Metabolic reprogramming is a defining hallmark of cancer, enabling malignant cells to sustain growth while adapting to nutrient scarcity and immune surveillance. Among the diverse substrates that fuel these processes, amino acids occupy a central position due to their essential roles in bioenergetics, biosynthesis, and signaling. Cancer cells frequently develop “amino acid addiction,” a state of heightened dependency on specific amino acids such as glutamine, serine, glycine, tryptophan, arginine, and methionine. This rewiring not only supports proliferation and redox balance but also remodels the tumor microenvironment (TME) by impairing immune surveillance and promoting therapeutic resistance. Pharmacological inhibition of metabolic enzymes, enzyme deprivation strategies, and dietary interventions have shown efficacy in selectively disrupting amino acid–dependent pathways. Moreover, integrating amino acid–directed therapies with immunotherapy or chemotherapy holds potential to overcome resistance and enhance clinical outcomes. Despite these advances, challenges remain, including tumor heterogeneity, adaptive resistance mechanisms, and the need for patient stratification based on metabolic profiles. This review summarizes the molecular mechanisms underlying amino acid metabolic reprogramming, delineates its interactions with the tumor microenvironment, and discusses potential therapeutic approaches aimed at exploiting amino acid vulnerabilities in cancer.
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