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

• Published in: Cell reports. Medicine 2024-02, Vol.5 (2), p.101357-101357, Article 101357
• Main Authors: Wang, Qun, Wang, Jinxin, Yu, Dianping, Zhang, Qing, Hu, Hongmei, Xu, Mengting, Zhang, Hongwei, Tian, Saisai, Zheng, Guangyong, Lu, Dong, Hu, Jiajia, Guo, Mengmeng, Cai, Minchen, Geng, Xiangxin, Zhang, Yanyan, Xia, Jianhua, Zhang, Xing, Li, Ang, Liu, Sanhong, Zhang, Weidong
• Format: Article
• Language: English
• Subjects: Animals; B7-H1 Antigen; benzosceptrin C; cancer immunotherapy; colorectal cancer; DHHC3; Imidazoles; Lysosomes - metabolism; Mice; Neoplasms - drug therapy; Neoplasms - metabolism; PD-L1; Programmed Cell Death 1 Receptor; Pyrroles
• ISSN: 2666-3791; 2666-3791
• DOI: 10.1016/j.xcrm.2023.101357

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. [Display omitted] •Benzosceptrin C promotes PD-L1 degradation in a lysosomal pathway•Inhibition of DHHC3 activity destabilizes PD-L1•Benzosceptrin C enhances the cytotoxicity of T cells•Combination of benzosceptrin C and anti-CTLA4 effectively suppresses tumor growth Wang et al. explored the ability of benzosceptrin C (BC) to reduce PD-L1 expression. Subsequently, DHHC3 was identified as the target protein for BC through methods such as DARTS, CETSA, MST, and molecular docking. BC exerts its antitumor effect on MC38 tumor mice by activating tumor-infiltrating T cell immunity.