The cGAS–STING pathway plays an important role in ischemia-reperfusion injury in the heart,liver,brain,and kidney,but its role and mechanisms in cerebral ischemia-reperfusion injury have not been systematically revie...The cGAS–STING pathway plays an important role in ischemia-reperfusion injury in the heart,liver,brain,and kidney,but its role and mechanisms in cerebral ischemia-reperfusion injury have not been systematically reviewed.Here,we outline the components of the cGAS–STING pathway and then analyze its role in autophagy,ferroptosis,cellular pyroptosis,disequilibrium of calcium homeostasis,inflammatory responses,disruption of the blood–brain barrier,microglia transformation,and complement system activation following cerebral ischemia-reperfusion injury.We further analyze the value of cGAS–STING pathway inhibitors in the treatment of cerebral ischemia-reperfusion injury and conclude that the pathway can regulate cerebral ischemia-reperfusion injury through multiple mechanisms.Inhibition of the cGAS–STING pathway may be helpful in the treatment of cerebral ischemia-reperfusion injury.展开更多
Manganese(Mn)has been characterized as an environmental pollutant.Excessive releases of Mn due to human activities have increased Mn levels in the environment over the years,posing a threat to human health and the env...Manganese(Mn)has been characterized as an environmental pollutant.Excessive releases of Mn due to human activities have increased Mn levels in the environment over the years,posing a threat to human health and the environment.Long-term exposure to high concentrations of Mn can induce neurotoxicity.Therefore,toxicological studies on Mn are of paramount importance.Mn induces oxidative stress through affecting the level of reactive oxygen species(ROS),and the overabundance of ROS further triggers ferroptosis.Additionally,Mn^(2+) was found to be a novel activator of the cyclic guanosine-adenosine synthase(cGAS)−stimulator of interferon genes(STING)pathway in the innateimmune system.Thus,we speculate thatMn exposuremay promote ROS production by activating the cGAS−STING pathway,which further induces oxidative stress and ferroptosis,and ultimately triggers Mn neurotoxicity.This review discusses the mechanism between Mn-induced oxidative stress and ferroptosis via activation of the cGAS−STING pathway,which may offer a prospective direction for future in-depth studies on the mechanism of Mn neurotoxicity.展开更多
Background:Recurrent implantation failure(RIF)is a difficult problem with a multifaceted cause.Recent studies have demonstrated that stimulator of interferon genes-induced immune-related genes(STIRGs)are associated wi...Background:Recurrent implantation failure(RIF)is a difficult problem with a multifaceted cause.Recent studies have demonstrated that stimulator of interferon genes-induced immune-related genes(STIRGs)are associated with immune disorders that may affect the endometrial immune micro-environment.However,the effect of STRIGs on RIF remains unknown.Methods:Training(GSE111974)and validation(GSE106602)cohorts were acquired from the Gene Expression Omnibus database.STIRGs were extracted from the Molecular Signatures Database and relevant studies.Consensus clustering analysis was used to identify RIF molecular subtypes.Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment and immune infiltration analyses were performed between RIF subtypes.Drug-related potential therapeutic target genes were discovered.Results:Two distinct molecular subtypes were discovered in both the training and validation groups according to STIRGs.In subtype C2,there was a notable decrease in the presence of different types of immune cells,such as natural killer cells and macrophages.Furthermore,the examination of Gene Ontology and Kyoto Encyclopedia of Genes and Genomes indicated a decrease in numerous immune-related biological processes within subtype C2.Finally,nine hub genes(CXCR4,POU5F1,PPARG,TLR2,EGFR,CSF1,BCL2A1,BTK,and SRGN)were identified as potential therapeutic targets for RIF.Conclusion:Based on STIRGs,we identified a new molecular subtype with significantly reduced immune infiltration in RIF.Nine genes might be potential therapeutic targets for RIF.展开更多
