The cyclic guanosine monophosphate-adenosine monophosphate synthase and the stimulator of interferon genes(cGAS-STING)has emerged as a promising target for cancer immunotherapy.However,the development of natural STING...The cyclic guanosine monophosphate-adenosine monophosphate synthase and the stimulator of interferon genes(cGAS-STING)has emerged as a promising target for cancer immunotherapy.However,the development of natural STING agonists is impeded by several challenges,including limited biostability,poor pharmacokinetics,and inefficient cytosolic delivery.Herein,we meticulously designed a doublelayer polyethylenimine(PEI)modified nanoscale covalent organic polymer(CPGP)for efficient delivery of 23cyclic guanosine monophosphate-adenosine monophosphate(cGAMP),a natural STING agonist.The double-layer PEI structured CPGP enhanced both the loading capacity and stability of cGAMP.Furthermore,CPGP improved the intracellular delivery efficiency and amplified the activation of STING pathway for the secretion of type-I interferon and pro-inflammatory cytokines.In contrast,single-layered nanoparticles failed to permit stable loading and intracellular delivery of cGAMP for immune response.The nano-STING agonist also mitigated the immunosuppressive tumor microenvironment(TME)by reducing regulatory T cells and polarizing M2 macrophages to the M1 phenotype,thereby creating an immune-supportive TME to enhance adaptive immune responses.The combination of CPGP and immune checkpoint blockers showed synergistic effect,further enhancing the inhibition effect on tumor growth.This double-layer PEI modified CPGP may offer a generalizable platform for other natural dinucleotide STING agonists to overcome the cascade delivery barriers,augmenting immune activation for tumor immunotherapy.展开更多
The intricate interplay between the human immune system and cancer development underscores the central role of immunotherapy in cancer treatment.Within this landscape,the innate immune system,a critical sentinel prote...The intricate interplay between the human immune system and cancer development underscores the central role of immunotherapy in cancer treatment.Within this landscape,the innate immune system,a critical sentinel protecting against tumor incursion,is a key player.The cyclic GMP-AMP synthase(c GAS)and stimulator of interferon genes(STING)pathway has been found to be a linchpin of innate immunity:activation of this signaling pathway orchestrates the production of type I interferon(IFN-α/β),thus fostering the maturation,differentiation,and mobilization of immune effectors in the tumor microenvironment.Furthermore,STING activation facilitates the release and presentation of tumor antigens,and therefore is an attractive target for cancer immunotherapy.Current strategies to activate the STING pathway,including use of pharmacological agonists,have made substantial advancements,particularly when combined with immune checkpoint inhibitors.These approaches have shown promise in preclinical and clinical settings,by enhancing patient survival rates.This review describes the evolving understanding of the c GAS-STING pathway's involvement in tumor biology and therapy.Moreover,this review explores classical and non-classical STING agonists,providing insights into their mechanisms of action and potential for optimizing immunotherapy strategies.Despite challenges and complexities,the c GAS-STING pathway,a promising avenue for enhancing cancer treatment efficacy,has the potential to revolutionize patient outcomes.展开更多
The stimulator of interferon genes(STING)shows promising clinical activity in infectious diseases and tumors.However,the lack of targeting capability and intracellular stability of STING agonists severely limits the t...The stimulator of interferon genes(STING)shows promising clinical activity in infectious diseases and tumors.However,the lack of targeting capability and intracellular stability of STING agonists severely limits the therapeutic efficacy.Recently,drug delivery systems(DDSs)overcome these delivery barriers of STING agonists via passive or active cell targeting,prolonged blood circulation and drug release,and lysosome escape,etc.In this review,we will describe in detail how existing DDSs are designed to overcome delivery barriers and activate the STING pathway,and the current biomedical applications of STING-activating DDSs in the treatments of infectious diseases and tumors.Finally,the prospects and challenges of DDSs in STING activation are discussed.展开更多
