The use of bacteria to specifically migrate to cancerous tissue and elicit an antitumor immune response provides a promising platform against cancer with significantly high potency.With dozens of clinical trials under...The use of bacteria to specifically migrate to cancerous tissue and elicit an antitumor immune response provides a promising platform against cancer with significantly high potency.With dozens of clinical trials underway,some researchers hold the following views:“humans are nearing the first commercial live bacteria therapeutic.”However,the facultative anaerobe Salmonella typhimurium VNP20009,which is particularly safe and shows anticancer effects in preclinical studies,had failed in a phase I clinical trial due to low tumor regression and undesired dose-dependent side effects.This is almost certain to disappoint people’s inflated expectations,but it is noted that recent stateof-the-art research has turned attention to bacteria-mediated synergistic cancer therapy(BMSCT).In this review,the foundation of bacteria-mediated bio-therapy is outlined.Then,we summarize the potential benefits and challenges of bacterial bio-therapy in combination with different traditional anticancer therapeutic modalities(chemotherapy,photothermal therapy,reactive oxygen and nitrogen species therapy,immunotherapy,or prodrug-activating therapy)in the past 5 years.Next,we discuss multiple administration routes of BMSCT,highlighting potentiated antitumor responses and avoidance of potential side effects.Finally,we envision the opportunities and challenges for BMSCT development,with the purpose of inspiring medicinal scientists to widely utilize the microbiome approach in patient populations.展开更多
Bacterial-based antitumor immunity has become a promising strategy to activate the immune system for fighting cancer.However,the potential application of bacterial therapy is hindered by the presence of instability an...Bacterial-based antitumor immunity has become a promising strategy to activate the immune system for fighting cancer.However,the potential application of bacterial therapy is hindered by the presence of instability and susceptibility to infections within bacterial populations.Furthermore,monotherapy is ineffective in completely eliminating complex cancer with multiple contributing factors.In this study,based on our discovery that spore shell(SS)of Bacillus coagulans exhibits excellent tumor-targeting ability and adjuvant activity,we develop a biomimetic spore nanoplatform to boost bacteria-mediated antitumor therapy,chemodynamic therapy and antitumor immunity for synergistic cancer treatment.In detail,SS is separated from probiotic spores and then attached to the surface of liposome(Lipo)that was loaded with hemoglobin(Hb),glucose oxidase(GOx)and JQ1to construct SS@Lipo/Hb/GOx/JQ1.In tumor tissue,highly toxic hydroxyl radicals(·OH)are generated via sequential catalytic reactions:GOx catalyzing glucose into H_(2)O_(2)and Fe^(2+)in Hb decomposing H_(2)O_(2)into·OH.The combination of·OH and SS adjuvant can improve tumor immunogenicity and activate immune system.Meanwhile,JQ1-mediated down-regulation of PD-L1 and Hb-induced hypoxia alleviation synergistically reshape immunosuppressive tumor microenvironment and potentiate immune response.In this manner,SS@Lipo/Hb/GOx/JQ1 significantly suppresses tumor growth and metastasis.To summarize,the nanoplatform represents an optimum strategy to potentiate bacteria-based cancer immunotherapy.展开更多
Introduction Cancer is an attractive target of gene therapy and currently represents the disease in most clinical trials[1]. Strategies for cancer gene therapy include: (1) stimulation of immune responses to tumor cel...Introduction Cancer is an attractive target of gene therapy and currently represents the disease in most clinical trials[1]. Strategies for cancer gene therapy include: (1) stimulation of immune responses to tumor cells,(2) delivery of specific enzymes展开更多
Conventional polymerizations mediated by living cells typically require synthetic transition-metal complexes or photoredox catalysts.Herein,we report an alternative photoinduced polymerization strategy for preparing f...Conventional polymerizations mediated by living cells typically require synthetic transition-metal complexes or photoredox catalysts.Herein,we report an alternative photoinduced polymerization strategy for preparing functional polymer hydrogels through bacteria-initiated radical polymerization of acrylamides in ordinary culture media.Upon light irradiation under ambient conditions,polyacrylamides were obtained with molecular weights of over 150 kDa using various bacteria.展开更多
