Casitas B-lineage lymphoma-b (CBLB) is an E3 ubiquitin–protein ligase that functions as an intracellular checkpoint and master negative regulator of T‑cell and natural killer (NK) cell activation, playing a central role in modulating T-cell activation and immune tolerance, and its inhibition enhances T cells and NK cells function, also provides a strategy for the function restoration of exhausted T cells.