DEPDC5 protects CD8+ T cells from ferroptosis by limiting mTORC1-mediated purine catabolism. This study reveals that DEPDC5 is crucial for maintaining CD8+ T cell homeostasis and anti-tumor immunity. Patients with DEPDC5 mutations have reduced peripheral CD8+ T cells, while high DEPDC5 expression correlates with increased CD8+ T cell infiltration in tumors and improved patient survival. In mice with T cell-specific DEPDC5 deletion, CD8+ T cell numbers decrease and anti-tumor immunity is impaired. Mechanistically, DEPDC5 deficiency leads to hyperactivation of mTORC1, which increases ATF4 expression, promoting xanthine oxidase (XO) and lipid ROS production, resulting in ferroptosis. DEPDC5 restricts purine metabolism by limiting mTORC1 activity, thereby preventing ferroptosis. In Depdc5-deficient CD8+ T cells, increased XO activity leads to elevated ROS and lipid peroxidation, contributing to ferroptosis. Inhibiting ferroptosis with DFO or allopurinol rescues CD8+ T cell numbers and restores anti-tumor immunity. These findings highlight DEPDC5's role in protecting CD8+ T cells from ferroptosis and suggest that targeting ferroptosis could enhance anti-tumor immunity.DEPDC5 protects CD8+ T cells from ferroptosis by limiting mTORC1-mediated purine catabolism. This study reveals that DEPDC5 is crucial for maintaining CD8+ T cell homeostasis and anti-tumor immunity. Patients with DEPDC5 mutations have reduced peripheral CD8+ T cells, while high DEPDC5 expression correlates with increased CD8+ T cell infiltration in tumors and improved patient survival. In mice with T cell-specific DEPDC5 deletion, CD8+ T cell numbers decrease and anti-tumor immunity is impaired. Mechanistically, DEPDC5 deficiency leads to hyperactivation of mTORC1, which increases ATF4 expression, promoting xanthine oxidase (XO) and lipid ROS production, resulting in ferroptosis. DEPDC5 restricts purine metabolism by limiting mTORC1 activity, thereby preventing ferroptosis. In Depdc5-deficient CD8+ T cells, increased XO activity leads to elevated ROS and lipid peroxidation, contributing to ferroptosis. Inhibiting ferroptosis with DFO or allopurinol rescues CD8+ T cell numbers and restores anti-tumor immunity. These findings highlight DEPDC5's role in protecting CD8+ T cells from ferroptosis and suggest that targeting ferroptosis could enhance anti-tumor immunity.