Successful responses to immune checkpoint blockade depend on T-cell mediated antitumor immunity. Salmon and Shavkunov et al. find that T-cell expression of the transcriptional regulator BHLHE40 is required for effective immune checkpoint blockade in tumor-bearing mice. Single-cell RNA sequencing of intratumoral immune cells revealed that in the absence of BHLHE40, the tumor immune microenvironment is dysregulated, including showing a defective IFNγ response. The data provide new insight into the molecular features of T cells that mediate effective antitumor immunity following immune checkpoint blockade and suggest that BHLHE40 could be a potential biomarker for response to such treatments. Read more in this issue on page 597. Original image from Fig. 4A. Artwork by Lewis Long.