Emerging concepts on one-carbon metabolism as a unique and actionable vulnerability in cancer

Metabolic reprogramming is a defining feature of cancer, and folate-mediated one-carbon (C1) metabolism occupies a central role in supporting malignant growth, survival, and immune evasion. While cytosolic C1 enzymes have long been exploited for the therapy of a host of cancers through the use of “classical” antifolates, growing evidence suggests that mitochondrial C1 metabolism is a critical driver of tumor progression, metastasis, and redox homeostasis. Mitochondrial serine catabolism via serine hydroxymethyltransferase 2 and 5,10-methylene tetrahydrofolate dehydrogenase 2 provides formate, glycine, and reducing equivalents to sustain nucleotide and amino acid biosynthesis, biological methylation reactions, and antioxidant defenses. Dysregulation of mitochondrial C1 metabolism promotes formate “overflow”, alters tumor–immune interactions, and supports metastatic signaling. This review synthesizes recent key advances in folate biology, and compartmentalized C1 metabolism, leading to the development of an exciting new generation of cytosolic- and mitochondrial-targeted therapies. We examine emerging links between C1 metabolism and the tumor microenvironment, including relationships between C1 metabolism and immune suppression, T-cell infiltration, and macrophage polarization. Finally, we highlight critical unresolved questions and vexing future challenges in implementing the next generation of C1-targeted anticancer agents. Collectively, these insights underscore the remarkable biology of mitochondrial C1 metabolism and its potential as a multifaceted and therapeutically actionable vulnerability in cancer.