Targeting the PD-1/PD-L1 axis with small-molecular inhibitors is a promising approach for immunotherapy.Here,we identify a natural pentacyclic triterpenoid,Pygenic Acid A(PA),as a PD-1 signaling inhibitor.PA exerts an...Targeting the PD-1/PD-L1 axis with small-molecular inhibitors is a promising approach for immunotherapy.Here,we identify a natural pentacyclic triterpenoid,Pygenic Acid A(PA),as a PD-1 signaling inhibitor.PA exerts anti-tumor activity in hPD-1 knock-in C57BL/6 mice and enhances effector functions of T cells to promote immune responses by disrupting the PD-1 signaling transduction.Furthermore,we identify SHP-2 as the direct molecular target of PA for inhibiting the PD-1 signaling transduction.Subsequently,mechanistic studies suggest that PA binds to a new druggable site in the phosphorylated PD-1 ITSM recognition site of SHP-2,inhibiting the recruitment of SHP-2 by PD1.Taken together,our findings demonstrate that PA has a potential application in cancer immunotherapy and occupying the phosphorylated ITSM recognition site of SHP-2 may serve as an alternative strategy to develop PD-1 signaling inhibitors.In addition,our success in target recognition provides a paradigm of target identification and confirmation for natural products.展开更多
基金supported in part by the National Natural Science Foundation of China(81825020,82150208,82260682)the National Key R&D Program of China(2022YFC3400501,2022YFC3400504)+1 种基金the Shanghai Science and Technology Commission Biomedical Science and Technology Support Special Project(21S11907900,20S11901000)Project of Yunnan Characteristic Plant Screening and R&D Service CXO Platform(2022YKZY001).
文摘Targeting the PD-1/PD-L1 axis with small-molecular inhibitors is a promising approach for immunotherapy.Here,we identify a natural pentacyclic triterpenoid,Pygenic Acid A(PA),as a PD-1 signaling inhibitor.PA exerts anti-tumor activity in hPD-1 knock-in C57BL/6 mice and enhances effector functions of T cells to promote immune responses by disrupting the PD-1 signaling transduction.Furthermore,we identify SHP-2 as the direct molecular target of PA for inhibiting the PD-1 signaling transduction.Subsequently,mechanistic studies suggest that PA binds to a new druggable site in the phosphorylated PD-1 ITSM recognition site of SHP-2,inhibiting the recruitment of SHP-2 by PD1.Taken together,our findings demonstrate that PA has a potential application in cancer immunotherapy and occupying the phosphorylated ITSM recognition site of SHP-2 may serve as an alternative strategy to develop PD-1 signaling inhibitors.In addition,our success in target recognition provides a paradigm of target identification and confirmation for natural products.
