Arginine connects one-carbon metabolism to histone methylation in CAR T cells with enhanced metabolic fitness and anti-tumor efficacy
How arginine fuels T cell anti-tumor function is poorly understood. We developed an arginine conditioning strategy to enhance human CAR T cell metabolic fitness and anti-tumor efficacy. We show that arginine induces methylation at arginine 35 on histone H4; uncovering an epigenetic mark with no known roles in T cells until now. Using genomic and metabolic modeling, we found that arginine increases one-carbon metabolism. Enhanced serine as well as folate/methionine metabolism support s-adenosyl methionine (SAM) production for biomass accrual and epigenetic remodeling. Our transcriptomic and genetic analyses reveal several candidates supporting this model. In particular, protein arginine methyltransferase PRMT3, the amino transaminase GOT1, arginosuccinate synthase ASS1, and acetyl-CoA acyltransferase ACAA2 define the epigenetic and metabolic phenotype of CART cells with superior metabolic fitness and anti-tumor function. From these novel insights, we propose that arginine is a master regulator of metabolic reprogramming in CAR T cells. Our findings reveal how arginine enhances mitochondrial structural integrity, optimizes fuel selection, modifies histone proteins, alters gene expression, and increases CAR T cells anti-tumor function and durability in vivo. Importantly, our model asserts that the value of arginine lies in its abundance rather than its scarcity. This is explained by its broad network to serine metabolism, folate/methionine cycle, ASS1, GOT1, and fatty acid oxidation. Finally, our study reveals several molecular targets to pursue for adoptive immunotherapies, and defines an actionable conditioning strategy to bolster CAR T cell anti-tumor function.