Nature 576, 471–476 (2019)

Activated T cells often become less functional in the tumor microenvironment or during chronic infection. In Nature, Chi and colleagues describe an unbiased CRISPR-Cas9 screen in CD8+ T cells that identifies Regnase-1 as a negative regulator of T cell function within the tumor environment. Regnase-1-null CD8+ T cells persist longer in tumors, exhibit enhanced mitochondrial spare respiratory capacity and increased oxidative phosphorylation, and express more effector molecules as compared to wild-type cells. Tumor-bearing mice receiving Regnase-1-null CD8+ T cells also survive longer. The authors also identify mRNAs encoding the transcription factor BATF as a major target of Regnase-1, as deletion of Batf abolished the enhanced antitumor activity of Regnase-1-null CD8+ T cells. These findings reveal Regnase-1 as a regulator of cytotoxic T cell function within the tumor microenvironment.