Cancer immunotherapy using immune-checkpoint blockade has displayed promising clinical effects, but prevalent antibody-based inhibitors face multiple challenges such as low response rate, acquired resistance, and adverse effects. The intracellular expression of PD-1/PD-L1 in recycling endosomes and their active trafficking to membrane highlight the importance of depleting rather than interfering with checkpoint proteins. Preclinical investigations on the therapeutic effects of lead compounds that function by degrading immune checkpoint ligands and receptors have reported highly promising results. By harnessing the degradation capabilities of the lysosome, proteasome and autophagosomes, different small molecules and peptides potently induced degradation of checkpoint proteins and enhanced anti-tumor immunity. Both in vitro and in vivo experiments support the therapeutic efficacy of these molecules. Thus, targeted degradation through endo-lysosomal, autophagic, proteasomal, or endoplasmic reticulum-related pathways may provide promising strategies for tackling the challenges in cancer immunotherapy.