Deletion of CIS in CAR-NK cells enhances IL-15 signaling by removing an immune checkpoint, which leads to increased activation of the AKT/mTOR pathway and, in the presence of tumor cells, enhanced c-Myc activation. These signaling pathways result in greater glycolytic capacity of CAR-NK cells and subsequently increased cytotoxicity against tumor targets. IFN-γ, interferon-γ; JAK, Janus kinase; mTOR, mammalian target of rapamycin; STAT, signal transducer and activator of transcription; TNF-α, tumor necrosis factor-α. See the visual abstract in the article by Daher et al that begins on page 624.