Up-regulation of Tim-3 Expression Contributes to Development of Burn-induced T Cell Immune Suppression in Mice

T cell immunoglobulin and mucin domain 3 （Tim-3） is well known to negatively regulate T cells responses, but its role in burn-induced T cells immune suppression remains unclear. In the present study, in order to identify the relationship between Tim-3 expression and post-burn T cells immune suppression, C57BL/6 mice were subjected to burn injury or sham injury, and the liver and spleen were harvested at the day 1 after operation. The expression level of Tim-3 on hepatic or splenic T cells and the functional properties of Tim-3＋ T cells were evaluated. It was found burn injury induced dramatically elevated Tim-3 expression on both hepatic and splenic CD4＋ and CD8＋ T cells in contrast with the post-burn depletion of T cells. Furthermore, Tim-3 expression was correlated with the suppressive phenotype of T cells following burn injury, including increased expression of anti-inflammatory cytokine IL-10, decreased expression of pro-inflammatory cytokines IFN-γ and TNF-α, reduced T cell proliferation and elevated co-expression of Tim-3 and PD-1. Moreover, Tim-3＋ T cells subsets were more prone to spontaneous apoptosis than Tim-3- T cells subsets. Our findings reinforce the idea that the up-regulated expression of Tim-3 on T cells after burn injury plays an important role in the development and maintenance of burn-induced T cell immune suppression.

Contribution of myeloid-derived suppressor cells to tumor-induced immune suppression,angiogenesis,invasion and metastasis

Growing evidence suggests that myeloid-derived suppressor cells （MDSCs）,which have been named ＂immature myeloid cells＂ or ＂myeloid suppressor cells＂ （MSCs）,play a critical role during the progression of cancer in tumor-bearing mice and cancer patients.As their name implies,these cells are derived from bone marrow and have a tremendous potential to suppress immune responses.Recent studies indicated that these cells also have a crucial role in tumor progression.MDSCs can directly incorporate into tumor endothelium.They secret many pro-angiogenic factors as well.In addition,they play an essential role in cancer invasion and metastasis through inducing the production of matrix metalloproteinases （MMPs）,chemoattractants and creating a pre-metastatic environment.Increasing evidence supports the idea that cancer stem cells （CSCs） are responsible for tumorigenesis,resistance to therapies,invasion and metastasis.Here,we hypothesize that CSCs may ＂hijack＂ MDSCs for use as alternative niche cells,leading to the maintenance of stemness and enhanced chemo-and radio-therapy resistance.The countermeasure that directly targets to MDSCs may be useful for against angiogenesis and preventing cancer from invasion and metastasis.Therefore,the study of MDSCs is important to understand tumor progression and to enhance the therapeutic efficacy against cancer.

Tricking the tumour microenvironment into becoming our best rational drug design factory:reversal of immune suppression

The immune cellular components of the tumour microenvironment are a diverse group of cells that paradoxically are now appreciated to have a coordinated opposing duality of either promoting or retarding tumour growth.Manipulating this seemingly dynamic interaction for therapeutic benefit is a hotbed of much research.Recent findings in tumour immunology(both preclinical and clinical)build on more than a century of insights and provide a way forward to improving patient outcomes,long term survival and the predictability of“cures”.This opinion piece attempts to summarise some of these historical and contemporary insights with a view to describing eminently testable therapeutic solutions.

Effect of Fuzheng Jiedu granule on immunological function and level of immune-related cytokines in immune-suppressed mice

Fuzheng Jiedu granule exhibits a number of health benefits and it is thought that the mechanisms involved in these effects are due to the modulation of immunity. In this article, we studied the effect of Fuzheng Jiedu granule on immunological function and the expression of immune-related cytokines in immune-suppressed mice. 72 mice were randomly divided into six groups, with 12 in each group. The control groups included an untreated group, a negative control group（Cyclophosphamide） and a positive control group（Astragalus polysaccharide）. There were three treated groups, which were given different doses of Fuzheng Jiedu granule： a low dose（100 mg kg^（–1））, a medium dose（400 mg kg^（–1）） and a high dose（600 mg kg^（–1））. With the exception of the untreated control animals, each group received an intraperitoneal injection of Cyclophosphamide（100 mg kg^（–1）） for 3 days to establish the immune-suppressed model. Mice were then treated for 19 consecutive days and, 24 h after the last treatment, blood was taken for the eyeballs and serum separation was performed. Analysis was made of the levels of related cytokines（IgA, IgG, IgM, IL-6, IFN-γ, C3, C4 and TNF-α）, the transformation of lymphocytes and the immune organ indexes. The results showed that Fuzheng Jiedu granule can improve the levels of cytokines, the rate of proliferation of lymphocytes and the immune organ indexes of immune-suppressed mice.

Immune phenotypes of prostate cancer cells: Evidence of epithelial immune cell-like transition?

Prostate cancers(PCa)have been reported to actively suppress antitumor immune responses by creating an immune-suppressive microenvironment.There is mounting evidence that PCas may undergo an‘‘Epithelial Immune Cell-like Transition’’(EIT)by expressing molecules conventionally associated with immune cells(e.g.,a variety of cytokines/receptors,immune transcription factors,Ig motifs,and immune checkpoint molecules),which subsequently results in the suppression of anti-cancer immune activity within the tumor microenvironment.Recent progress within the field of immune therapy has underscored the importance of immune checkpoint molecules in cancer development,thus leading to the development of novel immunotherapeutic approaches.Here,we review the expression of select immune checkpoint molecules in PCa epithelial and associated immune cells,with particular emphasis on clinical data supporting the concept of an EIT-mediated phenotype in PCa.Furthermore,we summarize current advances in anti-immune checkpoint therapies,and provide perspectives on their potential applicability.

