The Role of One‐Carbon Metabolism in Cancer and Its Therapeutic Significance

ABSTRACT Metabolic reprogramming is a hallmark of cancer that sustains uncontrolled proliferation, supports adaptation to hypoxia and nutrient limitation, and shapes antitumor immunity. In this context, one‐carbon (1C) metabolism is increasingly recognized as a key integrative pathway that supports proliferative and stress‐adaptive programs. 1C metabolism links serine and glycine metabolism with folate and methionine cycles to fuel nucleotide synthesis, methylation, and redox homeostasis. Here, we systematically integrate the biochemical architecture and compartmentalization of 1C metabolism with its cancer‐associated rewiring in tumor cells and the tumor microenvironment, spanning biosynthetic, epigenetic, redox, and mitochondrial translation functions, as well as the noncanonical moonlighting functions of metabolic enzymes. We further synthesize emerging evidence for tumor‐stroma metabolite exchange and immune‐cell metabolic reprogramming and discuss therapeutic opportunities arising from context‐dependent 1C vulnerabilities, specifically highlighting the potential of small‐molecule inhibitors and dietary interventions. By consolidating mechanistic and translational advances, this review highlights strategies to exploit these specific metabolic fragilities and proposes considerations for biomarker‐guided precision anticancer therapy. This synthesis provides a framework for prioritizing targets, interpreting resistance mechanisms, and designing metabolism‐informed clinical trials to improve efficacy while mitigating toxicity.