This study investigates the role of DEPDC5 in regulating peripheral CD8+ T cell homeostasis and anti-tumor immunity. The authors found that DEPDC5 expression is positively correlated with tumor-infiltrating CD8+ T cells and overall cancer patient survival. In mice with T cell-specific *Depdc5* deletion, peripheral CD8+ T cell counts were reduced, and anti-tumor immunity was impaired. Mechanistically, *Depdc5*-deficient CD8+ T cells exhibited hyper-mTORC1 activity, leading to increased expression of ATF4 and downstream target genes, particularly Xdh, which encodes the short-form xanthine oxidase (XO). This resulted in elevated levels of lipid ROS and ferroptosis, a form of regulated cell death. Inhibition of ferroptosis using vitamin E or an iron-free diet rescued CD8+ T cell counts and improved anti-tumor immunity in *Depdc5* knockout mice. The study highlights a novel mechanism by which DEPDC5 protects CD8+ T cells from ferroptosis, providing a potential strategy to enhance anti-tumor immunity.This study investigates the role of DEPDC5 in regulating peripheral CD8+ T cell homeostasis and anti-tumor immunity. The authors found that DEPDC5 expression is positively correlated with tumor-infiltrating CD8+ T cells and overall cancer patient survival. In mice with T cell-specific *Depdc5* deletion, peripheral CD8+ T cell counts were reduced, and anti-tumor immunity was impaired. Mechanistically, *Depdc5*-deficient CD8+ T cells exhibited hyper-mTORC1 activity, leading to increased expression of ATF4 and downstream target genes, particularly Xdh, which encodes the short-form xanthine oxidase (XO). This resulted in elevated levels of lipid ROS and ferroptosis, a form of regulated cell death. Inhibition of ferroptosis using vitamin E or an iron-free diet rescued CD8+ T cell counts and improved anti-tumor immunity in *Depdc5* knockout mice. The study highlights a novel mechanism by which DEPDC5 protects CD8+ T cells from ferroptosis, providing a potential strategy to enhance anti-tumor immunity.