Targeting purine synthesis in ASS1 expressing tumors enhances the response to immune checkpoint inhibitors

ASS1 downregulation in different tumors has been shown to support cell proliferation and yet, in several common cancer subsets ASS1 expression associates with a poor patients prognosis. Here we demonstrate that ASS1 expression under glucose deprivation is induced by cMYC, providing survival benefit by increasing NO synthesis and activating the gluconeogenic enzymes PC and PCK2 by 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 breast cancer patients with high ASS1 have more metastasis. We further find that inhibiting purine synthesis increases pyrimidine to purine ratio, elevates the expression of the immunoproteasome and significantly enhances the response of autologous primary CD8 T cells to antiPD1. 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.