Abstract
Progenitor CD8(+) T cells differentiate into effector and exhausted progenies during chronic antigen stimulation; however, mechanisms that restrain exhaustion and sustain effector differentiation remain incompletely defined. Here we identified the transcription factor ZFP148 as a repressor of CD8(+) T cell effector differentiation. ZFP148-deficient CD8(+) T cells displayed increased frequency of cytolytic effector cells and reduced frequency of exhausted cells compared with Zfp148(fl/fl) controls during chronic viral infection. Mechanistically, ZFP148 limited the chromatin accessibility of effector-driving transcription factor motifs and directly repressed expression of the transcription factor KLF2. Furthermore, conditional ZFP148 ablation in CD8(+) T cells synergized with programmed cell death-1 blockade to improve tumor control in syngeneic mouse models. Consistently, cancer patients with lower ZNF148 expression in tumor-infiltrating CD8(+) T cells showed improved responsiveness to immunotherapies. Collectively, our study identifies ZFP148 as a transcriptional repressor of CD8(+) T cell effector differentiation and highlights its therapeutic potential for enhancing antitumor immunity.