Hsc70 promotes anti-tumor immunity by targeting PD-L1 for lysosomal degradation

Nat Commun. 2024 May 18;15(1):4237. doi: 10.1038/s41467-024-48597-3.


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. Either Hsc70 overexpression or AUY-922 treatment can reduce PD-L1 expression, inhibit tumor growth and promote anti-tumor immunity in female mice; AUY-922 can further enhance the anti-tumor efficacy of anti-PD-L1 and anti-CTLA4 treatment. Our study elucidates a molecular mechanism of Hsc70-mediated PD-L1 lysosomal degradation and provides a target and therapeutic strategies for tumor immunotherapy.

MeSH terms

  • Animals
  • B7-H1 Antigen* / genetics
  • B7-H1 Antigen* / metabolism
  • CTLA-4 Antigen / antagonists & inhibitors
  • CTLA-4 Antigen / immunology
  • CTLA-4 Antigen / metabolism
  • Cell Line, Tumor
  • Cell Membrane / metabolism
  • Endosomes / metabolism
  • Female
  • HSC70 Heat-Shock Proteins* / metabolism
  • HSP90 Heat-Shock Proteins / antagonists & inhibitors
  • HSP90 Heat-Shock Proteins / metabolism
  • Humans
  • Immune Checkpoint Inhibitors / pharmacology
  • Immune Checkpoint Inhibitors / therapeutic use
  • Lysosomes* / metabolism
  • MARVEL Domain-Containing Proteins
  • Mice
  • Mice, Inbred C57BL
  • Myelin Proteins
  • Neoplasms / immunology
  • Neoplasms / metabolism
  • Proteolysis


  • CD274 protein, human
  • HSPA8 protein, human
  • CMTM6 protein, human
  • Cd274 protein, mouse