevated levels of the active vitamin D3 metabolite 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) during the early phase of allogeneic hematopoietic stem-cell transplantation (HSCT) can predict one-year transplant-related mortality (1y-TRM). Given that the liver and kidneys are the primary organs responsible for the effective conversion of vitamin D3, we investigated whether liver and/or kidney function, inflammation, or patient sex might influence vitamin D3 metabolism and, consequently, patient outcomes during transplantation. We found that female patients exhibited higher levels of 1,25(OH)2D3 at the time of transplantation compared with male patients. However, 1,25(OH)2D3 levels were associated with 1y-TRM in both sexes. No correlation was found between liver-associated markers, such as bilirubin, or the inflammation marker C-reactive protein (CRP) and serum levels of vitamin D3 metabolites in either female or male patients. However, serum levels of 1,25(OH)2D3, but not 25(OH)D3 correlated with the creatinine-based estimated glomerular filtration rate (eGFR), indicating that 1,25(OH)2D3 levels are associated with kidney function in HSCT patients. However, a Cox regression analysis, adjusted for baseline risk factors, demonstrated that high peri-transplant levels of 1,25(OH)2D3 (measured from days −2 to 7) remained a significant predictor of patient survival, even when eGFR was taken into account (hazard ratio = 0.99; p = 0.004). These findings suggest that optimal serum levels of 1,25(OH)2D3 may not be achievable in some HSCT patients and that kidney function alone cannot explain why some patients fail to reach the optimal 1,25(OH)2D3 threshold. These data support the potential use of 1,25(OH)2D3 as a prophylactic agent, particularly in patients with pre-existing kidney disease.