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

#Anti-Human/Mouse CD11b FITC ;  #03221-50 ; 

Cell Rep Med. 2024 Feb 20;5(2):101357.

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 expand

• PMID: 38237597
• PMCID: PMC10897506
• 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.