Resetting the Hsc70-mediated lysosomal degradation of PD-L1 via a supramolecular meso peptide for the restoration of acquired anti-tumor T cell immunity.

ABSTRACT: The reduction of cellular PD-L1 abundance through lysosomal degradation is recognized as essential for effective and sustained targeting of PD-L1-dependent immune evasion in cancer. While Hsc70 can interact with PD-L1 to promote its lysosomal degradation, the overexpression of CMTM6 competitively inhibits this interaction, leading to the blockade of PD-L1 lysosomal degradation. To overcome this issue, a meso chimeric peptide ^PEPPDL1 was designed to specifically bind the PD-1 binding domain of PD-L1 instead of the Hsc70/CMTM6 binding domain, while also binding to Hsc70 to facilitate the dragging of PD-L1 into Hsc70-mediated chaperone-mediated autophagy (CMA), thereby achieving lysosomal degradation. In order to enable internalization into tumor cells, supramolecular engineering t

SUBMITTER: Zhao Y 

PROVIDER: S-EPMC11792358 | biostudies-literature | 2025 Feb

REPOSITORIES: biostudies-literature