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Summary Depleting the microenvironment of important nutrients such as arginine is a key strategy for immune evasion by cancer cells. Many tumors overexpress arginase, but it is unclear how these cancers, but not T cells, tolerate arginine depletion. In this study, we show that tumor cells synthesize arginine from citrulline by upregulating argininosuccinate synthetase 1 (ASS1). Under arginine starvation, ASS1 transcription is induced by ATF4 and CEBPβ binding to an enhancer within ASS1. T cells cannot induce ASS1, despite the presence of active ATF4 and CEBPβ, as the gene is repressed. Arginine starvation drives global chromatin compaction and repressive histone methylation, which disrupts ATF4/CEBPβ binding and target gene transcription. We find that T cell activation is impaired in arginine-depleted conditions, with significant metabolic perturbation linked to incomplete chromatin remodeling and misregulation of key genes. Our results highlight a T cell behavior mediated by nutritional stress, exploited by cancer cells to enable pathological immune evasion., Graphical abstract, Highlights • Arginine starvation induces ASS1 expression in some cancers but not in T cells • ATF4 binds an internal ASS1 enhancer to drive expression in cancer but not T cells • T cell activation is disrupted by arginine starvation, with a loss of reprogramming • Arginine starvation compacts chromatin in T cells, disrupting ATF4 binding, Arginine depletion by many tumors generates an immunosuppressive microenvironment. Crump et al. show that cancer cells can tolerate this by inducing ATF4-dependent upregulation of ASS1, allowing de novo arginine synthesis. T cells are unable to synthesize arginine as ASS1 is repressed, disrupting T cell function and the chromatin remodeling associated with activation.