Tumoral Metabolism at the Intersection of Oncogene Signaling, Epigenetics and Immunology: Emerging Therapeutic Strategies in Cancer.

Metabolic reprogramming is a unifying characteristic of cancer and involves orchestrated changes in glucose, amino acid, lipid, and mitochondrial metabolism that go beyond the well-known Warburg effect. Evidence is accumulating that these metabolic states are actively remodeled by oncogene signaling and tumor suppressor loss, allowing cancer cells to sustain anabolic growth, redox homeostasis, and therapeutic stress. This review provides an overview of new findings on tumor metabolism, mechanisms, and the molecular networks governing this reprogramming. We discuss how the major oncogenic pathways, such as MYC, mTOR, HIF, and AMPK, reprogram metabolism using transcriptional, epigenetic, and post-translational control of metabolic flux. A focus is placed on mitochondrial bioenergetics, dynamics, and metabolite signaling such as cancer cell fitness and stress tolerance-defining factors. We also discussed metabolic crosstalk in the tumor ecosystem, including nutrient competition, metabolite coupling, and immunometabolic reprogramming to coordinate metabolism-mediated effects on tumorigenesis and therapeutic response. The review further considers the mechanistic basis for metabolism-targeted therapies, including pathway dependencies, adaptive responses, and micro-environmental context that constrain clinical benefit. Recent innovations such as spatial metabolomics, single-cell metabolic profiling, and systems-level models have unveiled significant intratumoral heterogeneity of metabolism, and they have provided important information about diverse vulnerabilities to therapeutic intervention. Accordingly, understanding the complex crosstalk between these metabolic networks is crucial to rationally designing combination strategies that selectively leverage cancer-specific metabolic liabilities with minimal toxicities against normal tissues.