African swine fever virus(ASFV)is an important pathogen causing acute infectious disease in domestic pigs and wild boars that seriously endangers the global swine industry.As ASFV is structurally complex and encodes a...African swine fever virus(ASFV)is an important pathogen causing acute infectious disease in domestic pigs and wild boars that seriously endangers the global swine industry.As ASFV is structurally complex and encodes a large number of functional proteins,no effective vaccine has been developed to date.Thus,dissecting the mechanisms of immune escape induced by ASFV proteins is crucial.A previous study showed that the ASFV-encoded protein is an important factor in host immunity.In this study,we identified a negative regulator,MGF505-3R,that significantly downregulated cGAS/STING-and poly(dG:dC)-mediated IFN-βand interferon stimulation response element(ISRE)reporter activity and suppressed IFNB1 and IFIT2 mRNA levels.In addition,TBK1,IRF3 and IκBαphosphorylation levels were also inhibited.Mechanistically,MGF505-3R interacted with cGAS/TBK1/IRF3 and targeted TBK1 for degradation,thereby disrupting the cGAS-STING-mediated IFN-βsignaling pathway,which appears to be highly correlated with autophagy.Knockdown MGF505-3R expression enhanced IFN-βand IL-1βproduction.Taken together,our study revealed a negative regulatory mechanism involving the MGF505-3R-cGAS-STING axis and provided insights into an evasion strategy employed by ASFV that involves autophagy and innate signaling pathways.展开更多
Radiotherapy(RT)is a widely used cancer treatment,and the use of metal-based nano-radiotherapy sensitizers has shown promise in enhancing its efficacy.However,efficient accumulation and deep penetration of these sensi...Radiotherapy(RT)is a widely used cancer treatment,and the use of metal-based nano-radiotherapy sensitizers has shown promise in enhancing its efficacy.However,efficient accumulation and deep penetration of these sensitizers within tumors remain challenging.In this study,we present the development of bismuth/manganese biomineralized nanoparticles(Bi Mn/BSA)with multiple radiosensitizing mechanisms,including high atomic number element-mediated radiation capture,catalase-mimic oxygenation,and activation of the stimulator of interferon genes(STING)pathway.Significantly,we demonstrate that low-dose RT induces the recruitment of macrophages and subsequent upregulation of Matrix metalloproteinases(MMP)-2 and MMP-9 that degrade the extracellular matrix(ECM).This dynamic process facilitates the targeted delivery and deep penetration of Bi Mn/BSA nanoparticles within tumors,thereby enhancing the effectiveness of RT.By combining low-dose RT with Bi Mn/BSA nanoparticles,we achieved complete suppression of tumor growth in mice with excellent biocompatibility.This study provides a novel and clinically relevant strategy for targeted nanoparticle delivery to tumors,and establishes a safe and effective sequential radiotherapy approach for cancer treatment.These findings hold great promise for improving the outcomes of RT and advancing the field of nanomedicine in cancer therapy.展开更多
Although cancer immunotherapy has made great strides in the clinic,it is still hindered by the tumor immunosuppressive microenvironment(TIME).The stimulator of interferon genes(STING)pathway which can modulate TIME ef...Although cancer immunotherapy has made great strides in the clinic,it is still hindered by the tumor immunosuppressive microenvironment(TIME).The stimulator of interferon genes(STING)pathway which can modulate TIME effectively has emerged as a promising therapeutic recently.However,the delivery of most STING agonists,specifically cyclic dinucleotides(CDNs),is performed intratumorally due to their insufficient pharmacological properties,such as weak permeability across cell membranes and vulnerability to nuclease degradation.To expand the clinical applicability of CDNs,a novel pH-sensitive polycationic polymer-modified lipid nanoparticle(LNP-B)system was developed for intravenous delivery of CDNs.LNP-B significantly extended the circulation of CDNs and enhanced the accumulation of CDNs within the tumor,spleen,and tumor-draining lymph nodes compared with free CDNs thereby triggering the STING pathway of dendritic cells and repolarizing pro-tumor macrophages.These events subsequently gave rise to potent anti-tumor immune reactions and substantial inhibition of tumors in CT26 colon cancer-bearing mouse models.In addition,due to the acid-sensitive property of the polycationic polymer,the delivery system of LNP-B was more biocompatible and safer compared with lipid nanoparticles formulated with an indissociable cationic DOTAP(LNP-D).These findings suggest that LNP-B has great potential in the intravenous delivery of CDNs for tumor immunotherapy.展开更多
Recently,nanovaccine-based immunotherapy has been robustly investigated due to its potential in governing the immune response and generating long-term protective immunity.However,the presentation of a tumor peptide-ma...Recently,nanovaccine-based immunotherapy has been robustly investigated due to its potential in governing the immune response and generating long-term protective immunity.However,the presentation of a tumor peptide-major histocompatibility complex to T lymphocytes is still a challenge that needs to be addressed for eliciting potent antitumor immunity.Type 1 conventional dendritic cell(cDC1)subset is of particular interest due to its pivotal contribution in the cross-presentation of exogenous antigens to CD8+T cells.Here,the DC-derived nanovaccine(denoted as Si9GM)selectively targets cDC1s with marginal loss of premature