Glutamine-driven mTORC1 activity enforces glycolytic bias, hyperactivation and aberrant proliferation in T cells in chronic B-cell leukemia

T-cell metabolic dysfunction is increasingly recognized as a hallmark of poor antitumor responses. Still, how distinct metabolic states shape T-cell function and which signaling pathways sustain them remains unclear. Here, we show that T cells from patients with chronic lymphocytic leukemia (CLL) adopt a hyperactivated phenotype characterized by high cytokine production, aberrant proliferation and a bias toward glycolysis, supported by sustained glutamine-driven mTORC1 activity. In parallel, T cells from these patients display alterations in mitochondrial network and cristae architecture, which further limit oxidative phosphorylation. mTORC1 inhibition reduces glucose dependence, restores mitochondrial metabolic engagement and normalizes T-cell activation and proliferation. Together, these findings identify metabolic disbalance as a central contributor to the hyperactivated state of T cells in CLL. We propose a model in which reduced OXPHOS reflects both mitochondrial defects that pre-exist in T cells from patients before TCR engagement, and a failure to engage mitochondrial metabolism upon activation supported by the actionable target mTORC1. HighlightsO_LIT cells from patients with chronic lymphocytic leukemia display high cytokine production and excessive division cycles upon CD3/28 engagement. C_LIO_LImTORC1-sustained glycolysis and defects in mitochondrial structure compromise OXPHOS in hyperactivated T cells. C_LIO_LIExogenous glutamine uptake sustains non-lysosomal mTORC1 activity in T cells. C_LI