Dual activation of CD8⁺ T cells by CRBN modulators and checkpoint inhibitors. Avadomide induces IKZF1 degradation through the CRBN E3 ligase inhibiting proliferation in CLL cells and enhancing IFN type I and II signaling in T cells. IFN signaling induces activation, proliferation, and chemokine release of cytotoxic T cells but also upregulation of autoinhibitory PD-L1. Blocking PD-L1 or PD-1 by antibodies enables synapse formation and T-cell–mediated killing of CLL cells.