This study investigates the role of Hsc70 in promoting anti-tumor immunity by targeting PD-L1 for lysosomal degradation. Hsc70 is found to promote PD-L1 degradation through the endosome-lysosome pathway, reducing PD-L1 recycling to the cell membrane. This effect is dependent on the binding of Hsc70 to PD-L1, which inhibits the interaction between CMTM6 and PD-L1. The Hsp90α/β inhibitor AUY-922 is identified as an agent that induces Hsc70 expression and PD-L1 lysosomal degradation. Both Hsc70 overexpression and AUY-922 treatment reduce PD-L1 expression, inhibit tumor growth, and enhance anti-tumor immunity in female mice. AUY-922 also enhances the efficacy of anti-PD-L1 and anti-CTLA4 treatments. The study provides a molecular mechanism for Hsc70-mediated PD-L1 lysosomal degradation and suggests a therapeutic strategy for tumor immunotherapy.This study investigates the role of Hsc70 in promoting anti-tumor immunity by targeting PD-L1 for lysosomal degradation. Hsc70 is found to promote PD-L1 degradation through the endosome-lysosome pathway, reducing PD-L1 recycling to the cell membrane. This effect is dependent on the binding of Hsc70 to PD-L1, which inhibits the interaction between CMTM6 and PD-L1. The Hsp90α/β inhibitor AUY-922 is identified as an agent that induces Hsc70 expression and PD-L1 lysosomal degradation. Both Hsc70 overexpression and AUY-922 treatment reduce PD-L1 expression, inhibit tumor growth, and enhance anti-tumor immunity in female mice. AUY-922 also enhances the efficacy of anti-PD-L1 and anti-CTLA4 treatments. The study provides a molecular mechanism for Hsc70-mediated PD-L1 lysosomal degradation and suggests a therapeutic strategy for tumor immunotherapy.