The clinical use of cancer vaccines is hampered by the low magnitude of induced T-cell responses and the need for repetitive antigen stimulation.Here,we demonstrate that liposomal formulations with incorporated STING ...The clinical use of cancer vaccines is hampered by the low magnitude of induced T-cell responses and the need for repetitive antigen stimulation.Here,we demonstrate that liposomal formulations with incorporated STING agonists are optimally suited to deliver peptide antigens to dendritic cells in vivo and to activate dendritic cells in secondary lymphoid organs.One week after liposomal priming,systemic administration of peptides and a costimulatory agonistic CD40 antibody enables ultrarapid expansion of T cells,resulting in massive expansion of tumor-specific T cells in the peripheral blood two weeks after priming.In the MC-38 colon cancer model,this synthetic prime-boost regimen induces rapid regression and cure of large established subcutaneous cancers via the use of a single tumor-specific neoantigen.These experiments demonstrate the feasibility of liposome-based heterologous vaccination regimens to increase the therapeutic efficacy of peptide vaccines in the context of immunogenic adjuvants and costimulatory booster immunizations.Our results provide a rationale for the further development of modern liposomal peptide vaccines for cancer therapy.展开更多
As a key sensor of double-stranded DNA(dsDNA),cyclic GMP-AMP synthase(cGAS)detects cytosolic dsDNA and initiates the synthesis of 2′3′cyclic GMP-AMP(cGAMP)that activates the stimulator of interferon genes(STING).Thi...As a key sensor of double-stranded DNA(dsDNA),cyclic GMP-AMP synthase(cGAS)detects cytosolic dsDNA and initiates the synthesis of 2′3′cyclic GMP-AMP(cGAMP)that activates the stimulator of interferon genes(STING).This finally promotes the production of type I interferons(IFN-I)that is crucial for bridging innate and adaptive immunity.Recent evidence show that several antitumor therapies,including radiotherapy(RT),chemotherapy,targeted therapies and immunotherapies,activate the cGAS-STING pathway to provoke the antitumor immunity.In the last decade,the development of STING agonists has been a major focus in both basic research and the pharmaceutical industry.However,up to now,none of STING agonists have been approved for clinical use.Considering the broad expression of STING in whole body and the direct lethal effect of STING agonists on immune cells in the draining lymph node(dLN),research on the optimal way to activate STING in tumor microenvironment(TME)appears to be a promising direction.Moreover,besides enhancing IFN-I signaling,the cGAS-STING pathway also plays roles in senescence,autophagy,apoptosis,mitotic arrest,and DNA repair,contributing to tumor development and metastasis.In this review,we summarize the recent advances on cGAS-STING pathway’s response to antitumor therapies and the strategies involving this pathway for tumor treatment.展开更多
Cyclic dinucleotides(CDNs)as stimulator of interferon genes(STING)agonists capable of inducing strong antitumor innate immune response are highly promising for tumor immunotherapy.The efficacy of these CDNs is,however...Cyclic dinucleotides(CDNs)as stimulator of interferon genes(STING)agonists capable of inducing strong antitumor innate immune response are highly promising for tumor immunotherapy.The efficacy of these CDNs is,however,reduced greatly by their fast clearance,poor cell uptake and inefficient cytosolic transportation.Here,we report that reduction-responsive biodegradable chimaeric polymersomes(CPs)markedly enhance tumor retention and cytosolic delivery of a synthetic CDN,ADU-S100,and bolster STING pathway activation in the tumor microenvironment and tumor draining lymph nodes,giving significantly better tumor repression and survival of B16F10 melanoma-bearing mice compared with free CDN control.The superiority of CPs-mediated CDN delivery is further verified in combination therapy with low-dose fractionated radiation,which brings about clearly stronger and longer-term immunotherapeutic effects and protection against tumor re-challenge.The development of nano-STING agonists that are able to overcome the delivery barriers of CDNs represents an effective strategy to potentiate cancer immunotherapy.展开更多
