Degradation of IKZF1 prevents epigenetic progression of T cell exhaustion in an antigen-specific assay

Chronic antigen stimulation in cancer drives effector T cells toward exhaustion, reducing the effectiveness of T cell-based therapies. Recent studies have shown that epigenetic reprogramming plays a critical role in the transition of T cells from an effector state to an exhausted state, rendering a subset of exhausted T cells unresponsive to PD-1 checkpoint blockade. In this study, we present an antigen-specific assay for T cell exhaustion that produces T cells with phenotypic and transcriptional profiles resembling those found in human tumors. Through a screen of human epigenetic regulators, we identify IKZF1 as a key driver of T cell exhaustion. Our findings demonstrate that the IKZF1 degrader iberdomide prevents exhaustion by inhibiting chromatin remodeling at T cell effector enhancers, thereby maintaining the activity of transcription factors such as AP-1, NF-κB, and NFAT. These results highlight IKZF1 as a critical regulator of T cell exhaustion via epigenetic mechanisms and provide a strong rationale for exploring iberdomide as a therapeutic strategy to prevent T cell exhaustion in solid tumors.