Argininosuccinate synthase (ASS1) downregulation in different tumors has been shown to support cell proliferation and yet, in several common cancer subsets ASS1 expression associates with poor patient prognosis. Here we demonstrate that ASS1 expression under glucose deprivation is induced by c-MYC, providing survival benefit by increasing nitric oxide synthesis and activating the gluconeogenic enzymes pyruvate carboxylase and phosphoenolpyruvate carboxykinase by S-nitrosylation. The resulting increased flux through gluconeogenesis enhances serine, glycine and subsequently purine synthesis. Notably, high ASS1-expressing breast cancer mice do not respond to immune checkpoint inhibitors and patients with breast cancer with high ASS1 have more metastases. We further find that inhibiting purine synthesis increases pyrimidine to purine ratio, elevates expression of the immunoproteasome and significantly enhances the response of autologous primary CD8⁺ T cells to anti-PD-1. These results suggest that treating patients with high-ASS1 cancers with purine synthesis inhibition is beneficial and may also sensitize them to immune checkpoint inhibition therapy.

已显示不同肿瘤中的精氨琥珀酸合酶 (ASS1) 下调支持细胞增殖，然而，在几种常见的癌症亚群中，ASS1 表达与患者预后不良有关。在这里，我们证明了葡萄糖剥夺下的 ASS1 表达是由 c-MYC 诱导的，通过增加一氧化氮合成和通过 S-亚硝基化激活糖异生酶丙酮酸羧化酶和磷酸烯醇丙酮酸羧激酶来提供生存益处。通过糖异生产生的通量增加增强了丝氨酸、甘氨酸和随后的嘌呤合成。值得注意的是，高表达 ASS1 的乳腺癌小鼠对免疫检查点抑制剂没有反应，高 ASS1 的乳腺癌患者有更多的转移灶。我们进一步发现抑制嘌呤合成会增加嘧啶与嘌呤的比例，⁺ T 细胞抗 PD-1。这些结果表明，用嘌呤合成抑制治疗高 ASS1 癌症患者是有益的，也可能使他们对免疫检查点抑制治疗敏感。