antigen release for effective stimulator of interferon genes(STING)-mediated antigen cross-presentation.Bone marrow dendritic cell(BMDC)-derived membranes,conjugated to cDC1-specific antibody(αCLEC9A)and binding to tumor peptide(OVA257-264),are coated onto dendrimer-like polyethylenimine(PEI)-grafted silica nanoparticles.Distinct molecular weight-cargos(αCLEC9A-OVA257-264 conjugates and 2′3′-cGAMP STING agonists)are loaded in hierarchical center-radial pores that enables lysosome escape for potent antigen-cross presentation and activates interferon type I,respectively.Impressively,Si9GM vaccination leads to the upregulation of cytotoxic T cells,a reduction in tumor regulatory T cells(Tregs),M1/M2 macrophage polarization,and immune response that synergizes with αPD-1 immune checkpoint blockade.This nanovaccine fulfills a dual role for both direct T cell activation as an artificial antigen-presenting cell and DC subset maturation,indicating its utility in clinical therapy and precision medicine.展开更多
Despite the great potential of anti-PD-L1 antibodies for immunotherapy,their low response rate due to an immunosuppressive tumor microenvironment has hampered their application.To address this issue,we constructed a c...Despite the great potential of anti-PD-L1 antibodies for immunotherapy,their low response rate due to an immunosuppressive tumor microenvironment has hampered their application.To address this issue,we constructed a cell membrane-coated nanosystem(mB4S)to reverse an immunosuppressive microenvironment to an immuno-supportive one for strengthening the anti-tumor effect.In this system,Epirubicin(EPI)as an immunogenic cell death(ICD)inducer was coupled to a branched glycopolymer via hydrazone bonds and diABZI as a stimulator of interferon genes(STING)agonist was encapsulated into mB4S.After internalization of mB4S,EPI was acidic-responsively released to induce ICD,which was characterized by an increased level of calreticulin(CRT)exposure and enhanced ATP secretion.Meanwhile,diABZI effectively activated the STING pathway.Treatment with mB4S in combination with an anti-PD-L1 antibody elicited potent immune responses by increasing the ratio of matured dendritic cells(DCs)and CD8+T cells,promoting cytokines secretion,up-regulating M1-like tumor-associated macrophages(TAMs)and down-regulating immunosuppressive myeloid-derived suppressor cells(MDSCs).Therefore,this nanosystem for co-delivery of an ICD inducer and a STING agonist achieved promotion of DCs maturation and CD8+T cells infiltration,creating an immuno-supportive microenvironment,thus potentiating the therapy effect of the anti-PD-L1 antibody in both 4T1 breast and CT26 colon tumor mice.展开更多
Limited by low tumor immunogenicity and the immunosuppressive tumor microenvironment(TME),triple-negative breast cancer(TNBC)has been poorly responsive to immunotherapy so far.Herein,a Ca&Mn dual-ion hybrid nanost...Limited by low tumor immunogenicity and the immunosuppressive tumor microenvironment(TME),triple-negative breast cancer(TNBC)has been poorly responsive to immunotherapy so far.Herein,a Ca&Mn dual-ion hybrid nanostimulator(CMS)is constructed to enhance anti-tumor immunity through ferroptosis inducing and innate immunity awakening,which can serve as a ferroptosis inducer and immunoadjuvant for TNBC concurrently.On one hand,glutathione(GSH)depletion and reactive oxygen species(ROS)generation can be achieved due to the mixed valence state of Mn in CMS.On the other hand,as an exotic Ca2+supplier,CMS causes mitochondrial Ca2+overload,which further amplifies the oxidative stress.Significantly,tumor cells undergo ferroptosis because of the inactivation of glutathione peroxidase 4(GPX4)and accumulation of lipid peroxidation(LPO).More impressively,CMS can act as an immunoadjuvant to awaken innate immunity by alleviating intra-tumor hypoxia and Mn2+-induced activation of the STING signaling pathway,which promotes polarization of tumor-associated macrophages(TAMs)and activation of dendritic cells(DCs)for antigen presentation and subsequent infiltration of tumor-specific cytotoxic T lymphocytes(CTLs)into tumor tissues.Taken together,this work demonstrates a novel strategy of simultaneously inducing ferroptosis and awakening innate immunity,offering a new perspective for effective tumor immunotherapy of TNBC.展开更多
