Zosuquidar Promotes Antitumor Immunity by Inducing Autophagic Degradation of PD-L1

The intracellular distribution and transportation process are essential for maintaining PD-L1 (programmed death-ligand 1) expression, and intervening in this cellular process may provide promising therapeutic strategies. Here, through a cell-based high content screening, it is found that the ABCB1 (ATP binding cassette subfamily B member 1) modulator zosuquidar dramatically suppresses PD-L1 expression by triggering its autophagic degradation. Mechanistically, ABCB1 interacts with PD-L1 and impairs COP II-mediated PD-L1 transport from ER (endoplasmic reticulum) to Golgi apparatus. The treatment of zosuquidar enhances ABCB1-PD-L1 interaction and leads the ER retention of PD-L1, which is subsequently degraded in the SQSTM1-dependent selective autophagy pathway. In CT26 mouse model and a humanized xenograft mouse model, zosuquidar significantly suppresses tumor growth and accompanies by increased infiltration of cytotoxic T cells. In summary, this study indicates that ABCB1 serves as a negative regulator of PD-L1, and zosuquidar may act as a potential immunotherapy agent by triggering PD-L1 degradation in the early secretory pathway. Newly synthesized programmed death-ligand 1 (PD-L1) needs to be sequentially transported to endoplasmic reticulum (ER) and Golgi apparatus for post-translational modification. The adenosine 5'-triphosphate (ATP) binding cassette subfamily B member 1 (ABCB1) modulator zosuquidar disrupts PD-L1 translocating from ER to Golgi apparatus, dramatically triggers autophagic degradation of PD-L1, and exhibits significant anti-tumor effect in vivo. image