CD73 is an ectonucleotidase overexpressed on
tumor cells that suppresses anti-
tumor immunity. Accordingly, several CD73 inhibitors are currently being evaluated in the clinic, including in large randomized clinical trials. Yet, the
tumor cell-intrinsic impact of CD73 remain largely uncharacterized. Using metabolomics, we discovered that CD73 significantly enhances
tumor cell mitochondrial respiration and
aspartate biosynthesis. Importantly, rescuing
aspartate biosynthesis was sufficient to restore proliferation of CD73-deficient
tumors in immune deficient mice. Seahorse analysis of a large panel of mouse and human
tumor cells demonstrated that CD73 enhanced oxidative phosphorylation (OXPHOS) and glycolytic reserve. Targeting CD73 decreased
tumor cell metabolic fitness, increased
genomic instability and suppressed
poly ADP ribose polymerase (PARP) activity. Our study thus uncovered an important immune-independent function for CD73 in promoting
tumor cell metabolism, and provides the rationale for previously unforeseen combination
therapies incorporating CD73 inhibition.