The ubiquitin-editing enzyme A20 is known to regulate inflammation and maintain homeostasis,but its role in self-DNA-mediated inflammation in acute kidney injury(AKI)is not well understood.Here,our study demonstrated ...The ubiquitin-editing enzyme A20 is known to regulate inflammation and maintain homeostasis,but its role in self-DNA-mediated inflammation in acute kidney injury(AKI)is not well understood.Here,our study demonstrated that oxidized self-DNA accumulates in the serum of AKI mice and patients.This oxidized self-DNA exacerbates the progression of AKI by activating the cGAS-STING pathway and NLRP3 inflammasome.While inhibition of the STING pathway only slightly attenuates AKI progression,suppression of NLRP3 inflammasome-mediated pyroptosis significantly alleviates AKI progression and improves the survival of AKI mice.Subsequently,we found that Tnfaip3(encoding A20)is significantly upregulated following oxidized self-DNA treatment.A20 significantly alleviates AKI development by dampening STING signaling pathway and NLRP3-mediated pyroptosis.Moreover,A20-derived peptide(P-II)also significantly alleviates ox-dsDNA-induced pyroptosis and improves the survival and renal injury of AKI mice.Mechanistically,A20 competitively binds with NEK7 and thus inhibiting NLRP3 inflammasome.A20 and P-II interfere with the interaction between NEK7 and NLRP3 through Lys140 of NEK7.Mutation of Lys140 effects on the interaction of NEK7 with A20 and/or NLRP3 complex.Conditional knockout of NEK7 in macrophages or pharmacological inhibition of NEK7 both significantly rescue AKI mouse models.This study reveals a new mechanism by which A20 attenuates oxidized self-DNA-mediated inflammation and provides a new therapeutic strategy for AKI.展开更多
Mitochondrion is known as the energy factory of the cell, which is also a unique mammalian organelle and con. sidered to be evolved from aerobic prokaryotes more than a billion years ago. Mitochondrial DNA, similar to...Mitochondrion is known as the energy factory of the cell, which is also a unique mammalian organelle and con. sidered to be evolved from aerobic prokaryotes more than a billion years ago. Mitochondrial DNA, similar to that of its bacterial ancestor＇s, consists of a circular loop and contains significant number of unmethylated DNA as CpG islands. The innate immune system plays an important role in the mammalian immune response. Recent research has demonstrated that mitochondrial DNA （mtDNA） activates several innate immune path- ways involving TLR9, NLRP3 and STING signaling, which contributes to the signaling platforms and results in effector responses. In addition to facilitating antibac- terial immunity and regulating antiviral signaling, mounting evidence suggests that mtDNA contributes to inflammatory diseases following cellular damage and stress. Therefore, in addition to its well-appreciated roles in cellular metabolism and energy production, mtDNA appears to function as a key member in the innate immune system. Here, we highlight the emerging roles of mtDNA in innate immunity.展开更多
Oncolytic viruses have emerged as new powerful therapeutic agents for cancer therapy by specifically lysing cancer cells while activating innate immune responses at the same time.However,due to the thorny issues of sa...Oncolytic viruses have emerged as new powerful therapeutic agents for cancer therapy by specifically lysing cancer cells while activating innate immune responses at the same time.However,due to the thorny issues of safety concerns and host immune reaction,the clinical application of oncolytic viruses is still limited.Herein,we report a rationally designed oncolytic virus-like nanoparticles(OV-NPs)composed of stimulator of interferon genes(STING)-stimulating polymer loaded with therapeutic genes for cancer immunotherapy.After injection into tumor,the OV-NPs carrying OX40L plasmid could reprogram tumor cells to express OX40L immune checkpoint molecules and activate the STING pathway for cooperatively enhancing antitumor immunity,with a tumor suppression rate of 92.3%in B16F10 tumor model and 78.7%in MC38 tumor model without causing any toxicity.The OV-NPs could be further applied in carrying other plasmids(IL-12)and utilization in gene combination therapy.This study should inspire designing synthetic OV-NPs as alternative strategies for extending oncolytic virus application in cancer immunotherapy.展开更多
基金supported by Yuan Du Scholars,Clinical Research Center of Affiliated Hospital of Shandong Second Medical University,No.2022WYFYLCYJ02Weifang Key Laboratory,Weifang Science and Technology Development Plan Project Medical Category,No.2022YX093.
文摘The cGAS–STING pathway plays an important role in ischemia-reperfusion injury in the heart,liver,brain,and kidney,but its role and mechanisms in cerebral ischemia-reperfusion injury have not been systematically reviewed.Here,we outline the components of the cGAS–STING pathway and then analyze its role in autophagy,ferroptosis,cellular pyroptosis,disequilibrium of calcium homeostasis,inflammatory responses,disruption of the blood–brain barrier,microglia transformation,and complement system activation following cerebral ischemia-reperfusion injury.We further analyze the value of cGAS–STING pathway inhibitors in the treatment of cerebral ischemia-reperfusion injury and conclude that the pathway can regulate cerebral ischemia-reperfusion injury through multiple mechanisms.Inhibition of the cGAS–STING pathway may be helpful in the treatment of cerebral ischemia-reperfusion injury.