Breast cancer is the most prevalent and lethal malignancy among females,with a critical need for safer and less invasive treatments.Photodynamic therapy(PDT)can effectively eliminate tumor cells with minimal side effe...Breast cancer is the most prevalent and lethal malignancy among females,with a critical need for safer and less invasive treatments.Photodynamic therapy(PDT)can effectively eliminate tumor cells with minimal side effects.Furthermore,the combination of PDT and immunotherapy using nanoparticles has shown promise in treating both primary and distant metastatic tumor cells.Therefore,this study proposes applying the PDT-immunotherapy combination to breast cancer treatment.However,the low immunogenicity characteristic of“cold”tumors in part of breast cancer significantly diminishes therapeutic efficacy.To address this challenge,here,a nano-gel system(designated as HCSC-gel)is constructed,which co-delivers a mitochondria-targeted photosensitizer and a STING agonist,capable of robustly activating“cold”tumor immunity.This system is further enhanced by collagenase(CN)to improve therapeutic outcomes.Upon injection into the primary tumor site,HCSC-gel rapidly forms a gel matrix,releasing CN to degrade the tumor extracellular matrix and facilitate the penetration of photosensitizers,STING agonists,and oxygen into the tumor tissue.Under laser irradiation,PDT and STING-mediated immune responses are activated,reversing the low immunogenicity of breast cancer and effectively treating both primary and metastatic lesions.This HCSC-gel nano hydrogel delivery platform is anticipated to provide novel insights for the clinical management of breast cancer and other low immunogenic“cold”tumors,offering significant benefits to patients.展开更多
Immunotherapy is emerging as a powerful tool for combating many human diseases.However,the application of this life-saving treatment in serious brain diseases,including glioma,is greatly restricted.The major obstacle ...Immunotherapy is emerging as a powerful tool for combating many human diseases.However,the application of this life-saving treatment in serious brain diseases,including glioma,is greatly restricted.The major obstacle is the lack of effective technologies for transporting therapeutic agents across the blood-brain barrier(BBB)and achieving targeted delivery to specific cells once across the BBB.Ferritin,an iron storage protein,traverses the BBB via receptor-mediated transcytosis by binding to transferrin receptor 1(TfR1)overexpressed on BBB endothelial cells.Here,we developed bioengineered ferritin nanoparticles as drug delivery carriers that enable the targeted delivery of a small-molecule immunomodulator to achieve enhanced immunotherapeutic efficacy in an orthotopic glioma-bearing mouse model.We fused different glioma-targeting moieties on self-assembled ferritin nanoparticles via genetic engineering,and RGE fusion protein nanoparticles(RGE-HFn NPs)were identified as the best candidate.Furthermore,RGE-HFn NPs encapsulating a stimulator of interferon genes(STING)agonist(SR717@RGE-HFn NPs)maintained stable self-assembled structure and targeting properties even after traversing the BBB.In the glioma-bearing mouse model,SR717@RGE-HFn NPs elicited a potent local innate immune response in the tumor microenvironment,resulting in significant tumor growth inhibition and prolonged survival.Overall,this biomimetic brain delivery platform offers new opportunities to overcome the BBB and provides a promising approach for brain drug delivery and immunotherapy in patients with glioma.展开更多
Stimulator of interferon genes,namely STING,an adaptor protein located in the endoplasmic reticulum,has been recognized as a shining target for cancer and infection research.However,STING agonists cyclic dinucleotides...Stimulator of interferon genes,namely STING,an adaptor protein located in the endoplasmic reticulum,has been recognized as a shining target for cancer and infection research.However,STING agonists cyclic dinucleotides(CDNs)have shown almost zero efficacy in phase I clinical trials as a monotherapy,likely due to poor cellular permeability and rapid diffusion despite intratumoral injection.These deficiencies further affect other applications of CDNs,such as pandemic SARS-CoV-2 prevention and therapy.Here,we rationally design a supramolecular cytosolic delivery system based on controllable recognition of calixarene,namely CASTING(CAlixarene-STING),to improve CDN druggability,including degradation stability,cellular permeability,and tissue retention.CASTING efficiently enhances the immunostimulatory potency of CDGSF[a chemically modified cyclic di-GMP(CDG)]to generate an immunogenic microenvironment for melanoma regression,anti-PD-1 response rate increase,and durable memory formation against tumor recurrence.More importantly,CASTING displays a superior adjuvant activity on SARSCoV-2 recombinant spike/receptor binding domain vaccines,inducing robust and coordinated T-cell and antibody responses against SARS-CoV-2 infection in vivo.Collectively,the CASTING design represents an innovative advancement to facilitate the clinical translational capability of STING agonists.展开更多
基金supported by the Beijing Natural Science Foundation(No.Z230021)the National Natural Science Foundation of China(No.52202356)+1 种基金the Non-profit Central Research Institute Fund of Chinese Academy of Medical Sciences(No.2021-RC350-001)the CAMS Innovation Fund for Medical Sciences(No.2022-I2M-1-013).
