Cystine deprivation triggers CD36-mediated ferroptosis and dysfunction of tumor infiltrating CD8+ T cells. Cancer cells compete with T cells for cystine uptake, leading to T-cell exhaustion and ferroptosis. This study shows that tumor cells outcompete T cells for cystine, causing T-cell dysfunction, reduced cytokine secretion, and increased PD-1 and TIM-3 expression. Cystine deprivation disrupts glutathione synthesis, promoting CD36-mediated lipid uptake and ferroptosis. Mechanistically, cystine deprivation leads to glutamate accumulation, which enhances CD36 expression and lipid peroxidation, resulting in T-cell exhaustion and ferroptosis. Enforced expression of glutamate-cysteine ligase catalytic subunit (Gclc) promotes glutathione synthesis and prevents CD36 upregulation, thereby enhancing T-cell anti-tumor immunity. The findings reveal that cystine is an intracellular metabolic checkpoint that regulates T-cell survival and differentiation, and highlight Gclc as a potential therapeutic target for enhancing T-cell anti-tumor function. Cystine supplementation in the tumor microenvironment improves T-cell anti-tumor immunity by reducing ferroptosis and exhaustion. The study also demonstrates that dysregulated cystine/glutamate exchange upregulates CD36 expression, leading to lipid accumulation and ferroptosis. Gclc overexpression protects T cells from ferroptosis and enhances anti-tumor immunity. These findings provide insights into the role of cystine metabolism in T-cell function and suggest that targeting cystine availability or CD36 could be therapeutic strategies for improving T-cell anti-tumor immunity.Cystine deprivation triggers CD36-mediated ferroptosis and dysfunction of tumor infiltrating CD8+ T cells. Cancer cells compete with T cells for cystine uptake, leading to T-cell exhaustion and ferroptosis. This study shows that tumor cells outcompete T cells for cystine, causing T-cell dysfunction, reduced cytokine secretion, and increased PD-1 and TIM-3 expression. Cystine deprivation disrupts glutathione synthesis, promoting CD36-mediated lipid uptake and ferroptosis. Mechanistically, cystine deprivation leads to glutamate accumulation, which enhances CD36 expression and lipid peroxidation, resulting in T-cell exhaustion and ferroptosis. Enforced expression of glutamate-cysteine ligase catalytic subunit (Gclc) promotes glutathione synthesis and prevents CD36 upregulation, thereby enhancing T-cell anti-tumor immunity. The findings reveal that cystine is an intracellular metabolic checkpoint that regulates T-cell survival and differentiation, and highlight Gclc as a potential therapeutic target for enhancing T-cell anti-tumor function. Cystine supplementation in the tumor microenvironment improves T-cell anti-tumor immunity by reducing ferroptosis and exhaustion. The study also demonstrates that dysregulated cystine/glutamate exchange upregulates CD36 expression, leading to lipid accumulation and ferroptosis. Gclc overexpression protects T cells from ferroptosis and enhances anti-tumor immunity. These findings provide insights into the role of cystine metabolism in T-cell function and suggest that targeting cystine availability or CD36 could be therapeutic strategies for improving T-cell anti-tumor immunity.