ArticleEBioMedicine2026
d-serine as a metabolic immune checkpoint in the tumour microenvironment.
Article in EBioMedicine, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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28 authors.
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Abstract
backgroundd-amino acids (D-AAs), the enantiomers of proteinogenic l-amino acids, are detectable in mammals, yet their biological roles in cancer immunity remain largely unexplored. Whether specific D-AAs modulate tumour progression or influence responsiveness to immunotherapy in gastrointestinal cancer is unknown. We aimed to determine how D-AAs, particularly d-serine (D-ser), shape the tumour immune microenvironment and affect clinical outcomes in gastrointestinal cancers.
methodsMechanistic studies were conducted using murine MC38 tumours and orthotopic gastric cancer (GC) organoid allografts with or without D-AAs supplementation. Immune landscape alterations were assessed using single-cell RNA sequencing of tumour-infiltrating immune cells, flow cytometry, ex vivo macrophage-T cell co-culture assays, and microbiome manipulation experiments. D-AAs concentrations in plasma, urine, and stool were quantified in healthy controls (HCs; n = 87) and patients with GC across three cohorts (Cohort 1, n = 14; Cohort 2, n = 108; Cohort 3, n = 28). Associations between plasma D-ser levels, disease stage, immune cell infiltration, and clinical outcomes following anti-PD-1 antibody therapy were analysed.
findingsD-ser promoted tumour progression by suppressing CD8
interpretationThis study identifies D-ser as a previously unrecognised immunosuppressive metabolite that promotes tumour immune evasion by increased macrophages and reduced CD8
fundingThis work was supported by The Japan Science and Technology Agency (JST) Fusion Oriented Research for Disruptive Science and Technology (FOREST)[JPMJFR210P], Grants-in-Aid from the Japanese Society for the Promotion of Science (JSPS) (25K10430, 21K18272, 23H02899, 23K27590, 25K22627), KGRI challenge grant, Sakaguchi Memorial Foundation, Japan Agency for Medical Research and Development (CREST 21gm1510002h0001), and Miyarisan Pharmaceutical Grant.
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