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

Area of Science:

• Immunology
• Pharmacology
• Oncology

Background:

• The programmed death-1 (PD-1)/programmed cell death ligand-1 (PD-L1) pathway is a key target in cancer immunotherapy.
• Small molecules offer a promising approach to modulate this axis for enhanced therapeutic effects.

Purpose of the Study:

• To investigate the potential of the natural product oridonin as a small molecule inhibitor of the PD-1/PD-L1 axis.
• To elucidate the antitumor mechanisms of oridonin, focusing on PD-L1 modulation.

Main Methods:

• Assessed oridonin's effect on PD-L1 expression in various cancer cell lines.
• Evaluated oridonin's impact on T-cell cytotoxicity and tumor microenvironment composition.
• Investigated the molecular mechanisms underlying oridonin-induced PD-L1 downregulation, including NLRP3 degradation and STAT3 inhibition.
• Tested oridonin's efficacy in a murine B16F10 melanoma model.

Main Results:

• Oridonin significantly reduced PD-L1 abundance in cancer cells and enhanced T-cell cytotoxicity at submicromolar concentrations.
• Mechanistically, oridonin induced PD-L1 downregulation via proteasomal degradation of NLRP3 and STAT3 inhibition.
• In vivo, oridonin promoted cytotoxic T-cell infiltration, reduced regulatory T cells (Tregs), and suppressed tumor growth.
• Oridonin demonstrated effective tumor inhibition by modulating PD-L1 protein expression, distinct from its direct cytotoxic effects.

Conclusions:

• Oridonin exhibits a novel antitumor mechanism by downregulating PD-L1 expression and modulating the tumor immune microenvironment.
• Oridonin represents a potential lead compound for developing novel small molecule PD-L1 modulators for cancer immunotherapy.