Metabolic vulnerabilities and therapeutic opportunities in diffuse large B-cell lymphoma

Diffuse large B cell lymphoma (DLBCL), the most common type of non-Hodgkin lymphoma (NHL), exhibits considerable biological heterogeneity. While its classification has traditionally relied on genetic and transcriptomic features, emerging evidence points to distinct metabolic subtypes that may represent novel therapeutic vulnerabilities. Intriguingly, current chemoimmunotherapy regimens exert profound but non-specific effects on tumour metabolism, inadvertently exploiting metabolic dependencies yet without precision. Novel inhibitors targeting glucose, amino acid, lipid, and mitochondrial metabolism demonstrate selective cytotoxicity in metabolically defined lymphoma subsets. This review investigates how standard therapies exploit DLBCL metabolism and examines heterogeneity across subtypes, and evaluates targeted metabolic therapies. We discuss emerging combination strategies with current therapeutic regimes and immunotherapy. Particular focus is given to the metabolic interactions between tumour cells and immune effectors, including CAR T cells and bispecific antibodies. We highlight the importance of translational research to validate metabolic subtypes through metabolomic profiling, identify predictive biomarkers, and develop rational combinations. Moving beyond empiric therapy towards strategic metabolic targeting offers an opportunity to enhance outcomes for patients with this aggressive and diverse lymphoma.