文摘The cyclic guanosine monophosphate-adenosine monophosphate synthase and the stimulator of interferon genes(cGAS-STING)has emerged as a promising target for cancer immunotherapy.However,the development of natural STING agonists is impeded by several challenges,including limited biostability,poor pharmacokinetics,and inefficient cytosolic delivery.Herein,we meticulously designed a doublelayer polyethylenimine(PEI)modified nanoscale covalent organic polymer(CPGP)for efficient delivery of 23cyclic guanosine monophosphate-adenosine monophosphate(cGAMP),a natural STING agonist.The double-layer PEI structured CPGP enhanced both the loading capacity and stability of cGAMP.Furthermore,CPGP improved the intracellular delivery efficiency and amplified the activation of STING pathway for the secretion of type-I interferon and pro-inflammatory cytokines.In contrast,single-layered nanoparticles failed to permit stable loading and intracellular delivery of cGAMP for immune response.The nano-STING agonist also mitigated the immunosuppressive tumor microenvironment(TME)by reducing regulatory T cells and polarizing M2 macrophages to the M1 phenotype,thereby creating an immune-supportive TME to enhance adaptive immune responses.The combination of CPGP and immune checkpoint blockers showed synergistic effect,further enhancing the inhibition effect on tumor growth.This double-layer PEI modified CPGP may offer a generalizable platform for other natural dinucleotide STING agonists to overcome the cascade delivery barriers,augmenting immune activation for tumor immunotherapy.
基金the National Key Research and Development Program of China(Grant Nos.2022YFC3401500 and 2020YFA0803201 to P.W.,and 2021YFA1302200 to L.F.)the National Natural Science Foundation of China(Grant Nos.31830053,31920103007,and 82341028 to P.W.+1 种基金82122056,82073153,and 31871398 to L.F.and 31900568 to P.W.)the Natural Science Foundation of Shanghai(Grant No.22ZR1450700 to Z.J.W.)。
文摘The intricate interplay between the human immune system and cancer development underscores the central role of immunotherapy in cancer treatment.Within this landscape,the innate immune system,a critical sentinel protecting against tumor incursion,is a key player.The cyclic GMP-AMP synthase(c GAS)and stimulator of interferon genes(STING)pathway has been found to be a linchpin of innate immunity:activation of this signaling pathway orchestrates the production of type I interferon(IFN-α/β),thus fostering the maturation,differentiation,and mobilization of immune effectors in the tumor microenvironment.Furthermore,STING activation facilitates the release and presentation of tumor antigens,and therefore is an attractive target for cancer immunotherapy.Current strategies to activate the STING pathway,including use of pharmacological agonists,have made substantial advancements,particularly when combined with immune checkpoint inhibitors.These approaches have shown promise in preclinical and clinical settings,by enhancing patient survival rates.This review describes the evolving understanding of the c GAS-STING pathway's involvement in tumor biology and therapy.Moreover,this review explores classical and non-classical STING agonists,providing insights into their mechanisms of action and potential for optimizing immunotherapy strategies.Despite challenges and complexities,the c GAS-STING pathway,a promising avenue for enhancing cancer treatment efficacy,has the potential to revolutionize patient outcomes.
基金This work is financially supported by National Key R&D Program of China(No.2018YFA0704000)National Natural Science Foundation of China(No.82071985)+3 种基金Basic Research Program of Shenzhen(Nos.JCYJ20180507182413022,JCYJ20170412111100742)Guangdong Province Natural Science Foundation of Major Basic Research and Cultivation Project(No.2018B030308003)Shenzhen Science and Technology Program(No.KQTD20190929172538530)the Fok Ying-Tong Education Foundation for Young Teachers in the Higher Education Institutions of China(No.161032).
文摘The stimulator of interferon genes(STING)shows promising clinical activity in infectious diseases and tumors.However,the lack of targeting capability and intracellular stability of STING agonists severely limits the therapeutic efficacy.Recently,drug delivery systems(DDSs)overcome these delivery barriers of STING agonists via passive or active cell targeting,prolonged blood circulation and drug release,and lysosome escape,etc.In this review,we will describe in detail how existing DDSs are designed to overcome delivery barriers and activate the STING pathway,and the current biomedical applications of STING-activating DDSs in the treatments of infectious diseases and tumors.Finally,the prospects and challenges of DDSs in STING activation are discussed.
基金supported by a grant from the Deutsche Forschungsgemeinschaft(SFB TR209,Project C05)TCW holds the patent(Nr.:M1073PCT-EP)on the here described vaccination method.
