Objectives:This study aimed to determine the role and mechanism underlying migration and invasion inhibitory protein(MIIP)modulation in M2 macrophages within the tumor microenvironment and the potential of targeting t...Objectives:This study aimed to determine the role and mechanism underlying migration and invasion inhibitory protein(MIIP)modulation in M2 macrophages within the tumor microenvironment and the potential of targeting the MIIP-stimulator of interferon genes(STING)pathway in colorectal cancer(CRC)therapy.Methods:MIIP expression was analyzed for associations with the STING pathway and M2 macrophage infiltration using public datasets and clinical CRC samples.CRC cells were genetically modified using lentiviral vectors to overexpress or silence MIIP and STING.The interactions of genetically modified CRC cells with macrophages were studied in co-culture systems.Techniques,including immunofluorescence staining,RT‒qPCR,western blot,ELISA,flow cytometry,and Transwell migration and invasion assays,were used to evaluate the crosstalk between CRC cells and macrophages.An orthotopic mouse CRC model was developed to study the effects of MIIP on M2 macrophage polarization and tumor metastasis through the STING-NFκB2-IL10 axis.The therapeutic significance of a STING antagonist was also assessed in vivo.Results:Analyses of The Cancer Genome Atlas(TCGA)cohort and our CRC cohort revealed low MIIP expression is associated with STING pathway activation,increased M2 macrophage infiltration,and poor clinical outcomes.The results of functional experiments demonstrated that MIIP inhibits IL10 production via the STING-TRAF3-NFκB2 axis in CRC cells,suppressing M2 macrophage polarization in co-culture systems.Conversely,M2 macrophages promoted CRC cell migration and invasion in an IL10-dependent manner.In vitro and in vivo studies confirmed that the MIIP-mediated feedback loop between CRC cells and macrophages depends on the STING-NFκB2-IL10 axis.Furthermore,inhibition of STING expression in a mouse model reduced M2 macrophage polarization and tumor metastasis.Conclusions:This study established MIIP as a crucial regulator of macrophage polarization in the CRC tumor microenvironment,providing new insights into the role in suppressing CRC progression and immune-tumor crosstalk.These findings highlight the potential of targeting the STING pathway as a therapeutic strategy for CRC patients who respond poorly to immune checkpoint inhibitors.展开更多
The tumor microenvironment(TME)is a complex network composed of non-tumor cells,extracellular matrix,blood vessels,and various molecular signals that surround and profoundly influence tumor progression.As one of the k...The tumor microenvironment(TME)is a complex network composed of non-tumor cells,extracellular matrix,blood vessels,and various molecular signals that surround and profoundly influence tumor progression.As one of the key immune effector cells within the TME,mast cells(MCs)exhibit functional complexity,and their specific roles remain widely debated.Depending on the cancer type,spatial distribution,and interactions with other TME components,MCs can demonstrate dual regulatory capabilities—either promoting or inhibiting tumor growth.This characteristic has made them an important focus in current tumor immunology research.This review aims to systematically review the current understanding of MCs in the TME,with emphasis on their characteristics and functional differences across various tumor types,pathological status,and species.In recent years,advances in the understanding of MC markers,activation mechanisms,and biological functions have made targeting specific MC subsets an emerging therapeutic strategy.By comprehensively examining the origin,activation mechanisms,cellular interactions,and therapeutic regulation ofMCs,this review provides new perspectives and a basis for future directions in tumor research and treatment.展开更多
文摘Objectives:This study aimed to determine the role and mechanism underlying migration and invasion inhibitory protein(MIIP)modulation in M2 macrophages within the tumor microenvironment and the potential of targeting the MIIP-stimulator of interferon genes(STING)pathway in colorectal cancer(CRC)therapy.Methods:MIIP expression was analyzed for associations with the STING pathway and M2 macrophage infiltration using public datasets and clinical CRC samples.CRC cells were genetically modified using lentiviral vectors to overexpress or silence MIIP and STING.The interactions of genetically modified CRC cells with macrophages were studied in co-culture systems.Techniques,including immunofluorescence staining,RT‒qPCR,western blot,ELISA,flow cytometry,and Transwell migration and invasion assays,were used to evaluate the crosstalk between CRC cells and macrophages.An orthotopic mouse CRC model was developed to study the effects of MIIP on M2 macrophage polarization and tumor metastasis through the STING-NFκB2-IL10 axis.The therapeutic significance of a STING antagonist was also assessed in vivo.Results:Analyses of The Cancer Genome Atlas(TCGA)cohort and our CRC cohort revealed low MIIP expression is associated with STING pathway activation,increased M2 macrophage infiltration,and poor clinical outcomes.The results of functional experiments demonstrated that MIIP inhibits IL10 production via the STING-TRAF3-NFκB2 axis in CRC cells,suppressing M2 macrophage polarization in co-culture systems.Conversely,M2 macrophages promoted CRC cell migration and invasion in an IL10-dependent manner.In vitro and in vivo studies confirmed that the MIIP-mediated feedback loop between CRC cells and macrophages depends on the STING-NFκB2-IL10 axis.Furthermore,inhibition of STING expression in a mouse model reduced M2 macrophage polarization and tumor metastasis.Conclusions:This study established MIIP as a crucial regulator of macrophage polarization in the CRC tumor microenvironment,providing new insights into the role in suppressing CRC progression and immune-tumor crosstalk.These findings highlight the potential of targeting the STING pathway as a therapeutic strategy for CRC patients who respond poorly to immune checkpoint inhibitors.
基金supported by the Guangdong Basic and Applied Basic Research Foundation(2022A1515220184,Lewei Zhu)Hebei Natural Science Foundation(H2024105019).
文摘The tumor microenvironment(TME)is a complex network composed of non-tumor cells,extracellular matrix,blood vessels,and various molecular signals that surround and profoundly influence tumor progression.As one of the key immune effector cells within the TME,mast cells(MCs)exhibit functional complexity,and their specific roles remain widely debated.Depending on the cancer type,spatial distribution,and interactions with other TME components,MCs can demonstrate dual regulatory capabilities—either promoting or inhibiting tumor growth.This characteristic has made them an important focus in current tumor immunology research.This review aims to systematically review the current understanding of MCs in the TME,with emphasis on their characteristics and functional differences across various tumor types,pathological status,and species.In recent years,advances in the understanding of MC markers,activation mechanisms,and biological functions have made targeting specific MC subsets an emerging therapeutic strategy.By comprehensively examining the origin,activation mechanisms,cellular interactions,and therapeutic regulation ofMCs,this review provides new perspectives and a basis for future directions in tumor research and treatment.
