Covalent Plant Natural Product that Potentiates Antitumor Immunity

• DOI: 10.1021/jacs.4c17837
• Publication Date: 2025-01-11T02:43:34Z
• Authors: Misao Takemoto; Sara Delghandi; Masahiro Abo; Keiko Yurimoto; Minami Odagi; Vaibhav Pal Singh; Jun Wang; Reiko Nakagawa; Shin-ichi Sato; Yasushi Takemoto; Asmaa M. A. S. Fa...; Yoshimasa Kawaguchi; Kazuo Nagasawa; Tasuku Honjo; Kenji Chamoto; Motonari Uesugi
• Keywords: Cancer Immunotherapy; Immune checkpoint; Natural product

Despite the unprecedented therapeutic potential of immune checkpoint antibody therapies, their efficacy is limited partly by dysfunction T cells within cancer microenvironment. Combination therapies with small molecules have also been explored, but clinical implementation has met significant challenges. To search for antitumor immunity activators, present study developed a cell-based system that emulates cancer-attenuated cells. The screening 232 natural products containing electrophilic reactive functional groups led to identification arvenin I, known as cucurbitacin B 2-O-β-d-glucoside (CuBg), plant product activates cancer-competitive environment. Chemoproteomic and mechanistic analyses indicated I covalently reacts hyperactivates MKK3, thereby reviving mitochondrial fitness exhausted through activation p38MAPK pathway. In mice, administration enhanced immunotherapy when used alone or in combination an inhibitor. These findings highlight covalent kinase activator potentiates immunity.