Ammonia is thought to be a cytotoxin and its increase in the blood impairs cell function. However, whether and how this toxin triggers cell death under pathophysiological conditions remains unclear. Here we show that ammonia induces a distinct form of cell death in effector T cells. We found that rapidly proliferating T cells use glutaminolysis to release ammonia in the mitochondria, which is then translocated to and stored in the lysosomes. Excessive ammonia accumulation increases lysosomal pH and results in the termination of lysosomal ammonia storage and ammonia reflux into mitochondria, leading to mitochondrial damage and cell death, which is characterized by lysosomal alkalization, mitochondrial swelling and impaired autophagic flux. Inhibition of glutaminolysis or blocking lysosomal alkalization prevents ammonia-induced T cell death and improves T cell-based antitumour immunotherapy. These findings identify a distinct form of cell death that differs from previously known mechanisms.

氨被认为是一种细胞毒素，它在血液中的增加会损害细胞功能。然而，这种毒素是否以及如何在病理生理条件下触发细胞死亡仍不清楚。在这里，我们表明氨在效应 T 细胞中诱导一种独特形式的细胞死亡。我们发现快速增殖的 T 细胞利用谷氨分解在线粒体中释放氨，然后将其转移到溶酶体并储存在溶酶体中。过量的氨积累会增加溶酶体的 pH 值，导致溶酶体氨储存终止，氨回流到线粒体中，导致线粒体损伤和细胞死亡，其特征是溶酶体碱化、线粒体肿胀和自噬通量受损。抑制谷氨酰胺分解或阻断溶酶体碱化可防止氨诱导的 T 细胞死亡，并改善基于 T 细胞的抗肿瘤免疫治疗。这些发现确定了一种不同于以前已知机制的不同形式的细胞死亡。