One-Carbon Metabolism in Cancer Cell Biology

One-carbon metabolism encompasses the folate and methionine cycles that shuttle single-carbon units from serine, glycine and formate into biosynthetic and regulatory pathways. In cancer cells, this network is reprogrammed to sustain rapid proliferation, enhanced nucleotide synthesis, redox balance and epigenetic modifications. Mitochondrial enzymes, such as serine hydroxymethyltransferase 2 (SHMT2) and methylenetetrahydrofolate dehydrogenase 2 (MTHFD2), generate formate and methyl donors that feed cytosolic reactions for purine and thymidylate production, and for S-adenosylmethionine-dependent methylation of DNA, RNA and proteins. The interplay between one-carbon flux and nutrient-sensing pathways—most notably AMPK and mTORC1—governs cell growth, differentiation and survival under stress. Aberrant activation of these routes contributes to therapy resistance, tumour heterogeneity and immune evasion. Targeted inhibition of key nodes in folate metabolism has thus emerged as a promising strategy to exploit metabolic vulnerabilities in a range of malignancies, offering opportunities for combination treatments and precision medicine.

Research from Nature Portfolio

Recent studies have shown that selective impairment of mitochondrial folate metabolism exerts profound effects on leukaemic stem cells. Inhibition of mitochondrial one-carbon flux reduces de novo purine synthesis, triggering AMPK activation and mTORC1 suppression, and promotes erythroid differentiation even in therapy-resistant chronic myeloid leukaemia models. Combining this approach with established tyrosine kinase inhibitors markedly reduces leukaemic stem cell burden in xenograft systems. In parallel, the discovery of a novel folate-trapping mechanism delineates how inhibition of nuclear MTHFD1, in the presence of continued mitochondrial formate overflow, leads to accumulation of 10-formyl-tetrahydrofolate. This ‘folate trap’ results in thymidylate depletion and selective killing of MTHFD2-expressing cancer cells, unveiling a distinct avenue to disrupt one-carbon metabolism in tumours.

One-Carbon Metabolism in Cancer Cell Biology publication trend

The graph below shows the total number of articles in one-carbon metabolism in cancer cell biology across all publications each year (not limited to Nature Index journals).

Technical terms

One-carbon metabolism: Network of enzyme-catalysed reactions that transfer single-carbon units for nucleotide and methyl group synthesis.

SHMT2: Mitochondrial serine hydroxymethyltransferase that converts serine to glycine and generates one-carbon units.

MTHFD2: Mitochondrial enzyme with dehydrogenase and cyclohydrolase activities in the folate cycle, producing formate.

mTORC1: Mechanistic target of rapamycin complex 1, a nutrient-sensing kinase that regulates growth and anabolic metabolism.

Folate trap: Accumulation of 10-formyl-tetrahydrofolate that impedes folate cycle progression and nucleotide synthesis.

References

1. Inhibition of mitochondrial folate metabolism drives differentiation through mTORC1 mediated purine sensing. Nature Communications (2024).
2. Formate overflow drives toxic folate trapping in MTHFD1 inhibited cancer cells. Nature Metabolism (2023).
3. Phosphorylated SHMT2 Regulates Oncogenesis Through m6A Modification in Lung Adenocarcinoma. Advanced Science (2024).
4. Serine Catabolism Feeds NADH when Respiration Is Impaired. Cell Metabolism (2020).