Covalent Plant Natural Product that Potentiates Antitumor Immunity

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.