One-carbon metabolism in cancer immunity: T-cell fitness, epigenetic programming, and therapeutic opportunities.

One-carbon metabolism has emerged as a critical interface between tumor metabolic adaptation and antitumor immunity. Beyond its canonical role in nucleotide biosynthesis and redox balance, this metabolic network regulates methyl-donor availability, epigenetic programming, and immune-cell state transitions within the tumor microenvironment. Recent studies show that tumor cells can outcompete T cells for methionine, thereby depleting intracellular S-adenosylmethionine, impairing histone methylation, and driving effector dysfunction or exhaustion. At the same time, tumor-intrinsic one-carbon enzymes such as MTHFD2 actively promote immune escape through PD-L1 upregulation and suppression of innate immune sensing. Serine-related pathways further shape the immune landscape in a context-dependent manner, supporting either immunosuppressive cell accumulation or enhanced tumor immunogenicity depending on the cellular compartment and metabolic state. Importantly, one-carbon metabolism also represents a therapeutic opportunity. Strategies including methionine restriction, formate supplementation, serine-pathway targeting, and methyl-donor modulation have shown potential to enhance antitumor immunity and improve responses to immune checkpoint blockade. However, because one-carbon metabolism is required by both tumor cells and immune cells, effective intervention will require careful attention to cell-type specificity, metabolic context, and therapeutic timing. In this review, we discuss how one-carbon metabolism governs T-cell fitness, epigenetic regulation, and the broader tumor immune ecosystem, and we highlight emerging translational strategies for exploiting this pathway in cancer immunotherapy.