Antifolates, which inhibit de novo purine synthesis, were some of the first chemotherapeutics used to treat cancer. However, how the de novo purine synthesis and purine salvage pathways interact, and the therapeutic implications therein, are poorly defined. In their study on page 82, Tabata and colleagues found that purine salvage rate-limiting enzyme hypoxanthine phosphoribosyltransferase 1 (HPRT1) is often expressed in small cell lung cancer (SCLC), and that HPRT1 deletion using CRISPR-Cas9 sensitizes SCLC cell lines to pharmacologic de novo purine synthesis pathway inhibition. Using metabolomic and isotope tracing analyses, the authors demonstrated that HPRT1 loss increased metabolic flux through the de novo purine synthesis pathway, suggesting purine salvage is a compensatory pathway that can be targeted to enhance de novo purine synthesis inhibition efficacy. The cover features a bubble plot depicting metabolic pathways enriched in HPRT1-deficient SCLC cells. This study is also Highlighted on page 5.