ETV7 limits the antiviral and antitumor efficacy of CD8 T cells by diverting their fate toward exhaustion.

Terminal exhaustion is a critical barrier to antitumor immunity. By integrating and analyzing single-cell RNA-sequencing and single-cell assay for transposase-accessible chromatin with sequencing data, we found that ETS variant 7 (ETV7) is indispensable for determining CD8 T cell fate in tumors. ETV7 introduction drives T cell differentiation from memory to terminal exhaustion, limiting antiviral and antitumor efficacy in male mice. Mechanistically, ETV7 acts as a central transcriptional node by binding to specific memory genes and exhaustion genes and functionally skewing these transcriptional programs toward exhaustion. Clinically, ETV7 expression is negatively correlated with progression and responsiveness to immune checkpoint blockade in various human cancers. ETV7 depletion strongly enhances the antitumor efficacy of CD8 T cells and engineered chimeric antigen receptor T cells in solid tumors. Thus, these findings demonstrate a decisive role for ETV7 in driving CD8 T cell terminal exhaustion and reveal that ETV7 may be a promising target and biomarker for improving the efficacy of cancer immunotherapy.