Salmonella:mediated cancer therapy has achieved remarkable anti-tumor effects in experimental animal models,but the detailed mechanism remains unsolved.In this report,the active involvement of the host immune response...Salmonella:mediated cancer therapy has achieved remarkable anti-tumor effects in experimental animal models,but the detailed mechanism remains unsolved.In this report,the active involvement of the host immune response in this process was confirmed by comparing the tumor-suppressive effects of Salmonella in immunocompetent and immunodeficient mice bearing melanoma allografts.Since flagella are key inducers of the host immune response during bacterial infection,flagella were genetically disrupted to analyse their involvement in Salmonella-mediated cancer therapy.The results showed that flagellum-deficient strains failed to induce significant anti-tumor effects,even when more bacteria were administered to offset the difference in invasion efficiency.Flagella mainly activate immune cells via Flagellin/Toll-like receptor 5(TLR5)signalling pathway.Indeed,we showed that exogenous activation of TLR5 signalling by recombinant Flagellin and exogenous expression of TLR5 both enhanced the therapeutic efficacy of flagellum-deficient Salmonella against melanoma.Our study highlighted the therapeutic value of the interaction between Salmonella and the host immune response through Flagellin/TLR5 signalling pathway during Salmonella-mediated cancer therapy,thereby suggesting the potential application of TLR5 agonists in the cancer immune therapy.展开更多
Autologous cancer vaccine that stimulates tumor-specific immune responses for personalized immunotherapy holds great potential for tumor therapy.However,its efficacy is still suboptimal due to the immunosuppressive tu...Autologous cancer vaccine that stimulates tumor-specific immune responses for personalized immunotherapy holds great potential for tumor therapy.However,its efficacy is still suboptimal due to the immunosuppressive tumor microenvironment(ITM).Here,we report a new type of bacteria-based autologous cancer vaccine by employing calcium carbonate(CaCO_(3))biomineralized Salmonella(Sal)as an in-situ cancer vaccine producer and systematical ITM regulator.CaCO_(3) can be facilely coated on the Sal surface with calcium ionophore A23187 co-loading,and such biomineralization did not affect the bioactivities of the bacteria.Upon intratumoral accumulation,the CaCO_(3) shell was decomposed at an acidic microenvironment to atenuate tumor acidity,accompanied by the release of Sal and Ca^(2+)/A23187.Specifically,Sal served as a cancer vaccine producer by inducing cancer cells'immunogenic cell death(ICD)and promoting the gap junction formation between tumor cells and dendritic cells(DCs)to promote antigen presentation.Ca^(2+),on the other hand,was intermalized into various types of immune cells with the aid of A23187 and synergized with Sal to systematically regulate the immune system,including DCs maturation,macrophages polarization,and T cells activation.As a result,such bio-vaccine achieved remarkable effcacy against both primary and metastatic tumors by eliciting potent anti-tumor immunity with full biocompatibility.This work demonstrated the potential of bioengineered bacteria as bio-active vaccines for enhanced tumor immunotherapy.展开更多
Specific tumor-targeted gene delivery remains an unsolved therapeutic issue due to aberrant vascularization in tumor microenvironment(TME).Some bacteria exhibit spontaneous chemotaxis to-ward the anaerobic and immune-...Specific tumor-targeted gene delivery remains an unsolved therapeutic issue due to aberrant vascularization in tumor microenvironment(TME).Some bacteria exhibit spontaneous chemotaxis to-ward the anaerobic and immune-suppressive TME,which makes them ideal natural vehicles for cancer gene therapy.Here,we conjugated ZIF-8 metal-organic frameworks encapsulating eukaryotic murine interleukin 2(Il2)expression plasmid onto the surface of VNP20009,an attenuated Salmonella typhimur-ium strain with well-documented anti-cancer activity,and constructed a TME-targeted Il2 delivery system named Il2/ZIF-8@Salmonella.Both in vitro and in vivo experiments demonstrated that Il2/ZIF-8@Sal-monella maintained the tumor-targeting feature of bacteria,and could be effectively phagocytosed by in-tratumoral macrophages,thus leading to the expression and secretion of IL2 in TME.The detailed analysis of tumor immune microenvironment(TIME)showed that one dose of combinatorial Il2/ZIF-8@Salmonella achieved synergistic actions on a potent remodeling of TIME,marked by the activation of cytotoxic T cells and M1-polarization of macrophages in TME,thus leading to significant anti-tumor effects in melanoma,orthotopic hepatocellular carcinoma,and pulmonary metastasis models.More importantly,Il2/ZIF-8@Salmonella exhibited high safety to major organs and hematopoietic systems.Taken together,we report a novel plasmid/ZIF-8@Salmonella system that simultaneously achieves effec-tive TME-targeted delivery of therapeutic gene,as well as synergistic re-activation of TIME.展开更多
基金Supported by National Natural Science Foundation of China,No.81773656Liaoning Revitalization Talents Program,No.XLYC1808017Shenyang Youth Science and Technology Innovation Talents Program,No.RC190454.
