5,7,4′‐Trimethoxyflavone triggers cancer cell PD‐L1 ubiquitin–proteasome degradation and facilitates antitumor immunity by targeting HRD1

• Published in: MedComm (2020) 2024-07, Vol.5 (7), p.e611-n/a
• Main Authors: Xia, Jianhua, Xu, Mengting, Hu, Hongmei, Zhang, Qing, Yu, Dianping, Cai, Minchen, Geng, Xiangxin, Zhang, Hongwei, Zhang, Yanyan, Guo, Mengmeng, Lu, Dong, Xu, Hanchi, Li, Linyang, Zhang, Xing, Wang, Qun, Liu, Sanhong, Zhang, Weidong
• Format: Article
• Language: English
• Subjects: 5,7,4′‐trimethoxyflavone; Colorectal cancer; HRD1; Original; PD‐L1
• ISSN: 2688-2663; 2688-2663
• DOI: 10.1002/mco2.611

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. A brief description of the role of TF in promoting PD‐L1 degradation in colorectal cancer (CRC). TF binds specifically to and stably expresses HRD1, thereby increasing the ubiquitination of PD‐L1 and leading to its degradation via the proteasome, which enhances T cell activity and activates the tumor immune microenvironment.