The research investigates the epigenetic and molecular mechanisms that drive CD8+ T cell exhaustion during chronic viral infections and cancer, identifying ZMYND8 as a critical chromatin reader that represses IL-2R–STAT5 signaling. Through in vivo single-cell CRISPR screens, the study demonstrates that ZMYND8 suppresses effector-like states and promotes terminal exhaustion by binding to active enhancer regions of the Il2ra gene and suppressing p300 histone acetyltransferase activity. Consequently, deleting or targeting ZMYND8 unleashes effector-like cell differentiation—particularly the TexKLR subset—while significantly boosting antiviral and antitumour immunity. Furthermore, combining ZMYND8 deficiency with IL-2 therapy or immune checkpoint blockade produces a synergistic therapeutic effect, overcoming a major barrier to effective immunotherapy.
References:
Wang Y, Shi H, Chapman N M, et al. Targeting ZMYND8 unleashes IL-2 signalling to override T cell exhaustion[J]. Nature, 2026: 1-10.
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