Mannose metabolism reshapes T cell differentiation to enhance anti-tumor immunity

Cellular metabolic status profoundly influences T cell differentiation, persistence, and anti-tumor efficacy. Our single-cell metabolic analyses of T cells reveal that diminished mannose metabolism is a prominent feature of T cell dysfunction. Conversely, experimental augmentation/restoration of mannose metabolism in adoptively transferred T cells via D-mannose supplementation enhances anti-tumor activity and restricts exhaustion differentiation both in vitro and in vivo. 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 T cells. Furthermore, in vitro expansion with D-mannose supplementation yields T cell 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+ T cell fate, decoupling proliferation/expansion from differentiation, and underscoring the therapeutic potential of mannose modulation in cancer immunotherapy. [Display omitted] •Enhancing mannose metabolism limits T cell differentiation to exhaustion•D-mannose alters T cell metabolic and epigenetic landscapes, promoting stemness•D-mannose remodels T cell O-GlcNAcylation of proteins and stabilizes β-catenin•T cells expanded with D-mannose show enhanced anti-tumor efficacy Qiu et al. identify that reduced mannose metabolism is a key characteristic of T cell dysfunction. Enhancing mannose metabolism in T cells through D-mannose supplementation boosts anti-tumor activity, limits exhaustion differentiation, and maintains T cell stemness. Mechanistically, D-mannose promotes the OGT-mediated O-GlcNAcylation and stabilization of β-catenin, enhancing T cell stemness.