Metabolic reprogramming in T-cell acute lymphoblastic leukemia: Mechanisms of therapy resistance and clinical applications.

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematologic malignancy in which therapy resistance remains a major cause of treatment failure and relapse. Increasing evidence indicates that metabolic reprogramming and metabolic plasticity can contribute to T-ALL persistence under therapeutic pressure, rather than reflecting a single uniform metabolic phenotype. In this review, we examine the reprogramming of glucose, amino acid, lipid, and nucleotide metabolism, as well as metabolic adaptations within the tumor microenvironment, and their associations with therapy resistance in T-ALL. We further discuss the regulatory roles of oncogenic signaling pathways and metabolism-epigenetics crosstalk in metabolic adaptation. Emerging metabolism-targeted strategies are also reviewed, with particular attention to their potential therapeutic vulnerabilities and the evidence supporting their use in different experimental and clinical contexts. Major barriers to clinical translation include metabolic heterogeneity, compensatory metabolic rewiring, and toxicity arising from metabolic dependencies shared with normal tissues. Future metabolic-directed therapies require precise metabolic subtyping guided by multi-omics approaches, the development of novel targeted drugs, and the implementation of rational combination therapies.