Targeting ZMYND8 unleashes IL-2 signalling to override T cell exhaustion.

Targeting ZMYND8 in CD8+ T cells enhances IL-2 signalling and promotes effector-like states, improving antiviral and antitumour responses in models of exhaustion.

• Why it matters: T cell exhaustion hampers control of chronic infections and cancer by downregulating IL-2R and STAT5 signals, but the epigenetic mechanisms behind this remain unclear, limiting therapeutic options.
• What they did: Using in vivo single-cell CRISPR screens, the study identified ZMYND8 as an epigenetic regulator that antagonizes IL-2R-STAT5 signals, with its deletion promoting effector-like T cell differentiation and improved immune responses.
• The result: ZMYND8 deficiency increased IL-2R expression and effector-like T cell states, especially when combined with IL-2 therapy or checkpoint blockade, suggesting ZMYND8 as a target to enhance immunotherapy efficacy.