Mannose metabolism reshapes T cell differentiation to enhance anti-tumor immunity
Cellular metabolic status profoundly influences T cell differentiation, persistence, and anti-tumor efficacy. 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.DOI: 110.1016/j.ccell.2024.11.003
Ammonia-induced lysosomal and mitochondrial damage causes cell death of effector CD8+ T cells
![]()
Zhang. et al.Nature Cell Biology. 2024
Ammonia, a byproduct of glutaminolysis, is toxic to cells, but its precise role in T cell death was unclear.The researcher investigated how ammonia accumulation causes cell death in effector CD8+ T cells, a distinct process not previously well characterized.
First, the researcher observed that activated CD8+ T cells accumulate ammonia during their clonal expansion phase. Excess ammonia originates from glutaminolysis in mitochondria and is stored in lysosomes. Next, excessive ammonia disrupts lysosomal pH balance, leading to alkalization and the termination of ammonia storage. The reflux of ammonia into mitochondria causes mitochondrial swelling, loss of ATP production, and eventual cell death.Then, experimental inhibition of glutaminolysis using GLS1 inhibitors (such as JHU083 and CB839) reduced ammonia levels, improved lysosomal function, and prevented cell death in vitro and in vivo. Additionally, the overexpression of CPS1, an enzyme involved in ammonia detoxification, mitigated ammonia accumulation and prolonged T cell survival.In summary, this study identifies a novel form of ammonia-induced cell death characterized by lysosomal and mitochondrial damage. These findings reveal ammonia as a key mediator of effector T cell death and highlight potential therapeutic strategies, such as targeting glutaminolysis, to enhance T cell survival in immunotherapy applications.DOI: 10.1038/s41556-024-01503-x
Editor & Reviewer: Congci Yu
