Checkpoints in immune cells fine tune the immune response to activation or tolerance. We have identified the E3 ligase Cbl-b as a key negative modulator of immune cells activation extending from T cells, NK cells and recently dendritic cells. Loss of Cbl-b licenses immune cells to spontaneously kill multiple cancers or even revert lethal fungal infections without severe side-effects to the tested animals. Thus, targeting Cbl-b provides a novel modality to activate the immune system to kill tumors which is currently explored in phase I clinical trials using a rapid and direct bed-side cell therapy approach.