Oridonin downregulates PD-L1 expression and promotes anti-tumor immunity via inhibiting NLRP3 and STAT3.

Blocking the programmed death-1 (PD-1)/programmed cell death ligand-1(PD-L1) axis has become an attractive treatment strategy for cancer immunotherapy. Small molecules are promising agents for targeting the PD-1/PD-L1 axis to enhance immunotherapy. Here, we identified a natural product, oridonin, that can significantly reduce the abundance of PD-L1 in various cancer cells and enhance the cytotoxicity of stimulated Jurkat T-cells against cancer cells at submicromolar levels. Mechanistic studies showed that oridonin-induced PD-L1 downregulation was involved in the degradation of NLRP3 through the proteasome and inhibition of STAT3. In addition, oridonin recruited the cytotoxic T cells and reduced regulatory T cells (Tregs) in the tumor microenvironment, and reduced the expression of tumor PD-L1 protein, thereby effectively inhibiting the growth of subcutaneous B16F10 tumors in C57BL/6 mice. Unlike previous studies that focused on the direct cytotoxicity of oridonin on tumor cells, our results demonstrated that oridonin could also inhibit tumor growth at lower concentrations by modulating PD-L1 protein. This study revealed an undescribed antitumor mechanism of oridonin and suggested that oridonin is a potential lead compound for developing new type small molecule PD-L1 modulators.