基金supported by Lanzhou Youth Science and Technology Talent Innovation Project(No.2023-QN-60)the Startup Fund for the Construction of the Double First-Class Project,Lanzhou University,China(No.561121203)+2 种基金the National Natural Science Foundation of China(No.31802256)the Medical Innovation and Development Project of Lanzhou University(No.lzuyxcx-2022-196)the Science Fund for Distinguished Young Scholars of Gansu Province(No.20JR5RA579).
文摘Manganese(Mn)has been characterized as an environmental pollutant.Excessive releases of Mn due to human activities have increased Mn levels in the environment over the years,posing a threat to human health and the environment.Long-term exposure to high concentrations of Mn can induce neurotoxicity.Therefore,toxicological studies on Mn are of paramount importance.Mn induces oxidative stress through affecting the level of reactive oxygen species(ROS),and the overabundance of ROS further triggers ferroptosis.Additionally,Mn^(2+) was found to be a novel activator of the cyclic guanosine-adenosine synthase(cGAS)−stimulator of interferon genes(STING)pathway in the innateimmune system.Thus,we speculate thatMn exposuremay promote ROS production by activating the cGAS−STING pathway,which further induces oxidative stress and ferroptosis,and ultimately triggers Mn neurotoxicity.This review discusses the mechanism between Mn-induced oxidative stress and ferroptosis via activation of the cGAS−STING pathway,which may offer a prospective direction for future in-depth studies on the mechanism of Mn neurotoxicity.
文摘Background:Recurrent implantation failure(RIF)is a difficult problem with a multifaceted cause.Recent studies have demonstrated that stimulator of interferon genes-induced immune-related genes(STIRGs)are associated with immune disorders that may affect the endometrial immune micro-environment.However,the effect of STRIGs on RIF remains unknown.Methods:Training(GSE111974)and validation(GSE106602)cohorts were acquired from the Gene Expression Omnibus database.STIRGs were extracted from the Molecular Signatures Database and relevant studies.Consensus clustering analysis was used to identify RIF molecular subtypes.Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment and immune infiltration analyses were performed between RIF subtypes.Drug-related potential therapeutic target genes were discovered.Results:Two distinct molecular subtypes were discovered in both the training and validation groups according to STIRGs.In subtype C2,there was a notable decrease in the presence of different types of immune cells,such as natural killer cells and macrophages.Furthermore,the examination of Gene Ontology and Kyoto Encyclopedia of Genes and Genomes indicated a decrease in numerous immune-related biological processes within subtype C2.Finally,nine hub genes(CXCR4,POU5F1,PPARG,TLR2,EGFR,CSF1,BCL2A1,BTK,and SRGN)were identified as potential therapeutic targets for RIF.Conclusion:Based on STIRGs,we identified a new molecular subtype with significantly reduced immune infiltration in RIF.Nine genes might be potential therapeutic targets for RIF.
基金supported by the National Natural Science Foundation of China(31941018,32072888,U21A20261)China Agriculture Research System of MOF and MARA(CARS-35)+1 种基金Science and Technology Development Program of Jilin Province(YDZJ202102CXJD029,20190301042NY,20200402041NC)Science and Technology Development Program of Changchun City(21ZY42).
文摘African swine fever virus(ASFV)is an important pathogen causing acute infectious disease in domestic pigs and wild boars that seriously endangers the global swine industry.As ASFV is structurally complex and encodes a large number of functional proteins,no effective vaccine has been developed to date.Thus,dissecting the mechanisms of immune escape induced by ASFV proteins is crucial.A previous study showed that the ASFV-encoded protein is an important factor in host immunity.In this study,we identified a negative regulator,MGF505-3R,that significantly downregulated cGAS/STING-and poly(dG:dC)-mediated IFN-βand interferon stimulation response element(ISRE)reporter activity and suppressed IFNB1 and IFIT2 mRNA levels.In addition,TBK1,IRF3 and IκBαphosphorylation levels were also inhibited.Mechanistically,MGF505-3R interacted with cGAS/TBK1/IRF3 and targeted TBK1 for degradation,thereby disrupting the cGAS-STING-mediated IFN-βsignaling pathway,which appears to be highly correlated with autophagy.Knockdown MGF505-3R expression enhanced IFN-βand IL-1βproduction.Taken together,our study revealed a negative regulatory mechanism involving the MGF505-3R-cGAS-STING axis and provided insights into an evasion strategy employed by ASFV that involves autophagy and innate signaling pathways.
