2. Academic Validation
  3. Covalent Plant Natural Product that Potentiates Antitumor Immunity

Covalent Plant Natural Product that Potentiates Antitumor Immunity

  • J Am Chem Soc. 2025 Jan 22;147(3):2902-2912. doi: 10.1021/jacs.4c17837.
Misao Takemoto 1,  Sara Delghandi 2,  Masahiro Abo 1,  Keiko Yurimoto 2,  Minami Odagi 3,  Vaibhav Pal Singh 1,  Jun Wang 2,  Reiko Nakagawa 4,  Shin-Ichi Sato 1,  Yasushi Takemoto 1,  Asmaa M A S Farrag 1,  Yoshimasa Kawaguchi 1,  Kazuo Nagasawa 3,  Tasuku Honjo 2,  Kenji Chamoto 2 5,  Motonari Uesugi 1 6 7
Affiliations

Affiliations

  • 1 Division of Biochemistry, Institute for Chemical Research (ICR), Kyoto University, Uji, Kyoto 611-0011, Japan.
  • 2 Department of Immunology and Genomic Medicine, Center for Cancer Immunotherapy and Immunobiology, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan.
  • 3 Department of Biotechnology and Life Science, Graduate School of Technology, Tokyo University of Agriculture and Technology, Koganei, Tokyo 184-8588, Japan.
  • 4 Laboratory for Cell-Free Protein Synthesis, RIKEN Center for Biosystems Dynamics Research, Kobe, Hyogo 650-0047, Japan.
  • 5 Department of Immuno-Oncology PDT, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan.
  • 6 Institute for Integrated Cell-Material Sciences (WPI-iCeMS), Kyoto University, Kyoto 606-8372, Japan.
  • 7 School of Pharmacy, Fudan University, Shanghai 201203, China.
PMID: 39794153 DOI: 10.1021/jacs.4c17837
Abstract

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

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