Molecular Mediators of Metabolic Reprogramming in Cancer: Mechanisms, Regulatory Networks, and Therapeutic Strategies

ABSTRACT Metabolic reprogramming is a hallmark of cancer, enabling tumour cells to flexibly adapt to fluctuating microenvironmental conditions, sustain uncontrolled proliferation, and acquire resistance to conventional therapies. Tumour metabolism is not limited to the classical Warburg effect but encompasses a dynamic interplay between glycolysis, oxidative phosphorylation (OXPHOS), fatty acid metabolism, and amino acid utilisation, each fine‐tuned according to tissue context, tumour type, and stage of progression. Central regulators such as hypoxia‐inducible factor‐1 (HIF‐1), MYC, p53, peroxisome proliferator‐activated receptors (PPARs), oestrogen receptor (ER), and sterol regulatory element‐binding proteins (SREBPs) orchestrate these pathways, linking nutrient availability to oncogenic signalling and transcriptional control. This review synthesises current evidence on these interconnected metabolic circuits and critically evaluates existing controversies, such as the dual reliance on glycolysis and OXPHOS, metabolic plasticity under therapeutic pressure, and the role of stromal–tumor metabolic crosstalk. Beyond established pathways, emerging areas are transforming our understanding of tumour metabolism. Single‐cell metabolic profiling and spatial metabolomics reveal profound intratumoral heterogeneity, while immunometabolism highlights the bidirectional influence of cancer cells and immune cells within the tumour microenvironment (TME). Epigenetic regulation, driven by metabolites that serve as cofactors for chromatin‐modifying enzymes, further integrates metabolic states with transcriptional reprogramming and therapy response. Translationally, targeting metabolic dependencies remains challenging; promising therapeutic opportunities are being developed, including inhibitors of lactate transporters, fatty acid oxidation, and glutamine metabolism. This review integrates mechanistic insights with translational perspectives, providing conceptual models, summary tables, and schematic illustrations to clarify complex networks and highlight clinically relevant opportunities. By mapping the evolving landscape of cancer metabolism, we aim to illuminate both the challenges and the therapeutic potential of exploiting metabolic vulnerabilities in oncology.