Metabolic reprogramming has emerged as a defining hallmark of cancer, reflecting the capacity of malignant cells to restructure bioenergetic and biosynthetic pathways in response to genetic alterations and microenvironmental pressures. Tumor cells exploit metabolic plasticity to sustain proliferation, maintain redox homeostasis, and adapt to nutrient fluctuations or hypoxia. Glucose metabolism is frequently diverted toward aerobic glycolysis, yielding both ATP and intermediates essential for macromolecule synthesis. In parallel, glutamine catabolism replenishes tricarboxylic acid cycle intermediates and supports nucleotide production, whereas lipid and amino acid metabolism undergo extensive remodeling to provide structural components and signaling molecules that promote tumor growth. Such multifaceted alterations integrate with oncogenic signaling networks, creating a finely tuned metabolic landscape that underlies malignancy. Metabolic reprogramming extends beyond intrinsic tumor processes to reshape the tumor microenvironment (TME). Excessive consumption of glucose and glutamine by cancer cells restricts nutrient access for effector immune populations, fostering immune suppression. Accumulated metabolites such as lactate, kynurenine, and adenosine acidify the extracellular milieu, polarize macrophages toward tumor-supportive phenotypes, and dampen cytotoxic T-cell activity. Cancer-associated fibroblasts further participate through metabolic symbiosis, providing energy-rich substrates that sustain tumor oxidative metabolism and angiogenesis. Hypoxia-driven stabilization of hypoxia-inducible factors reinforces glycolytic flux and vascular remodeling, perpetuating a self-sustaining cycle of metabolic and microenvironmental adaptation. Understanding these metabolic interactions can provide a deeper understanding of cancer pathophysiology and may also reveal exploitable vulnerabilities. Therapeutic strategies targeting metabolic enzymes or normalizing nutrient fluxes represent promising avenues for disrupting tumor–stroma cooperation and enhancing treatment efficacy.

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