Protein tyrosine phosphatase nonreceptor type 2(PTPN2)is a promising target for sensitizing solid tumors to immune checkpoint blockades.However,the highly polar active sites of PTPN2 hinder drug discovery efforts.Leve...Protein tyrosine phosphatase nonreceptor type 2(PTPN2)is a promising target for sensitizing solid tumors to immune checkpoint blockades.However,the highly polar active sites of PTPN2 hinder drug discovery efforts.Leveraging small interfering RNA(siRNA)technology,we developed a novel glutathione-responsive nano-platform HPssPT(HA/PEIss@siPtpn2)to silence PTPN2 and enhance immunotherapy efficacy in hepatocellular carcinoma(HCC).HPssPT showed potent transfection and favorable safety profiles.PTPN2 deficiency induced by HPssPT amplified the interferon g signaling in HCC cells by increasing the phosphorylation of Janus-activated kinase 1 and signal transducer and activator of transcription 1,resulting in enhanced antigen presentation and T cell activation.The nanoplatform was also able to promote the M1-like polarization of macrophages in vitro.The unique tropism of HPssPT towards tumor-associated macrophages,facilitated by hyaluronic acid coating and CD44 receptor targeting,allowed for simultaneous reprogramming of both tumor cells and tumor-associated macrophages,thereby synergistically reshaping tumor microenvironment to an immunostimulatory state.In HCC,colorectal cancer,and melanoma animal models,HPssPT monotherapy provoked robust antitumor immunity,thereby sensitizing tumors to PD-1 blockade,which provided new inspiration for siRNA-based drug discovery and tumor immunotherapy.展开更多
基金supported by the Natural Science Foundation of Shanghai Science and Technology Innovation Plan(No.22ZR1414100)Oriental Youth Talent Program(to T.Sun,China)+5 种基金Key Special Project of the Ministry of Science and Technology(2023YFC2510000,China)National Natural Science Foundation of China(No.81872808,81972234,82103252,82121002,82173122,and 82273027)Open Grant from the Pingyuan Lab(2023PY-OP-0106,China)Shanghai Municipal Science and Technology Major Project(No.2018SHZDZX01)ZJLab,Shanghai Science and Technology Committee(Nos.20Y11908100,and 22ZR1411800)Shanghai Sailing Program(No.21YF1407400).
文摘Protein tyrosine phosphatase nonreceptor type 2(PTPN2)is a promising target for sensitizing solid tumors to immune checkpoint blockades.However,the highly polar active sites of PTPN2 hinder drug discovery efforts.Leveraging small interfering RNA(siRNA)technology,we developed a novel glutathione-responsive nano-platform HPssPT(HA/PEIss@siPtpn2)to silence PTPN2 and enhance immunotherapy efficacy in hepatocellular carcinoma(HCC).HPssPT showed potent transfection and favorable safety profiles.PTPN2 deficiency induced by HPssPT amplified the interferon g signaling in HCC cells by increasing the phosphorylation of Janus-activated kinase 1 and signal transducer and activator of transcription 1,resulting in enhanced antigen presentation and T cell activation.The nanoplatform was also able to promote the M1-like polarization of macrophages in vitro.The unique tropism of HPssPT towards tumor-associated macrophages,facilitated by hyaluronic acid coating and CD44 receptor targeting,allowed for simultaneous reprogramming of both tumor cells and tumor-associated macrophages,thereby synergistically reshaping tumor microenvironment to an immunostimulatory state.In HCC,colorectal cancer,and melanoma animal models,HPssPT monotherapy provoked robust antitumor immunity,thereby sensitizing tumors to PD-1 blockade,which provided new inspiration for siRNA-based drug discovery and tumor immunotherapy.
