Exploiting metabolic vulnerabilities in cancer: From mechanisms to therapeutic opportunities

Metabolic reprogramming enables cancer cells to adapt to hostile microenvironments and resist therapy, while simultaneously revealing metabolic vulnerabilities that offer new opportunities for targeted treatment. This review is the first to propose a unified ‘Mechanism–Strategy–Translation’ framework, focusing on two core mechanisms underlying metabolic vulnerability: metabolic inflexibility and synthetic lethality. This dual-axis model not only elucidates how metabolic reprogramming drives tumor progression but also highlights the "Achilles' heel" of malignant tumors. The article provides an in-depth discussion of key metabolic pathways on which tumors depend (such as glucose metabolism), epigenetic regulation (e.g., lactylation), and multi-layered stress defense mechanisms—including autophagy, redox homeostasis, anti-ferroptosis, and cuproptosis—while dissecting their inherent vulnerabilities. Furthermore, it emphasizes the tripartite crosstalk among neural, immune, and metabolic components within the TME, systematically explaining how neural signals, immunometabolic reprogramming, and key metabolites collectively regulate tumorigenesis, along with a commentary on the role of microbiota in the TME. Based on these mechanisms, we summarize several emerging targets with clinical translational potential, providing clear directions for future research. Strategies such as combination therapies and dietary interventions are also considered highly promising. Despite ongoing challenges such as metabolic heterogeneity, the deepening integration of multidisciplinary approaches and advances in AI-driven multi-omics analyses are paving the way for transformative prospects in cancer therapy.