Inhibiting PD-L1 palmitoylation enhances T-cell immune responses against tumours

Nat Biomed Eng. 2019 Apr;3(4):306-317. doi: 10.1038/s41551-019-0375-6. Epub 2019 Mar 25.


Checkpoint blockade therapy targeting the programmed-death ligand 1 (PD-L1) and its receptor programmed cell death 1 promotes T-cell-mediated immunosurveillance against tumours, and has been associated with marked clinical benefit in cancer patients. Antibodies against PD-L1 function by blocking PD-L1 on the cell surface, but intracellular storage of PD-L1 and its active redistribution to the cell membrane can minimize the therapeutic benefits, which highlights the importance of targeting PD-L1 throughout the whole cell. Here, we show that PD-L1 is palmitoylated in its cytoplasmic domain, and that this lipid modification stabilizes PD-L1 by blocking its ubiquitination, consequently suppressing PD-L1 degradation by lysosomes. We identified palmitoyltransferase ZDHHC3 (DHHC3) as the main acetyltransferase required for the palmitoylation of PD-L1, and show that the inhibition of PD-L1 palmitoylation via 2-bromopalmitate, or the silencing of DHHC3, activates antitumour immunity in vitro and in mice bearing MC38 tumour cells. We also designed a competitive inhibitor of PD-L1 palmitoylation that decreases PD-L1 expression in tumour cells to enhance T-cell immunity against the tumours. These findings suggest new strategies for overcoming PD-L1-mediated immune evasion in cancer.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acyltransferases / metabolism
  • Animals
  • B7-H1 Antigen / metabolism*
  • Cell Line, Tumor
  • Humans
  • Lipoylation*
  • Lysosomes / metabolism
  • Mice
  • Neoplasms / immunology*
  • Peptides / metabolism
  • T-Lymphocytes / immunology*
  • Ubiquitination


  • B7-H1 Antigen
  • Peptides
  • Acyltransferases
  • ZDHHC3 protein, human