氨基酸剥夺，特别是正常细胞可以合成但生物合成途径中有特定缺陷的癌细胞不能合成的非必需氨基酸，已成为癌症治疗中的一种潜在策略。在正常细胞中，精氨酸是通过两种酶从瓜氨酸分两步合成的：精氨基琥珀酸合成酶 (ASS1) 和精氨基琥珀酸裂解酶。由于 ASS1 缺失或下调，一些癌细胞表现出精氨酸营养缺陷型。在精氨酸降解酶（如精氨酸脱氨酶 (ADI)）存在的情况下，这些细胞会经历饥饿诱导的细胞死亡。因此，ADI 已成为癌症治疗的潜在疗法。然而，ADI的使用有两个主要缺点：细菌来源的ADI在哺乳动物中具有强抗原性，并且ADI的循环半衰期短（∼5小时）。在这项研究中，我们设计了靶向肿瘤的鸡沙门氏菌来表达和分泌 ADI，并通过静脉途径将该菌株部署到植入 ASS1 缺陷型小鼠结直肠癌 (CT26) 的小鼠体内。观察到显着的抗肿瘤作用，这表明由于 ADI 由肿瘤靶向细菌组成型表达，因此克服了该缺点。与抑制自噬诱导的氯喹联合使用，进一步增强了效果。表达精氨酸脱亚胺酶 (ADI) 的鸡沙门氏菌对精氨酸依赖性原位肿瘤的抗癌作用。© 2024。作者，获得 Springer Nature Limited 的独家许可。

Amino acid deprivation, particularly of nonessential amino acids that can be synthesized by normal cells but not by cancer cells with specific defects in the biosynthesis pathway, has emerged as a potential strategy in cancer therapeutics. In normal cells, arginine is synthesized from citrulline in two steps via two enzymes: argininosuccinate synthetase (ASS1) and argininosuccinate lyase. Several cancer cells exhibit arginine auxotrophy due to the loss or down-regulation of ASS1. These cells undergo starvation-induced cell death in the presence of arginine-degrading enzymes such as arginine deaminase (ADI). Thus, ADI has emerged as a potential therapeutic in cancer therapy. However, the use of ADI has two major disadvantages: ADI of bacterial origin is strongly antigenic in mammals, and ADI has a short circulation half-life (∼5 h). In this study, we engineered tumor-targeting Salmonella Gallinarum to express and secrete ADI and deployed this strain into mice implanted with ASS1-defective mouse colorectal cancer (CT26) through an intravenous route. A notable antitumor effect was observed, suggesting that the disadvantages were overcome as ADI was expressed constitutively by tumor-targeting bacteria. A combination with chloroquine, which inhibits the induction of autophagy, further enhanced the effect. Anti-cancer effect of Salmonella Gallinarum expressing an arginine deiminase (ADI) on arginine-dependent tumors in situ.© 2024. The Author(s), under exclusive licence to Springer Nature Limited.