The availability of l-arginine in tumours is a key determinant of an efficient anti-tumour T cell response^1,2,3,4. Consequently, increases of typically low l-arginine concentrations within the tumour may greatly potentiate the anti-tumour responses of immune checkpoint inhibitors, such as programmed death-ligand 1 (PD-L1)-blocking antibodies⁵. However, currently no means are available to locally increase intratumoural l-arginine levels. Here we used a synthetic biology approach to develop an engineered probiotic Escherichia coli Nissle 1917 strain that colonizes tumours and continuously converts ammonia, a metabolic waste product that accumulates in tumours⁶, to l-arginine. Colonization of tumours with these bacteria increased intratumoural l-arginine concentrations, increased the number of tumour-infiltrating T cells and had marked synergistic effects with PD-L1 blocking antibodies in the clearance of tumours. The anti-tumour effect of these bacteria was mediated by l-arginine and was dependent on T cells. These results show that engineered microbial therapies enable metabolic modulation of the tumour microenvironment leading to enhanced efficacy of immunotherapies.

肿瘤中l-精氨酸的可用性是有效抗肿瘤 T 细胞反应^1,2,3,4的关键决定因素。因此，增加肿瘤内通常较低的l-精氨酸浓度可能会大大增强免疫检查点抑制剂的抗肿瘤反应，例如程序性死亡配体 1 (PD-L1) 阻断抗体⁵。然而，目前没有可用的方法来局部增加瘤内l-精氨酸水平。在这里，我们使用合成生物学方法开发了一种工程益生菌大肠杆菌Nissle 1917 菌株，该菌株定植于肿瘤并不断转化氨，氨是一种在肿瘤中积累的代谢废物⁶, 为l-精氨酸。这些细菌在肿瘤中的定植增加了肿瘤内l-精氨酸浓度，增加了肿瘤浸润 T 细胞的数量，并且与 PD-L1 阻断抗体在清除肿瘤方面具有显着的协同作用。这些细菌的抗肿瘤作用是由l-精氨酸介导的，并且依赖于 T 细胞。这些结果表明，工程微生物疗法能够对肿瘤微环境进行代谢调节，从而提高免疫疗法的功效。