文摘The clinical use of cancer vaccines is hampered by the low magnitude of induced T-cell responses and the need for repetitive antigen stimulation.Here,we demonstrate that liposomal formulations with incorporated STING agonists are optimally suited to deliver peptide antigens to dendritic cells in vivo and to activate dendritic cells in secondary lymphoid organs.One week after liposomal priming,systemic administration of peptides and a costimulatory agonistic CD40 antibody enables ultrarapid expansion of T cells,resulting in massive expansion of tumor-specific T cells in the peripheral blood two weeks after priming.In the MC-38 colon cancer model,this synthetic prime-boost regimen induces rapid regression and cure of large established subcutaneous cancers via the use of a single tumor-specific neoantigen.These experiments demonstrate the feasibility of liposome-based heterologous vaccination regimens to increase the therapeutic efficacy of peptide vaccines in the context of immunogenic adjuvants and costimulatory booster immunizations.Our results provide a rationale for the further development of modern liposomal peptide vaccines for cancer therapy.
基金supported by National Key Research and Development Program of China 2023YFC3404600National Natural Science Foundation of China grant(82371848)。
文摘As a key sensor of double-stranded DNA(dsDNA),cyclic GMP-AMP synthase(cGAS)detects cytosolic dsDNA and initiates the synthesis of 2′3′cyclic GMP-AMP(cGAMP)that activates the stimulator of interferon genes(STING).This finally promotes the production of type I interferons(IFN-I)that is crucial for bridging innate and adaptive immunity.Recent evidence show that several antitumor therapies,including radiotherapy(RT),chemotherapy,targeted therapies and immunotherapies,activate the cGAS-STING pathway to provoke the antitumor immunity.In the last decade,the development of STING agonists has been a major focus in both basic research and the pharmaceutical industry.However,up to now,none of STING agonists have been approved for clinical use.Considering the broad expression of STING in whole body and the direct lethal effect of STING agonists on immune cells in the draining lymph node(dLN),research on the optimal way to activate STING in tumor microenvironment(TME)appears to be a promising direction.Moreover,besides enhancing IFN-I signaling,the cGAS-STING pathway also plays roles in senescence,autophagy,apoptosis,mitotic arrest,and DNA repair,contributing to tumor development and metastasis.In this review,we summarize the recent advances on cGAS-STING pathway’s response to antitumor therapies and the strategies involving this pathway for tumor treatment.
基金supported by research grants from the National Natural Science Foundation of China(NSFC 52033006,51861145310,51773146 and 51633005)and the National Key R&D Program of China(2021YFB3800900).
文摘Cyclic dinucleotides(CDNs)as stimulator of interferon genes(STING)agonists capable of inducing strong antitumor innate immune response are highly promising for tumor immunotherapy.The efficacy of these CDNs is,however,reduced greatly by their fast clearance,poor cell uptake and inefficient cytosolic transportation.Here,we report that reduction-responsive biodegradable chimaeric polymersomes(CPs)markedly enhance tumor retention and cytosolic delivery of a synthetic CDN,ADU-S100,and bolster STING pathway activation in the tumor microenvironment and tumor draining lymph nodes,giving significantly better tumor repression and survival of B16F10 melanoma-bearing mice compared with free CDN control.The superiority of CPs-mediated CDN delivery is further verified in combination therapy with low-dose fractionated radiation,which brings about clearly stronger and longer-term immunotherapeutic effects and protection against tumor re-challenge.The development of nano-STING agonists that are able to overcome the delivery barriers of CDNs represents an effective strategy to potentiate cancer immunotherapy.
基金supported by the National Natural Science Foundation of China(32360237,82402823,81860543)Guizhou Provincial Science and Technology Projects(ZK[2023]Key Project 041)+1 种基金Science and Technology Fund Project of the Guizhou Provincial Health Commission(gzwkj2022-223)Cultivation Program of the Affiliated Hospital of Guizhou Medical University(gyfynsfc-2022-39).
文摘Breast cancer is the most prevalent and lethal malignancy among females,with a critical need for safer and less invasive treatments.Photodynamic therapy(PDT)can effectively eliminate tumor cells with minimal side effects.Furthermore,the combination of PDT and immunotherapy using nanoparticles has shown promise in treating both primary and distant metastatic tumor cells.Therefore,this study proposes applying the PDT-immunotherapy combination to breast cancer treatment.However,the low immunogenicity characteristic of“cold”tumors in part of breast cancer significantly diminishes therapeutic efficacy.To address this challenge,here,a nano-gel system(designated as HCSC-gel)is constructed,which co-delivers a mitochondria-targeted photosensitizer and a STING agonist,capable of robustly activating“cold”tumor immunity.This system is further enhanced by collagenase(CN)to improve therapeutic outcomes.Upon injection into the primary tumor site,HCSC-gel rapidly forms a gel matrix,releasing CN to degrade the tumor extracellular matrix and facilitate the penetration of photosensitizers,STING agonists,and oxygen into the tumor tissue.Under laser irradiation,PDT and STING-mediated immune responses are activated,reversing the low immunogenicity of breast cancer and effectively treating both primary and metastatic lesions.This HCSC-gel nano hydrogel delivery platform is anticipated to provide novel insights for the clinical management of breast cancer and other low immunogenic“cold”tumors,offering significant benefits to patients.
