Immune checkpoint inhibition targeting the PD-1/PD-L1 pathway is a powerful clinical strategy for treating cancer, but its efficacy is limited by resistance mechanisms, including PD-L1 internalization and recycling. This study demonstrates that Hsc70 promotes PD-L1 degradation via the endosome-lysosome pathway, reducing membrane PD-L1 and inhibiting tumor growth. Hsc70 achieves this by binding to PD-L1, inhibiting the CMTM6-PD-L1 interaction. The Hsp90α/β inhibitor AUY-922 enhances Hsc70 expression and PD-L1 degradation, further improving anti-tumor immunity and enhancing the efficacy of anti-PD-L1 and anti-CTLA4 therapies.
