Benzosceptrin C induces lysosomal degradation of PD-L1 and promotes antitumor immunity by targeting DHHC3

Cell Rep Med. 2024 Feb 20;5(2):101357. doi: 10.1016/j.xcrm.2023.101357. Epub 2024 Jan 17.


Programmed cell death-1 (PD-1)/programmed cell death ligand-1 (PD-L1) blockade has become a mainstay of cancer immunotherapy. Targeting the PD-1/PD-L1 axis with small molecules is an attractive approach to enhance antitumor immunity. Here, we identified a natural marine product, benzosceptrin C (BC), that enhances the cytotoxicity of T cells to cancer cells by reducing the abundance of PD-L1. Furthermore, BC exerts its antitumor effect in mice bearing MC38 tumors by activating tumor-infiltrating T cell immunity. Mechanistic studies suggest that BC can prevent palmitoylation of PD-L1 by inhibiting DHHC3 enzymatic activity. Subsequently, PD-L1 is transferred from the membrane to the cytoplasm and cannot return to the membrane via recycling endosomes, triggering lysosome-mediated degradation of PD-L1. Moreover, the combination of BC and anti-CTLA4 effectively enhances antitumor T cell immunity. Our findings reveal a previously unrecognized antitumor mechanism of BC and represent an alternative immune checkpoint blockade (ICB) therapeutic strategy to enhance the efficacy of cancer immunotherapy.

Keywords: DHHC3; PD-L1; benzosceptrin C; cancer immunotherapy; colorectal cancer.

MeSH terms

  • Animals
  • B7-H1 Antigen*
  • Imidazoles*
  • Lysosomes / metabolism
  • Mice
  • Neoplasms* / drug therapy
  • Neoplasms* / metabolism
  • Programmed Cell Death 1 Receptor
  • Pyrroles*


  • benzosceptrin C
  • B7-H1 Antigen
  • Programmed Cell Death 1 Receptor
  • Imidazoles
  • Pyrroles