基金the National Natural Science Foundation of China(Nos.81771827,82071986,82372072)the Key Research and Development Program of Hunan Province(No.2022SK2025)+5 种基金the Natural Science Foundation of Hunan Province(Nos.2023JJ40966,2021JJ20084)the Science and Technology Program of Hunan Province(Nos.2021RC4017,2021RC3020)the Youth Science Foundation of Xiangya Hospital(No.2022Q13)the Central South University Frontier Cross-disciplinary Project(No.2023QYJC021)the China Postdoctoral Science Foundation(No.2023M733954)the National Postdoctoral Program for Innovative Talents(No.BX20230432)。
文摘Radiotherapy(RT)is a widely used cancer treatment,and the use of metal-based nano-radiotherapy sensitizers has shown promise in enhancing its efficacy.However,efficient accumulation and deep penetration of these sensitizers within tumors remain challenging.In this study,we present the development of bismuth/manganese biomineralized nanoparticles(Bi Mn/BSA)with multiple radiosensitizing mechanisms,including high atomic number element-mediated radiation capture,catalase-mimic oxygenation,and activation of the stimulator of interferon genes(STING)pathway.Significantly,we demonstrate that low-dose RT induces the recruitment of macrophages and subsequent upregulation of Matrix metalloproteinases(MMP)-2 and MMP-9 that degrade the extracellular matrix(ECM).This dynamic process facilitates the targeted delivery and deep penetration of Bi Mn/BSA nanoparticles within tumors,thereby enhancing the effectiveness of RT.By combining low-dose RT with Bi Mn/BSA nanoparticles,we achieved complete suppression of tumor growth in mice with excellent biocompatibility.This study provides a novel and clinically relevant strategy for targeted nanoparticle delivery to tumors,and establishes a safe and effective sequential radiotherapy approach for cancer treatment.These findings hold great promise for improving the outcomes of RT and advancing the field of nanomedicine in cancer therapy.
基金supported by the National Science Foundation of China(8217070298,81773283)the Guangdong Basic and Applied Basic Research Foundation(2021A1515220011,China).
文摘Although cancer immunotherapy has made great strides in the clinic,it is still hindered by the tumor immunosuppressive microenvironment(TIME).The stimulator of interferon genes(STING)pathway which can modulate TIME effectively has emerged as a promising therapeutic recently.However,the delivery of most STING agonists,specifically cyclic dinucleotides(CDNs),is performed intratumorally due to their insufficient pharmacological properties,such as weak permeability across cell membranes and vulnerability to nuclease degradation.To expand the clinical applicability of CDNs,a novel pH-sensitive polycationic polymer-modified lipid nanoparticle(LNP-B)system was developed for intravenous delivery of CDNs.LNP-B significantly extended the circulation of CDNs and enhanced the accumulation of CDNs within the tumor,spleen,and tumor-draining lymph nodes compared with free CDNs thereby triggering the STING pathway of dendritic cells and repolarizing pro-tumor macrophages.These events subsequently gave rise to potent anti-tumor immune reactions and substantial inhibition of tumors in CT26 colon cancer-bearing mouse models.In addition,due to the acid-sensitive property of the polycationic polymer,the delivery system of LNP-B was more biocompatible and safer compared with lipid nanoparticles formulated with an indissociable cationic DOTAP(LNP-D).These findings suggest that LNP-B has great potential in the intravenous delivery of CDNs for tumor immunotherapy.
基金supported by a National Research Foundation of Korea(NRF)grant funded by the Korean government(MSIT,No.RS-2024-00352440 and No.NRF-2019R1A5A2027340).
