5,7,4′‐Trimethoxyflavone triggers cancer cell PD‐L1 ubiquitin–proteasome degradation and facilitates antitumor immunity by targeting HRD1
Jianhua Xia, Mengting Xu, Hongmei Hu, Qing Zhang, Dianping Yu, Minchen Cai, Xiangxin Geng, Hongwei Zhang, Yanyan Zhang, Mengmeng Guo, Lu Dong, Hanchi Xu, Linyang Li, Xing Zhang, Qun Wang, Sanhong Liu, Weidong Zhang
Abstract
Abstract Targeting the programmed cell death 1/programmed cell death ligand 1 (PD‐1/PD‐L1) pathway has been identified as a successful approach for tumor immunotherapy. Here, we identified that the small molecule 5,7,4′‐trimethoxyflavone (TF) from Kaempferia parviflora Wall reduces PD‐L1 expression in colorectal cancer cells and enhances the killing of tumor cells by T cells. Mechanistically, TF targets and stabilizes the ubiquitin ligase HMG‐CoA reductase degradation protein 1 (HRD1), thereby increasing the ubiquitination of PD‐L1 and promoting its degradation through the proteasome pathway. In mouse MC38 xenograft tumors, TF can activate tumor‐infiltrating T‐cell immunity and reduce the immunosuppressive infiltration of myeloid‐derived suppressor cells and regulatory T cells, thus exerting antitumor effects. Moreover, TF synergistically exerts antitumor immunity with CTLA‐4 antibody. This study provides new insights into the antitumor mechanism of TF and suggests that it may be a promising small molecule immune checkpoint modulator for cancer therapy.