2. Academic Validation
  3. Benzosceptrin C induces lysosomal degradation of PD-L1 and promotes antitumor immunity by targeting DHHC3

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

  • Cell Rep Med. 2024 Jan 11:101357. doi: 10.1016/j.xcrm.2023.101357.
Qun Wang 1,  Jinxin Wang 2,  Dianping Yu 1,  Qing Zhang 1,  Hongmei Hu 1,  Mengting Xu 1,  Hongwei Zhang 1,  Saisai Tian 2,  Guangyong Zheng 1,  Dong Lu 1,  Jiajia Hu 3,  Mengmeng Guo 1,  Minchen Cai 1,  Xiangxin Geng 1,  Yanyan Zhang 1,  Jianhua Xia 1,  Xing Zhang 1,  Ang Li 4,  Sanhong Liu 5,  Weidong Zhang 6
Affiliations

Affiliations

  • 1 Shanghai Frontiers Science Center of TCM Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
  • 2 Department of Phytochemistry, School of Pharmacy, Second Military Medical University, Shanghai, China.
  • 3 Department of Nuclear Medicine, Ruijin Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, China.
  • 4 State Key Laboratory of Bioorganic and Natural Products Chemistry, Center for Excellence in Molecular Synthesis, Shanghai Institute of Organic Chemistry, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China.
  • 5 Shanghai Frontiers Science Center of TCM Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, China. Electronic address: liush@shutcm.edu.cn.
  • 6 Shanghai Frontiers Science Center of TCM Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, China; Department of Phytochemistry, School of Pharmacy, Second Military Medical University, Shanghai, China; Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China; The Research Center for Traditional Chinese Medicine, Shanghai Institute of Infectious Diseases and Biosafety, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, China. Electronic address: wdzhangy@hotmail.com.
PMID: 38237597 DOI: 10.1016/j.xcrm.2023.101357
Abstract

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.

Figures
Products
嗨！很高兴为您提供帮助！

尊敬的 MCE 客户您好，
请您选择所在区域，我们将转接对应客服为您服务！

热门区域

A

B

C

F

G

H

J

L

N

Q

S

T

X

Y

Z

热 A B C F G H J L N Q S T X Y Z