CD200+ CD8 T Cell Generated through Arginine Deprivation to Activate Macrophage Cross-presentation and Improve Anti-Tumor Immunity [ATAC-Seq]

Arginine is indispensable for both tumor progression and the function of immune cells, yet how arginine deprivation within the tumor microenvironment shapes anti-tumor immunity has remained unclear. In this study, we established an in vivo arginine-restriction model using a diet lacking arginine, which significantly suppressed tumor growth and activated global anti-tumor immune responses. Mechanistically, arginine deprivation triggered the integrated stress response in CD8+ T cells via the GCN2–cREL signaling axis, leading to elevated CD200 expression. These CD200+ CD8+ T cells in turn enhanced the antigen cross-presentation capacity of tumor-associated macrophages through CD200–CD200R interactions, forming a cooperative immune network that reinforced anti-tumor activity. Moreover, this arginine deprivation–induced cellular synergy improved the therapeutic efficacy of immunotherapy in colorectal cancer models. We further conducted a single-arm phase I clinical trial (NCT07038044), which demonstrated that an arginine-free diet is both feasible and safe for modulating systemic immunity in patients. Together, our findings provide a new conceptual framework for understanding the role of arginine in reshaping the tumor immune microenvironment and highlight arginine restriction as a promising and clinically translatable anti-tumor strategy. Overall design: We established an in vitro culture system mimicking arginine deprivation. CD8+ T cells isolated from postnatal day 14 mice were first activated in nutrient-replete medium and subsequently transferred to arginine-containing or arginine-free medium for four days.