One-carbon metabolism in cancer: moonlighting functions of metabolic enzymes and anti-tumor therapy

One-carbon (1C) metabolism is a central metabolic network that supports nucleotide biosynthesis, amino acid metabolism, and redox homeostasis, playing a critical role in cellular proliferation. In cancer, dysregulation of this pathway fuels tumor progression by satisfying the heightened biosynthetic and energetic demands of malignant cells. Beyond their canonical metabolic roles, metabolites and enzymes within the one-carbon metabolic network exhibit moonlighting functions that contribute to tumorigenesis, immune evasion, and metastasis. These non-canonical functions include modulation of gene expression, epigenetic remodeling, and rewiring the oncogenic signaling pathways, underscoring their multifaceted roles in cancer biology. This review explores the production and utilization of one-carbon units, with a focus on the metabolic enzymes involved and their moonlighting functions in tumorigenesis. Additionally, we summarize the progress of ongoing clinical trials targeting the 1C network, highlighting the potential to exploit metabolic vulnerabilities for cancer therapy.