基金funded by the Interdisciplinary Program of Shanghai Jiao Tong University(project number ZH2018ZDA36(19X190020006))Shanghai Jiao Tong University Scientific and Technological Innovation Funds(2019TPA10)+1 种基金the Foundation of National Facility for Translational Medicine(Shanghai)(TMSK-2020-008).X.X.acknowledges support from the National Science Foundation(2001606)the Gustavus and Louise Pfeiffer Research Foundation Award.We greatly thank Xiyun Yan(Institute of Biophysics,CAS)for her generous gift of the pET-HFn plasmid.We also thank Kelong Fan(Institute of Biophysics,CAS)for his professional suggestions on protein purification.
文摘Immunotherapy is emerging as a powerful tool for combating many human diseases.However,the application of this life-saving treatment in serious brain diseases,including glioma,is greatly restricted.The major obstacle is the lack of effective technologies for transporting therapeutic agents across the blood-brain barrier(BBB)and achieving targeted delivery to specific cells once across the BBB.Ferritin,an iron storage protein,traverses the BBB via receptor-mediated transcytosis by binding to transferrin receptor 1(TfR1)overexpressed on BBB endothelial cells.Here,we developed bioengineered ferritin nanoparticles as drug delivery carriers that enable the targeted delivery of a small-molecule immunomodulator to achieve enhanced immunotherapeutic efficacy in an orthotopic glioma-bearing mouse model.We fused different glioma-targeting moieties on self-assembled ferritin nanoparticles via genetic engineering,and RGE fusion protein nanoparticles(RGE-HFn NPs)were identified as the best candidate.Furthermore,RGE-HFn NPs encapsulating a stimulator of interferon genes(STING)agonist(SR717@RGE-HFn NPs)maintained stable self-assembled structure and targeting properties even after traversing the BBB.In the glioma-bearing mouse model,SR717@RGE-HFn NPs elicited a potent local innate immune response in the tumor microenvironment,resulting in significant tumor growth inhibition and prolonged survival.Overall,this biomimetic brain delivery platform offers new opportunities to overcome the BBB and provides a promising approach for brain drug delivery and immunotherapy in patients with glioma.
基金supported by the National Key R&D Program of China(nos.2019YFA0904200 and 2018YFA0507600)the Tsinghua University Spring Breeze Fund(no.2020Z99CFY042)+1 种基金the National Natural Science Foundation of China(nos.92053108 and 31961143004)NCC Fund(no.NCC2020FH04).
文摘Stimulator of interferon genes,namely STING,an adaptor protein located in the endoplasmic reticulum,has been recognized as a shining target for cancer and infection research.However,STING agonists cyclic dinucleotides(CDNs)have shown almost zero efficacy in phase I clinical trials as a monotherapy,likely due to poor cellular permeability and rapid diffusion despite intratumoral injection.These deficiencies further affect other applications of CDNs,such as pandemic SARS-CoV-2 prevention and therapy.Here,we rationally design a supramolecular cytosolic delivery system based on controllable recognition of calixarene,namely CASTING(CAlixarene-STING),to improve CDN druggability,including degradation stability,cellular permeability,and tissue retention.CASTING efficiently enhances the immunostimulatory potency of CDGSF[a chemically modified cyclic di-GMP(CDG)]to generate an immunogenic microenvironment for melanoma regression,anti-PD-1 response rate increase,and durable memory formation against tumor recurrence.More importantly,CASTING displays a superior adjuvant activity on SARSCoV-2 recombinant spike/receptor binding domain vaccines,inducing robust and coordinated T-cell and antibody responses against SARS-CoV-2 infection in vivo.Collectively,the CASTING design represents an innovative advancement to facilitate the clinical translational capability of STING agonists.
