Programmed cell death-1 (PD-1)/
programmed cell death ligand-1 (PD-L1) blocking
therapy has become a major pillar of
cancer immunotherapy. Compared with
antibodies targeting, small-molecule checkpoint inhibitors which have favorable
pharmacokinetics are urgently needed. Here we identified
berberine (BBR), a proven anti-
inflammation drug, as a negative regulator of PD-L1 from a set of
traditional Chinese medicine (TCM) chemical monomers. BBR enhanced the
sensitivity of tumour
cells to co-cultured
T-cells by decreasing the level of PD-L1 in
cancer cells. In addition, BBR exerted its antitumor effect in Lewis
tumor xenograft mice through enhancing
tumor-infiltrating
T-cell immunity and attenuating the activation of immunosuppressive
myeloid-derived suppressor cells (
MDSCs) and
regulatory T-cells (Tregs). BBR triggered PD-L1 degradation through
ubiquitin (Ub)/
proteasome-dependent pathway. Remarkably, BBR selectively bound to the
glutamic acid 76 of constitutive photomorphogenic-9 signalosome 5 (CSN5) and inhibited PD-1/PD-L1 axis through its deubiquitination activity, resulting in
ubiquitination and degradation of PD-L1. Our data reveals a previously unrecognized antitumor mechanism of BBR, suggesting BBR is small-molecule immune checkpoint inhibitor for
cancer treatment.