文摘Recently,nanovaccine-based immunotherapy has been robustly investigated due to its potential in governing the immune response and generating long-term protective immunity.However,the presentation of a tumor peptide-major histocompatibility complex to T lymphocytes is still a challenge that needs to be addressed for eliciting potent antitumor immunity.Type 1 conventional dendritic cell(cDC1)subset is of particular interest due to its pivotal contribution in the cross-presentation of exogenous antigens to CD8+T cells.Here,the DC-derived nanovaccine(denoted as Si9GM)selectively targets cDC1s with marginal loss of premature antigen release for effective stimulator of interferon genes(STING)-mediated antigen cross-presentation.Bone marrow dendritic cell(BMDC)-derived membranes,conjugated to cDC1-specific antibody(αCLEC9A)and binding to tumor peptide(OVA257-264),are coated onto dendrimer-like polyethylenimine(PEI)-grafted silica nanoparticles.Distinct molecular weight-cargos(αCLEC9A-OVA257-264 conjugates and 2′3′-cGAMP STING agonists)are loaded in hierarchical center-radial pores that enables lysosome escape for potent antigen-cross presentation and activates interferon type I,respectively.Impressively,Si9GM vaccination leads to the upregulation of cytotoxic T cells,a reduction in tumor regulatory T cells(Tregs),M1/M2 macrophage polarization,and immune response that synergizes with αPD-1 immune checkpoint blockade.This nanovaccine fulfills a dual role for both direct T cell activation as an artificial antigen-presenting cell and DC subset maturation,indicating its utility in clinical therapy and precision medicine.
基金This work was supported by National Natural Science Foundation of China(32271445,52073193,and 82202322)National Science and Technology Major Project of China(2023YFB3810004)+2 种基金1·3·5 Project for Disciplines of Excellence,West China Hospital,Sichuan University(ZYJC21013,China)the Sichuan Science and Technology Program(2023NSFSC1592,China),the China Postdoctoral Science Foundation(2021M692255,China)the Post-Doctor Research Project,West China Hospital,Sichuan University(2020HXBH094,China).
文摘Despite the great potential of anti-PD-L1 antibodies for immunotherapy,their low response rate due to an immunosuppressive tumor microenvironment has hampered their application.To address this issue,we constructed a cell membrane-coated nanosystem(mB4S)to reverse an immunosuppressive microenvironment to an immuno-supportive one for strengthening the anti-tumor effect.In this system,Epirubicin(EPI)as an immunogenic cell death(ICD)inducer was coupled to a branched glycopolymer via hydrazone bonds and diABZI as a stimulator of interferon genes(STING)agonist was encapsulated into mB4S.After internalization of mB4S,EPI was acidic-responsively released to induce ICD,which was characterized by an increased level of calreticulin(CRT)exposure and enhanced ATP secretion.Meanwhile,diABZI effectively activated the STING pathway.Treatment with mB4S in combination with an anti-PD-L1 antibody elicited potent immune responses by increasing the ratio of matured dendritic cells(DCs)and CD8+T cells,promoting cytokines secretion,up-regulating M1-like tumor-associated macrophages(TAMs)and down-regulating immunosuppressive myeloid-derived suppressor cells(MDSCs).Therefore,this nanosystem for co-delivery of an ICD inducer and a STING agonist achieved promotion of DCs maturation and CD8+T cells infiltration,creating an immuno-supportive microenvironment,thus potentiating the therapy effect of the anti-PD-L1 antibody in both 4T1 breast and CT26 colon tumor mice.
基金supported by the National Key Research and Development Program of China(Grant No.2021YFB3801000)the National Natural Science Foundation of China(Grant No.32030061)+3 种基金the Basic Research Program of Shanghai Municipal Government(Grant No.21JC1406000)the Shanghai Sailing Program(Grant No.21YF1454200)Shanghai International Cooperation Project(Grant No.23490712900)All the animal experiments were performed with the approval of the Tongji University Experimental Animal Center,and the animal biomedical research authorization number is TJLAC-020-228.
文摘Limited by low tumor immunogenicity and the immunosuppressive tumor microenvironment(TME),triple-negative breast cancer(TNBC)has been poorly responsive to immunotherapy so far.Herein,a Ca&Mn dual-ion hybrid nanostimulator(CMS)is constructed to enhance anti-tumor immunity through ferroptosis inducing and innate immunity awakening,which can serve as a ferroptosis inducer and immunoadjuvant for TNBC concurrently.On one hand,glutathione(GSH)depletion and reactive oxygen species(ROS)generation can be achieved due to the mixed valence state of Mn in CMS.On the other hand,as an exotic Ca2+supplier,CMS causes mitochondrial Ca2+overload,which further amplifies the oxidative stress.Significantly,tumor cells undergo ferroptosis because of the inactivation of glutathione peroxidase 4(GPX4)and accumulation of lipid peroxidation(LPO).More impressively,CMS can act as an immunoadjuvant to awaken innate immunity by alleviating intra-tumor hypoxia and Mn2+-induced activation of the STING signaling pathway,which promotes polarization of tumor-associated macrophages(TAMs)and activation of dendritic cells(DCs)for antigen presentation and subsequent infiltration of tumor-specific cytotoxic T lymphocytes(CTLs)into tumor tissues.Taken together,this work demonstrates a novel strategy of simultaneously inducing ferroptosis and awakening innate immunity,offering a new perspective for effective tumor immunotherapy of TNBC.
