Nucleotides perform important metabolic functions, carrying energy and feeding
nucleic acid synthesis. Here, we use
isotope tracing-mass spectrometry to quantitate the contributions to
purine nucleotides of salvage versus de novo synthesis. We further explore the impact of augmenting a key precursor for
purine synthesis, one-
carbon (1C) units. We show that
tumors and
tumor-infiltrating T cells (relative to splenic T cells) synthesize
purines de novo.
Purine synthesis requires two 1C units, which come from
serine catabolism and circulating
formate. Shortage of 1C units is a potential bottleneck for anti-
tumor immunity. Elevating circulating
formate drives its usage by
tumor-infiltrating T cells. Orally administered
methanol functions as a
formate pro-drug, with deuteration enabling control of
formate-production kinetics. In MC38
tumors, safe doses of
methanol raise
formate levels and augment anti-PD-1 checkpoint blockade, tripling durable regressions. Thus, 1C deficiency can gate antitumor immunity and this metabolic checkpoint can be overcome with pharmacological 1C supplementation.