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

Immune checkpoint inhibition targeting the PD-1/PD-L1 pathway is a powerful clinical strategy for treating cancer, but its efficacy is limited by resistance mechanisms, including PD-L1 internalization and recycling. This study demonstrates that Hsc70 promotes PD-L1 degradation via the endosome-lysosome pathway, reducing membrane PD-L1 and inhibiting tumor growth. Hsc70 achieves this by binding to PD-L1, inhibiting the CMTM6-PD-L1 interaction. The Hsp90α/β inhibitor AUY-922 enhances Hsc70 expression and PD-L1 degradation, further improving anti-tumor immunity and enhancing the efficacy of anti-PD-L1 and anti-CTLA4 therapies.

Xiaoyan Xu, Tingxue Xie, Mengxin Zhou, Yaqin Sun, Fengqi Wang, Yanan Tian, Ziyan Chen, Yanqi Xie, Ronghai Wu, Xufeng Cen, Jichun Zhou, Tingjun Hou, Lei Zhang, Chaoyang Huang, Qingwei Zhao, Dongrui Wang, Hongguang Xia