基金funded by the National Natural Science Foundation of China(Nos.8197219382171003).
文摘The ubiquitin-editing enzyme A20 is known to regulate inflammation and maintain homeostasis,but its role in self-DNA-mediated inflammation in acute kidney injury(AKI)is not well understood.Here,our study demonstrated that oxidized self-DNA accumulates in the serum of AKI mice and patients.This oxidized self-DNA exacerbates the progression of AKI by activating the cGAS-STING pathway and NLRP3 inflammasome.While inhibition of the STING pathway only slightly attenuates AKI progression,suppression of NLRP3 inflammasome-mediated pyroptosis significantly alleviates AKI progression and improves the survival of AKI mice.Subsequently,we found that Tnfaip3(encoding A20)is significantly upregulated following oxidized self-DNA treatment.A20 significantly alleviates AKI development by dampening STING signaling pathway and NLRP3-mediated pyroptosis.Moreover,A20-derived peptide(P-II)also significantly alleviates ox-dsDNA-induced pyroptosis and improves the survival and renal injury of AKI mice.Mechanistically,A20 competitively binds with NEK7 and thus inhibiting NLRP3 inflammasome.A20 and P-II interfere with the interaction between NEK7 and NLRP3 through Lys140 of NEK7.Mutation of Lys140 effects on the interaction of NEK7 with A20 and/or NLRP3 complex.Conditional knockout of NEK7 in macrophages or pharmacological inhibition of NEK7 both significantly rescue AKI mouse models.This study reveals a new mechanism by which A20 attenuates oxidized self-DNA-mediated inflammation and provides a new therapeutic strategy for AKI.
文摘Mitochondrion is known as the energy factory of the cell, which is also a unique mammalian organelle and con. sidered to be evolved from aerobic prokaryotes more than a billion years ago. Mitochondrial DNA, similar to that of its bacterial ancestor＇s, consists of a circular loop and contains significant number of unmethylated DNA as CpG islands. The innate immune system plays an important role in the mammalian immune response. Recent research has demonstrated that mitochondrial DNA （mtDNA） activates several innate immune path- ways involving TLR9, NLRP3 and STING signaling, which contributes to the signaling platforms and results in effector responses. In addition to facilitating antibac- terial immunity and regulating antiviral signaling, mounting evidence suggests that mtDNA contributes to inflammatory diseases following cellular damage and stress. Therefore, in addition to its well-appreciated roles in cellular metabolism and energy production, mtDNA appears to function as a key member in the innate immune system. Here, we highlight the emerging roles of mtDNA in innate immunity.
基金supported by the National Natural Science Foundation of China (22222509,52025035,51973215,22375198,52103194)Bureau of International Cooperation Chinese Academy of Sciences (121522KYSB20200029)+5 种基金Jilin Province Science and Technology DevelopmentPlan (YDZJ202101ZYTS131,20220402037GH,20210508049RQ)Jilin Provincial International Cooperation Key Laboratory of Biomedical Polymers (20210504001GH)Changchun Science and Technology Development Plan (21ZY09,21ZGY30)the China Postdoctoral Science Foundation (E21S2101)the Youth Talents Promotion Project of Jilin Province (QT202103)the Youth Innovation Promotion Association of Chinese Academy of Sciences (2020232)。
文摘Oncolytic viruses have emerged as new powerful therapeutic agents for cancer therapy by specifically lysing cancer cells while activating innate immune responses at the same time.However,due to the thorny issues of safety concerns and host immune reaction,the clinical application of oncolytic viruses is still limited.Herein,we report a rationally designed oncolytic virus-like nanoparticles(OV-NPs)composed of stimulator of interferon genes(STING)-stimulating polymer loaded with therapeutic genes for cancer immunotherapy.After injection into tumor,the OV-NPs carrying OX40L plasmid could reprogram tumor cells to express OX40L immune checkpoint molecules and activate the STING pathway for cooperatively enhancing antitumor immunity,with a tumor suppression rate of 92.3%in B16F10 tumor model and 78.7%in MC38 tumor model without causing any toxicity.The OV-NPs could be further applied in carrying other plasmids(IL-12)and utilization in gene combination therapy.This study should inspire designing synthetic OV-NPs as alternative strategies for extending oncolytic virus application in cancer immunotherapy.
