Hsc70 promotes anti-tumor immunity by targeting PD-L1 for lysosomal degradation. This study reveals that Hsc70 promotes PD-L1 degradation through the endosome-lysosome pathway, reducing PD-L1 recycling to the cell membrane. This effect is dependent on Hsc70-PD-L1 binding, which inhibits the CMTM6-PD-L1 interaction. An Hsp90α/β inhibitor, AUY-922, induces Hsc70 expression and PD-L1 lysosomal degradation. Both Hsc70 overexpression and AUY-922 treatment reduce PD-L1 expression, inhibit tumor growth, and promote anti-tumor immunity in female mice. AUY-922 further enhances the anti-tumor efficacy of anti-PD-L1 and anti-CTLA4 treatment. The study elucidates a molecular mechanism of Hsc70-mediated PD-L1 lysosomal degradation and provides a target and therapeutic strategy for tumor immunotherapy. PD-L1 degradation is primarily through the proteasome and lysosome pathways. Hsc70 facilitates PD-L1 degradation via endosomes and lysosomes by competing with CMTM6 for binding to PD-L1. TFG is involved in the endosome-lysosome degradation of PD-L1. Hsc70 promotes anti-tumor immunity and controls in vivo tumor growth by downregulating PD-L1, enhancing T cell effector function, and reducing tumorigenesis. AUY-922 promotes PD-L1 degradation through Hsc70-mediated eMI and enhances anti-tumor immunity. AUY-922 also enhances the therapeutic effect of anti-PD-L1 or anti-CTLA4 ICI. The study highlights the potential of Hsc70 and AUY-922 as targets for combinational immunotherapy. The findings suggest that enhancing the interaction between Hsc70 and PD-L1 can alleviate disease progression and may be beneficial for other eMI-related diseases, including cancer, neurodegenerative diseases, and aging-related diseases.Hsc70 promotes anti-tumor immunity by targeting PD-L1 for lysosomal degradation. This study reveals that Hsc70 promotes PD-L1 degradation through the endosome-lysosome pathway, reducing PD-L1 recycling to the cell membrane. This effect is dependent on Hsc70-PD-L1 binding, which inhibits the CMTM6-PD-L1 interaction. An Hsp90α/β inhibitor, AUY-922, induces Hsc70 expression and PD-L1 lysosomal degradation. Both Hsc70 overexpression and AUY-922 treatment reduce PD-L1 expression, inhibit tumor growth, and promote anti-tumor immunity in female mice. AUY-922 further enhances the anti-tumor efficacy of anti-PD-L1 and anti-CTLA4 treatment. The study elucidates a molecular mechanism of Hsc70-mediated PD-L1 lysosomal degradation and provides a target and therapeutic strategy for tumor immunotherapy. PD-L1 degradation is primarily through the proteasome and lysosome pathways. Hsc70 facilitates PD-L1 degradation via endosomes and lysosomes by competing with CMTM6 for binding to PD-L1. TFG is involved in the endosome-lysosome degradation of PD-L1. Hsc70 promotes anti-tumor immunity and controls in vivo tumor growth by downregulating PD-L1, enhancing T cell effector function, and reducing tumorigenesis. AUY-922 promotes PD-L1 degradation through Hsc70-mediated eMI and enhances anti-tumor immunity. AUY-922 also enhances the therapeutic effect of anti-PD-L1 or anti-CTLA4 ICI. The study highlights the potential of Hsc70 and AUY-922 as targets for combinational immunotherapy. The findings suggest that enhancing the interaction between Hsc70 and PD-L1 can alleviate disease progression and may be beneficial for other eMI-related diseases, including cancer, neurodegenerative diseases, and aging-related diseases.