Covalent Plant Natural Product that Potentiates Antitumor Immunity.

Area of Science:

• Immunology
• Pharmacology
• Natural Products Chemistry

Background:

• Immune checkpoint inhibitors show therapeutic promise but are limited by T cell dysfunction in the tumor microenvironment.
• Small molecule combination therapies face clinical challenges.
• Developing novel strategies to activate antitumor immunity is crucial for cancer treatment.

Purpose of the Study:

• To identify novel activators of antitumor immunity.
• To develop a cell-based system to screen for compounds that can overcome T cell exhaustion in the cancer microenvironment.

Main Methods:

• Cell-based screening of 232 natural products with electrophilic functional groups.
• Chemoproteomic and mechanistic analyses to determine the molecular targets and pathways.
• In vivo studies in mice to evaluate the therapeutic potential in combination with immunotherapy.

Main Results:

• Arvenin I (cucurbitacin B 2-O-β-d-glucoside) was identified as a T cell activator.
• Arvenin I covalently activates MKK3, leading to p38MAPK pathway activation and improved mitochondrial fitness in exhausted T cells.
• Arvenin I enhanced cancer immunotherapy efficacy in mice, both as a monotherapy and in combination with immune checkpoint inhibitors.

Conclusions:

• Arvenin I is a potent covalent kinase activator that revitalizes exhausted T cells.
• Arvenin I demonstrates significant potential for enhancing cancer immunotherapy and boosting antitumor immunity.