ANKRD11 deficiency reprograms CD8+ T cell differentiation to enhance immunity in chronic infection and cancer.

CD8+ T cell dysfunction is a major obstacle to hepatitis B virus (HBV) clearance and antitumor immunity. Here, using a humanized mouse model, we identify a T cell receptor targeting a clinically relevant HBV epitope and reveal ANKRD11 as a key epigenetic regulator of CD8+ T cell dysfunction in chronic infection and tumors. Ankrd11 knockout in CD8+ T cells enhances HBV-specific T cell proliferation and effector differentiation, especially under immunosuppressive conditions, via AP-1 family gene upregulation. Loss of Ankrd11 both drives the conversion of progenitor exhausted T cells into terminally exhausted T cells, and reprograms PD-1-TOX- tolerant cells into functional effectors, improving antiviral and antitumor responses. Ankrd11-deficient T cells show increased granzyme and superior effector function, enhancing viral control and tumor regression. These findings position ANKRD11 as a promising immunotherapy target for chronic HBV infection and cancer.