부산대학교 도서관

Antitumor responses of [CD8.sup.+] T cells are tightly regulated by distinct metabolic fitness. High levels of glutathione (GSH) are observed in the majority of tumors, contributing to cancer progression and treatment resistance in part by preventing glutathione peroxidase 4-dependent (GPX4-dependent) ferroptosis. Here, we show the necessity of adenosine A2A receptor (A2AR) signaling and the GSH/GPX4 axis in orchestrating metabolic fitness and survival of functionally competent [CD8.sup.+] T cells. Activated [CD8.sup.+] T cells treated ex vivo with simultaneous inhibition of A2AR and lipid peroxidation acquire a superior capacity to proliferate and persist in vivo, demonstrating a translatable means to prevent ferroptosis in adoptive cell therapy. Additionally, we identify a particular cluster of intratumoral [CD8.sup.+] T cells expressing a putative gene signature of GSH metabolism (GMGS) in association with clinical response and survival across several human cancers. Our study addresses a key role of GSH/GPX4 and adenosinergic pathways in fine-tuning the metabolic fitness of antitumor [CD8.sup.+] T cells.
Introduction Glutathione (GSH) is the most abundant antioxidant that maintains cellular redox homeostasis. De novo synthesis of GSH is coordinated by the sequential actions of glutaminase, [gamma]-glutamate-cysteine ligase, and GSH [...]