Abstract
Cellular metabolic status profoundly influences Tcell differentiation, persistence, and anti-tumor efficacy. Our single-cell metabolic analyses of Tcells reveal that diminished mannose metabolism is a prominent feature of Tcell dysfunction. Conversely, experimental augmentation/restoration of mannose metabolism in adoptively transferred Tcells via D-mannose supplementation enhances anti-tumor activity and restricts exhaustion differentiation both invitro and invivo. Mechanistically, D-mannose treatment induces intracellular metabolic programming and increases the O-GlcNAc transferase (OGT)-mediated O-GlcNAcylation of β-catenin, which preserves Tcf7 expression and epigenetic stemness, thereby promoting stem-like programs in Tcells. Furthermore, invitro expansion with D-mannose supplementation yields Tcell products for adoptive therapy with stemness characteristics, even after extensive long-term expansion, that exhibits enhanced anti-tumor efficacy. These findings reveal cell-intrinsic mannose metabolism as a physiological regulator of CD8+ Tcell fate, decoupling proliferation/expansion from differentiation, and underscoring the therapeutic potential of mannose modulation in cancer immunotherapy.
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