PLPP1-deficiency-mediated ferroptosis induced by PD-1 signaling impairs antitumor activity of intratumoral CD8+ T cells I

Metabolic programming plays a crucial role in T-cell activation. Herein, we describe how phospholipid metabolism regulates CD8+ T-cell function in patients with cancer. We found that phosphatidylcholine (PC) and phosphatidyl ethanolamine (PE) levels were lower in intratumoral CD8+ T cells than in circulating CD8+ T cells. The expression of phospholipid phosphatase 1 (PLPP1), an enzyme that catalyzes PE and PC synthesis, was also downregulated in CD8+ T cells upon infiltrating tumors. Moreover, unsaturated fatty acid-mediated ferroptosis was a major factor impairing the antitumor function of PLPP1-deficient CD8+ T cells infiltrated in tumors, accompanied by enhanced reactive oxygen species production and lipid peroxidation. The activation of programmed cell death 1 (PD-1) signaling in CD8+ T cells suppressed the PLPP1 expression by increasing GATA1 binding to the promoter region of PLPP1. PLPP1 expression was upregulated after anti-PD-1 therapy. Our findings revealed therapeutic potential of enhancing PLPP1 levels to restore CD8+ T-cell function.