Rewiring tumor metabolism: heterogeneity, oncometabolites, and adaptive plasticity.

Abstract

Metabolic reprogramming is a well-established hallmark of cancer, driven by oncogenic mutations and microenvironmental pressures to support rapid proliferation and adaptation to stress. This reprogramming is not uniform but instead exhibits profound metabolic heterogeneity, with distinct tumor subpopulations and spatial niches relying on divergent metabolic pathways such as glycolysis, oxidative phosphorylation, and nutrient scavenging. This heterogeneity evolves dynamically during tumor progression and in response to therapy, driven by genetic and epigenetic alterations, hypoxia, nutrient gradients, and therapeutic influences. Critically, it contributes to major clinical challenges by promoting immune evasion through nutrient competition and the accumulation of immunosuppressive metabolites, and by fostering therapy-tolerant cell states. A deeper understanding of the spatiotemporal dynamics of tumor metabolism and their functional consequences reveals novel therapeutic vulnerabilities. This review examines the origins and biological implications of metabolic heterogeneity, discusses strategies to overcome therapeutic resistance by targeting context-specific metabolic dependencies or by combining metabolic inhibitors with immunotherapy, and highlights the potential of patient stratification based on metabolic profiles. Ultimately, elucidating this metabolic complexity is essential for the development of innovative, personalized therapeutic approaches that improve outcomes in cancer treatment.