Mannose metabolism reshapes T cell differentiation to enhance anti-tumor immunity: CUT&RUN
Cellular metabolic status profoundly influences T cell differentiation, persistence, and anti-tumor efficacy. By performing single-cell metabolic analyses of T cells from human cancer and mouse chronic infection atlases, we unveiled 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 enhanced anti-tumor activity and restricted exhaustion differentiation both in vitro and in vivo. Mechanistically, D-mannose treatment induced intracellular metabolic programming and increased the O-GlcNAcylation of beta-catenin, which preserved Tcf7 expression and epigenetic stemness, thereby promoting stem- like programs in T cells. Finally, in vitro expansion with mannose supplementation yielded T cell products for adoptive therapy with stemness characteristics, even after extensive long-term expansion, that exhibited enhanced anti-tumor efficacy. Thus, these findings reveal cell-intrinsic mannose metabolism as a physiological regulator of CD8+ T cell fate, decoupling proliferation/expansion from differentiation, and underscored the therapeutic potential of mannose modulation in cancer immunotherapy.