PD-1 signaling limits expression of phospholipid phosphatase 1 and promotes intratumoral CD8+ T cell ferroptosis

The tumor microenvironment (TME) promotes metabolic reprogramming and dysfunction in immune cells. Here, we examined the impact of the TME on phospholipid metabolism in CD8+ T cells. In lung cancer, phosphatidylcholine (PC) and phosphatidylethanolamine (PE) were lower in intratumoral CD8+ T cells than in circulating CD8+ T cells. Intratumoral CD8+ T cells exhibited decreased expression of phospholipid phosphatase 1 (PLPP1), which catalyzes PE and PC synthesis. T cell-specific deletion of Plpp1 impaired antitumor immunity and promoted T cell death by ferroptosis. Unsaturated fatty acids in the TME stimulated ferroptosis of Plpp1−/− CD8+ T cells. Mechanistically, programmed death-1 (PD-1) signaling in CD8+ T cells induced GATA1 binding to the promoter region Plpp1 and thereby suppressed Plpp1 expression. PD-1 blockade increased Plpp1 expression and restored CD8+ T cell antitumor function but did not rescue dysfunction of Plpp1−/− CD8+ T cells. Thus, PD-1 signaling regulates phospholipid metabolism in CD8+ T cells, with therapeutic implications for immunotherapy. [Display omitted] •Phospholipid metabolism mediated by Plpp1 in intratumoral CD8+ T cells is altered•Plpp1 loss promotes CD8+ T cell ferroptosis and impairs antitumor immunity•Unsaturated fatty acids drive ferroptosis in Plpp1-deficient CD8+ T cells•PD-1 signaling inhibits the expression of Plpp1 through Akt-GATA1 pathway The tumor microenvironment promotes metabolic reprogramming of tumor-infiltrating immune cells. Ping, Shan, Qin, et al. examine phospholipid metabolism in the TME and find an altered phospholipid profile in intratumoral CD8+ T cells. These alterations result from reduced expression of phospholipid phosphatase-1 downstream of PD-1 signaling and lead to CD8+ T cell ferroptosis and impaired antitumor function.