Despite advancements in treatment options, the overall cure and survival rates for non-small cell lung cancers (NSCLC) remain low. Using epigenome-wide CRISPR knockout screens, the histone chaperone nucleophosmin 1 (NPM1) was identified as a potential therapeutic target. Furthermore, genetic ablation of NPM1 rewired the balance of metabolism in cancer cells from predominant aerobic glycolysis to oxidative phosphorylation and reduced the population of tumor-propagating cells. The cover image shows that pentameric NPM1 is a therapeutic target for tumor-propagating cells in NSCLC. The pentameric protein is depicted in five different colors. Alveoli in the background show the context of NSCLC. For details, see article by Li and colleagues on page 3556.