Abstract In cancer, chronic antigen stimulation drives effector T cells to exhaustion, limiting the efficacy of T cell therapies. Recent studies have demonstrated that epigenetic rewiring governs the transition of T cells from effector to exhausted states and makes a subset of exhausted T cells non-responsive to PD1 checkpoint blockade. Here, we describe an antigen-specific assay for T cell exhaustion that generates T cells that are phenotypically and transcriptionally similar to those found in human tumors. We performed a screen of human epigenetic regulators, identifying and validating IKAROS as a driver of T cell exhaustion. We found that the IKAROS degrader iberdomide prevents exhaustion by blocking chromatin remodeling at T cell effector enhancers and preserving binding of AP-1, NF-κB, and NFAT. Thus, our study uncovered a role for IKAROS as a driver of T cell exhaustion through epigenetic modulation, providing a rationale for the potential use of iberdomide in solid tumors to prevent T cell exhaustion. Highlights Novel in vitro assay generates antigen-specific exhausted T cells from human T cells IKAROS (IKZF1) is a key driver of T cell exhaustion Iberdomide (IKZF1/3 degrader) prevents the progression of exhaustion TF footprinting reveals IKAROS silences effector genes by inhibiting AP-1, NF-κB and NFAT binding

Degradation of IKAROS prevents epigenetic progression of T cell exhaustion in a novel antigen-specific assay