Multiple cancer immunotherapies including chimeric antigen receptor T cell and immune checkpoint inhibitors(ICIs)have been successfully developed to treat various cancers by motivating the adaptive anti-tumor immunity...Multiple cancer immunotherapies including chimeric antigen receptor T cell and immune checkpoint inhibitors(ICIs)have been successfully developed to treat various cancers by motivating the adaptive anti-tumor immunity.Particularly,the checkpoint blockade approach has achieved great clinic success as evidenced by several U.S.Food and Drug Administration(FDA)-approved antiprogrammed death receptor 1/ligand 1 or anti-cytotoxic T lymphocyte associated protein 4 antibodies.However,the majority of cancers have low clinical response rates to these ICIs due to poor tumor immunogenicity.Indeed,the cyclic guanosine monophosphate-adenosine monophosphate synthase-stimulator of interferon genes-TANK-binding kinase 1(cGAS-STING-TBK1)axis is now appreciated as the major signaling pathway in innate immune response across different species.Aberrant signaling of this pathway has been closely linked to multiple diseases,including auto-inflammation,virus infection and cancers.In this perspective,we provide an updated review on the latest progress on the development of small molecule modulators targeting the cGAS-STING-TBK1 signaling pathway and their preclinical and clinical use as a new immune stimulatory therapy.Meanwhile,highlights on the clinical candidates,limitations and challenges,as well as future directions in this field are also discussed.Further,small molecule inhibitors targeting this signaling axis and their potential therapeutic use for various indications are discussed as well.展开更多
基金supported by grants from Natural Science Foundation of China(Nos.81773565,21877120,81703327,81430080,81573452,and 81773767,China)Supporting grants from the Key Program of the Frontier Science of the Chinese Academy of Sciences(No.160621,China)+1 种基金the Strategic Priority Research Program of the Chinese Academy of Sciences(No.XDA12020374,China)a start-up grant to the Research Laboratory of Medicinal Chemical Biology&Frontiers on Drug Discovery from Shanghai Jiao Tong University(China)are also appreciated
文摘Multiple cancer immunotherapies including chimeric antigen receptor T cell and immune checkpoint inhibitors(ICIs)have been successfully developed to treat various cancers by motivating the adaptive anti-tumor immunity.Particularly,the checkpoint blockade approach has achieved great clinic success as evidenced by several U.S.Food and Drug Administration(FDA)-approved antiprogrammed death receptor 1/ligand 1 or anti-cytotoxic T lymphocyte associated protein 4 antibodies.However,the majority of cancers have low clinical response rates to these ICIs due to poor tumor immunogenicity.Indeed,the cyclic guanosine monophosphate-adenosine monophosphate synthase-stimulator of interferon genes-TANK-binding kinase 1(cGAS-STING-TBK1)axis is now appreciated as the major signaling pathway in innate immune response across different species.Aberrant signaling of this pathway has been closely linked to multiple diseases,including auto-inflammation,virus infection and cancers.In this perspective,we provide an updated review on the latest progress on the development of small molecule modulators targeting the cGAS-STING-TBK1 signaling pathway and their preclinical and clinical use as a new immune stimulatory therapy.Meanwhile,highlights on the clinical candidates,limitations and challenges,as well as future directions in this field are also discussed.Further,small molecule inhibitors targeting this signaling axis and their potential therapeutic use for various indications are discussed as well.