文摘The use of bacteria to specifically migrate to cancerous tissue and elicit an antitumor immune response provides a promising platform against cancer with significantly high potency.With dozens of clinical trials underway,some researchers hold the following views:“humans are nearing the first commercial live bacteria therapeutic.”However,the facultative anaerobe Salmonella typhimurium VNP20009,which is particularly safe and shows anticancer effects in preclinical studies,had failed in a phase I clinical trial due to low tumor regression and undesired dose-dependent side effects.This is almost certain to disappoint people’s inflated expectations,but it is noted that recent stateof-the-art research has turned attention to bacteria-mediated synergistic cancer therapy(BMSCT).In this review,the foundation of bacteria-mediated bio-therapy is outlined.Then,we summarize the potential benefits and challenges of bacterial bio-therapy in combination with different traditional anticancer therapeutic modalities(chemotherapy,photothermal therapy,reactive oxygen and nitrogen species therapy,immunotherapy,or prodrug-activating therapy)in the past 5 years.Next,we discuss multiple administration routes of BMSCT,highlighting potentiated antitumor responses and avoidance of potential side effects.Finally,we envision the opportunities and challenges for BMSCT development,with the purpose of inspiring medicinal scientists to widely utilize the microbiome approach in patient populations.
基金supported by the National Natural Science Foundation of China(No.82272847,82202318,82304417,82303529)The Henan Province Fund for Cultivating Advantageous Disciplines(No.222301420012)+2 种基金Central Plains science and technology innovation leading talent project(No.234200510005)The project tackling of key scientific and technical problems of Henan Provine(No.232102311163)China Postdoctoral Science Foundation(2022TQ0310,2023TQ0307,2023M730971)。
文摘Bacterial-based antitumor immunity has become a promising strategy to activate the immune system for fighting cancer.However,the potential application of bacterial therapy is hindered by the presence of instability and susceptibility to infections within bacterial populations.Furthermore,monotherapy is ineffective in completely eliminating complex cancer with multiple contributing factors.In this study,based on our discovery that spore shell(SS)of Bacillus coagulans exhibits excellent tumor-targeting ability and adjuvant activity,we develop a biomimetic spore nanoplatform to boost bacteria-mediated antitumor therapy,chemodynamic therapy and antitumor immunity for synergistic cancer treatment.In detail,SS is separated from probiotic spores and then attached to the surface of liposome(Lipo)that was loaded with hemoglobin(Hb),glucose oxidase(GOx)and JQ1to construct SS@Lipo/Hb/GOx/JQ1.In tumor tissue,highly toxic hydroxyl radicals(·OH)are generated via sequential catalytic reactions:GOx catalyzing glucose into H_(2)O_(2)and Fe^(2+)in Hb decomposing H_(2)O_(2)into·OH.The combination of·OH and SS adjuvant can improve tumor immunogenicity and activate immune system.Meanwhile,JQ1-mediated down-regulation of PD-L1 and Hb-induced hypoxia alleviation synergistically reshape immunosuppressive tumor microenvironment and potentiate immune response.In this manner,SS@Lipo/Hb/GOx/JQ1 significantly suppresses tumor growth and metastasis.To summarize,the nanoplatform represents an optimum strategy to potentiate bacteria-based cancer immunotherapy.
基金supported by a predoctoral fellowship from the National Institutes of Health and a research grant from the National Science Foundation
文摘Introduction Cancer is an attractive target of gene therapy and currently represents the disease in most clinical trials[1]. Strategies for cancer gene therapy include: (1) stimulation of immune responses to tumor cells,(2) delivery of specific enzymes
基金supported by the Strategic Priority Research Program of the Chinese Academy of Sciences(grant no.XDA16020804)the National Natural Science Foundation of China(grant nos.21871016,22021002,and 220201020050).
文摘Conventional polymerizations mediated by living cells typically require synthetic transition-metal complexes or photoredox catalysts.Herein,we report an alternative photoinduced polymerization strategy for preparing functional polymer hydrogels through bacteria-initiated radical polymerization of acrylamides in ordinary culture media.Upon light irradiation under ambient conditions,polyacrylamides were obtained with molecular weights of over 150 kDa using various bacteria.
基金supported by grants from the Jiangsu Provincial Nature Science Foundation(BK20192005,China)National Natural Science Foundation of China(81630092,81903143,81802338,and 82072646)+1 种基金Zhejiang Provincial Natural Science Foundation of China for Distinguished Young Scholars(LR21H160001)Start-up Grant of HZNU(4125C5021820470,China)。
文摘Salmonella:mediated cancer therapy has achieved remarkable anti-tumor effects in experimental animal models,but the detailed mechanism remains unsolved.In this report,the active involvement of the host immune response in this process was confirmed by comparing the tumor-suppressive effects of Salmonella in immunocompetent and immunodeficient mice bearing melanoma allografts.Since flagella are key inducers of the host immune response during bacterial infection,flagella were genetically disrupted to analyse their involvement in Salmonella-mediated cancer therapy.The results showed that flagellum-deficient strains failed to induce significant anti-tumor effects,even when more bacteria were administered to offset the difference in invasion efficiency.Flagella mainly activate immune cells via Flagellin/Toll-like receptor 5(TLR5)signalling pathway.Indeed,we showed that exogenous activation of TLR5 signalling by recombinant Flagellin and exogenous expression of TLR5 both enhanced the therapeutic efficacy of flagellum-deficient Salmonella against melanoma.Our study highlighted the therapeutic value of the interaction between Salmonella and the host immune response through Flagellin/TLR5 signalling pathway during Salmonella-mediated cancer therapy,thereby suggesting the potential application of TLR5 agonists in the cancer immune therapy.
