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

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In cancer, chronic antigen stimulation drives effector Tcells to exhaustion, limiting the efficacy of Tcell therapies. Recent studies have demonstrated that epigenetic rewiring governs the transition of Tcells from effector to exhausted states and makes a subset of exhausted Tcells non-responsive to PD1 checkpoint blockade. Here, we describe an antigen-specific assay for Tcell exhaustion that generates Tcells phenotypically and transcriptionally similar to those found in human tumors. We perform a screen of human epigenetic regulators, identifying IKZF1 as a driver of Tcell exhaustion. We determine that the IKZF1 degrader iberdomide prevents exhaustion by blocking chromatin remodeling at Tcell effector enhancers and preserving the binding of AP-1, NF-κB, and NFAT. Thus, our study uncovers a role for IKZF1 as a driver of Tcell exhaustion through epigenetic modulation, providing a rationale for the use of iberdomide in solid tumors to prevent Tcell exhaustion.