iProXProteomicsHongguang XiaHomo Sapienshttp://www.iprox.org/page/project.html?id=IPX0008528000hongguangxia@zju.edu.cnResearch Center of Clinical Pharmacy of The First Affiliated Hospital & Liangzhu Laboratory, Zhejiang University School of MedicineiProXImmune 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.Hsc70 promotes anti-tumor immunity by targeting PD-L1 for lysosomal degradation.Xu Xiaoyan X, Xie Tingxue T, Zhou Mengxin M, Sun Yaqin Y, Wang Fengqi F, Tian Yanan Y, Chen Ziyan Z, Xie Yanqi Y, Wu Ronghai R, Cen Xufeng X, Zhou Jichun J, Hou Tingjun T, Zhang Lei L, Huang Chaoyang C, Zhao Qingwei Q, Wang Dongrui D, Xia Hongguang HfalseProteomics of Hsc70-interacting Proteinswe compared the interacting proteins between Hsc70-WT and Hsc70-3KA using mass spectrometry to discover additional mediators of this processFri Apr 05 00:00:00 BST 2024PXD051241960638762492