L-arginine modulates T cell metabolism and enhances survival and anti-tumor activity. Using high-resolution mass spectrometry, the study generated dynamic metabolome and proteome profiles of human primary naive T cells following activation. It revealed critical changes in arginine metabolism, leading to a drop in intracellular L-arginine concentration. Elevating L-arginine levels induced global metabolic changes, including a shift from glycolysis to oxidative phosphorylation in activated T cells and promoted the generation of central memory-like cells with enhanced survival capacity and anti-tumor activity. Proteome-wide analysis identified three transcriptional regulators (BAZ1B, PSIP1, and TSN) that sensed L-arginine levels and promoted T cell survival. Thus, intracellular L-arginine concentrations directly impact the metabolic fitness and survival capacity of T cells crucial for antitumor responses. The study also showed that increased intracellular L-arginine levels enhance T cell survival and anti-tumor activity in vivo. L-arginine improves anti-tumor T cell response by increasing the survival capacity of human and mouse T cells and favoring the formation of Tcm-like cells. The findings suggest that L-arginine plays a key role in T cell metabolism and survival, with potential therapeutic applications in improving adoptive T cell therapies.L-arginine modulates T cell metabolism and enhances survival and anti-tumor activity. Using high-resolution mass spectrometry, the study generated dynamic metabolome and proteome profiles of human primary naive T cells following activation. It revealed critical changes in arginine metabolism, leading to a drop in intracellular L-arginine concentration. Elevating L-arginine levels induced global metabolic changes, including a shift from glycolysis to oxidative phosphorylation in activated T cells and promoted the generation of central memory-like cells with enhanced survival capacity and anti-tumor activity. Proteome-wide analysis identified three transcriptional regulators (BAZ1B, PSIP1, and TSN) that sensed L-arginine levels and promoted T cell survival. Thus, intracellular L-arginine concentrations directly impact the metabolic fitness and survival capacity of T cells crucial for antitumor responses. The study also showed that increased intracellular L-arginine levels enhance T cell survival and anti-tumor activity in vivo. L-arginine improves anti-tumor T cell response by increasing the survival capacity of human and mouse T cells and favoring the formation of Tcm-like cells. The findings suggest that L-arginine plays a key role in T cell metabolism and survival, with potential therapeutic applications in improving adoptive T cell therapies.