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.

肿瘤微环境（TME）促进免疫细胞的代谢重编程和功能障碍。在这里，我们研究了 TME 对 CD8 ⁺ T 细胞磷脂代谢的影响。在肺癌中，瘤内 CD8 ⁺ T 细胞中的磷脂酰胆碱 (PC) 和磷脂酰乙醇胺 (PE) 低于循环 CD8 ⁺ T 细胞。瘤内 CD8 ⁺ T 细胞表现出催化 PE 和 PC 合成的磷脂磷酸酶 1 (PLPP1) 表达减少。 T 细胞特异性删除Plpp1会损害抗肿瘤免疫并促进 T 细胞因铁死亡而死亡。 TME 中的不饱和脂肪酸刺激Plpp1 ^−/− CD8 ⁺ T 细胞的铁死亡。从机制上讲，CD8 ⁺ T 细胞中的程序性死亡 1 (PD-1) 信号传导诱导 GATA1 与启动子区域Plpp1结合，从而抑制Plpp1表达。 PD-1阻断增加了Plpp1的表达并恢复了CD8 ⁺ T细胞的抗肿瘤功能，但并没有挽救Plpp1 ^−/− CD8 ⁺ T细胞的功能障碍。因此，PD-1 信号传导调节 CD8 ⁺ T 细胞中的磷脂代谢，对免疫疗法具有治疗意义。