biostudies-literatureXu XNatural Science Foundation of Zhejiang ProvinceNational Natural Science Foundation of ChinaNatural Science Foundation of Zhejiang Province (Zhejiang Provincial Natural Science Foundation)National Natural Science Foundation of China (National Science Foundation of China)4237https://www.ebi.ac.uk/biostudies/studies/S-EPMC11102475biostudies-literatureUnknown15(1)Immune checkpoint inhibition targeting the PD-1/PD-L1 pathway has become a powerful clinical strategy for treating cancer, but its efficacy is complicated by various resistance mechanisms. One of the reasons for the resistance is the internalization and recycling of PD-L1 itself upon antibody binding. The inhibition of lysosome-mediated degradation of PD-L1 is critical for preserving the amount of PD-L1 recycling back to the cell membrane. In this study, we find that Hsc70 promotes PD-L1 degradation through the endosome-lysosome pathway and reduces PD-L1 recycling to the cell membrane. This effect is dependent on Hsc70-PD-L1 binding which inhibits the CMTM6-PD-L1 interaction. We further identify an Hsp90α/β inhibitor, AUY-922, which induces Hsc70 expression and PD-L1 lysosomal degradation.Nature communicationsHsc70 promotes anti-tumor immunity by targeting PD-L1 for lysosomal degradation.PMC11102475LQ24C0700013222202332350016Zhou MXie THuang CXie YWang DHou TWang FZhang LSun YXia HChen ZZhao QTian YWu RCen XXu XZhou JfalseHsc70 promotes anti-tumor immunity by targeting PD-L1 for lysosomal degradation.Immune checkpoint inhibition targeting the PD-1/PD-L1 pathway has become a powerful clinical strategy for treating cancer, but its efficacy is complicated by various resistance mechanisms. One of the reasons for the resistance is the internalization and recycling of PD-L1 itself upon antibody binding. The inhibition of lysosome-mediated degradation of PD-L1 is critical for preserving the amount of PD-L1 recycling back to the cell membrane. In this study, we find that Hsc70 promotes PD-L1 degradation through the endosome-lysosome pathway and reduces PD-L1 recycling to the cell membrane. This effect is dependent on Hsc70-PD-L1 binding which inhibits the CMTM6-PD-L1 interaction. We further identify an Hsp90α/β inhibitor, AUY-922, which induces Hsc70 expression and PD-L1 lysosomal degradation.2024-01-01T00:00:00Z2024 May2026-06-02T02:20:33.283Z2026-04-13T03:12:14.144ZS-EPMC111024753876249210.1038/s41467-024-48597-3