基金supported by the National Natural Science Foundation of China(No.82073799)the Natural Science Foundation of Hunan Province in China(2021JJ20084)the Science and Technology Innovation Program of Hunan Province in China(2021RC3020).
文摘Autologous cancer vaccine that stimulates tumor-specific immune responses for personalized immunotherapy holds great potential for tumor therapy.However,its efficacy is still suboptimal due to the immunosuppressive tumor microenvironment(ITM).Here,we report a new type of bacteria-based autologous cancer vaccine by employing calcium carbonate(CaCO_(3))biomineralized Salmonella(Sal)as an in-situ cancer vaccine producer and systematical ITM regulator.CaCO_(3) can be facilely coated on the Sal surface with calcium ionophore A23187 co-loading,and such biomineralization did not affect the bioactivities of the bacteria.Upon intratumoral accumulation,the CaCO_(3) shell was decomposed at an acidic microenvironment to atenuate tumor acidity,accompanied by the release of Sal and Ca^(2+)/A23187.Specifically,Sal served as a cancer vaccine producer by inducing cancer cells'immunogenic cell death(ICD)and promoting the gap junction formation between tumor cells and dendritic cells(DCs)to promote antigen presentation.Ca^(2+),on the other hand,was intermalized into various types of immune cells with the aid of A23187 and synergized with Sal to systematically regulate the immune system,including DCs maturation,macrophages polarization,and T cells activation.As a result,such bio-vaccine achieved remarkable effcacy against both primary and metastatic tumors by eliciting potent anti-tumor immunity with full biocompatibility.This work demonstrated the potential of bioengineered bacteria as bio-active vaccines for enhanced tumor immunotherapy.
基金supported by“Pioneer”and“Leading Goose”R&D Program of Zhejiang Province(2022C03004 to Jianxiang Chen,China),Research Project of Jinan Microecological Biomedicine Shandong Laboratory(JNL-2022029C to Yiting Qiao,China),National Natural Science Foundation of China(82373888 to Yiting Qiao,82072646,82372664 to Jianxiang Chen),Non-profit Central Research Institute Fund of Chinese Academy of Medical Sciences(2023-PT320-02 to Yiting Qiao,China)The joint foundation of National Administration of Traditional Chinese Medicine&Zhejiang Province-major project(GZY-ZJ-KJ-24045 to Jianxiang Chen,China)+1 种基金Research Unit Project of Chinese Academy of Medical Sciences(2019‒I2M‒5‒030 to Shusen Zheng,China)Postgraduate research innovation project of Hangzhou Normal University(2022HSDYJ SKY244 to Yunxin Pei,2022HSDYJ SKY015 to Menglan Wang,China).
文摘Specific tumor-targeted gene delivery remains an unsolved therapeutic issue due to aberrant vascularization in tumor microenvironment(TME).Some bacteria exhibit spontaneous chemotaxis to-ward the anaerobic and immune-suppressive TME,which makes them ideal natural vehicles for cancer gene therapy.Here,we conjugated ZIF-8 metal-organic frameworks encapsulating eukaryotic murine interleukin 2(Il2)expression plasmid onto the surface of VNP20009,an attenuated Salmonella typhimur-ium strain with well-documented anti-cancer activity,and constructed a TME-targeted Il2 delivery system named Il2/ZIF-8@Salmonella.Both in vitro and in vivo experiments demonstrated that Il2/ZIF-8@Sal-monella maintained the tumor-targeting feature of bacteria,and could be effectively phagocytosed by in-tratumoral macrophages,thus leading to the expression and secretion of IL2 in TME.The detailed analysis of tumor immune microenvironment(TIME)showed that one dose of combinatorial Il2/ZIF-8@Salmonella achieved synergistic actions on a potent remodeling of TIME,marked by the activation of cytotoxic T cells and M1-polarization of macrophages in TME,thus leading to significant anti-tumor effects in melanoma,orthotopic hepatocellular carcinoma,and pulmonary metastasis models.More importantly,Il2/ZIF-8@Salmonella exhibited high safety to major organs and hematopoietic systems.Taken together,we report a novel plasmid/ZIF-8@Salmonella system that simultaneously achieves effec-tive TME-targeted delivery of therapeutic gene,as well as synergistic re-activation of TIME.