Does steroid-free immunosuppression improve the outcome in kidney transplant recipients compared to conventional protocols?

Steroids continue to be the cornerstone of immune suppression since the early days of organ transplantation.Steroids are key component of induction protocols,maintenance therapy and in the treatment of various forms of rejection.Prolonged steroid use resulted in significant side effects on almost all the body organs owing to the presence of steroid receptors in most of the mammalian cells.Kidney allograft recipients had to accept the short and long term complications of steroids because of lack of effective alternatives.This situation changed with the introduction of newer and more effective immune suppression agents with a relatively more acceptable side effect profile.As a result,the clinicians have been contemplating if it is the time to abandon the unquestionable reliance on maintenance steroids in modern transplantation practice.This review aims to evaluate the safety and efficacy of various steroid-minimization approaches(steroid avoidance,early steroid withdrawal,and late steroid withdrawal)in kidney transplant recipients.A meticulous electronic search was conducted through the available data resources like SCOPUS,MEDLINE,and Liverpool University library e-resources.Relevant articles obtained through our search were included.A total number of 90 articles were eligible to be included in this review[34 randomised controlled trials(RCT)and 56 articles of other research modalities].All articles were evaluating the safety and efficacy of various steroidfree approaches in comparison to maintenance steroids.We will cover only the RCT articles in this review.If used in right clinical context,steroid-free protocols proved to be comparable to steroid-based maintenance therapy.The appropriate approach should be tailored individually according to each recipient immunological challenges and clinical condition.

<i>Leishmania donovani</i>-Induced Immune Dysregulation among Sudanese Patients with Visceral and Post Kala-Azar Dermal Leishmaniases: Possible Roles in Pathogenesis

L. donovani infections (visceral and post kala-azar dermal leishmaniases) are characterized by infection-induced reversible immune suppression. Autoimmunity is a well-documented phenomenon among patients with primary immune deficiencies. This study aimed to study auto-immune phenomena accompanying L. donovani infections. In a prospective case-controlled study and following informed consent, 155 individuals with visceral leishmaniasis (VL;n = 62), post kala-azar dermal leishmaniasis (PKDL;n = 31) and apparently healthy volunteers (n = 62) were recruited. Sera antinuclear (ANA), anti-dsDNA, anti-thyroid peroxidase (TPO), anti-smooth muscles (ASMA) and F-actin auto-antibodies were measured using ELISA and indirect immune-fluorescence assay. The mean ages of VL, PDKL patients and apparently healthy volunteers were: 17.5 ± 12.5, 15.0 ± 7.0 and 17.5 ± 9.5 years with Male:Female ratios of 2:0, 1:2 and 1:5 respectively. Significantly high frequencies of F-actin (74.2%;46/62) and ASMA (50%;31/62) auto-antibodies were seen among VL patients (p = 0.003, p = 0.001) compared to apparently healthy volunteers. Likewise, significantly high frequencies of F-actin (64.5%;20/31;p = 0.001), ASMA (42%;13/31;p = 0.003), ANA (36%;11/31;p = 0.001) and anti-dsDNA (16%;5/31;p = 0.01) auto-antibodies were seen among PKDL patients. Development of tissue-based autoantibodies in L. donovani infections probably indicates loss of peripheral tolerance with activation of circulating auto-reactive T and B cells probably contributing to disease pathogenesis (increased bilirubin/liver enzymes, prolonged QT interval/arrythmias and blood cytopenias). In conclusion, L. donovani infection-induced immune suppression with development of tissue-based auto-antibodies is prevalent among Sudanese patients with VL and PKDL leishmaniases and contributes to some aspects of the disease pathogenesis.

Emerging roles of plasmacytoid dendritic cell crosstalk in tumor immunity

Plasmacytoid dendritic cells(pDCs)are a pioneer cell type that produces type I interferon(IFN-I)and promotes antiviral immune responses.However,they are tolerogenic and,when recruited to the tumor microenvironment(TME),play complex roles that have long been a research focus.The interactions between p DCs and other components of the TME,whether direct or indirect,can either promote or hinder tumor development;consequently,p DCs are an intriguing target for therapeutic intervention.This review provides a comprehensive overview of p DC crosstalk in the TME,including crosstalk with various cell types,biochemical factors,and microorganisms.An in-depth understanding of p DC crosstalk in TME should facilitate the development of novel p DC-based therapeutic methods.

Research progress of traditional Chinese medicine in regulating tumor microenvironment

The tumor microenvironment(TME)plays a crucial role in facilitating tumorigenesis and progression.Consequently,there is significant research interest within the oncology community in developing interventions that target the TME.Extensive research has been conducted on the mechanism of traditional Chinese medicine(TCM)in tumor therapy,revealing notable similarities between its theoretical framework and that of the TME.TCM has the ability to regulate various components of the microenvironment,including the modulation of proportions of T cell subsets,enhancement of the quantity and activity of NK cells,regulation of polarization of tumor-associated macrophages,suppression of expression of myeloid-derived suppressor cells,reduction of accumulation of tumor-associated endothelial cells,downregulation of the quantity and function of tumor-associated fibroblasts,and modulation of the architecture of the extracellular matrix.These multifaceted interventions ultimately lead to the attainment of anti-tumor objectives.This comprehensive review encompasses a thorough analysis of relevant literature from both domestic and international sources,with a specific emphasis on elucidating the mechanisms through which TCM compound formulas,single drugs,and monomeric components regulate the TME.

Downregulation of orosomucoid 2 acts as a prognostic factor associated with cancer-promoting pathways in liver cancer

BACKGROUND Liver cancer has a high mortality and morbidity rate throughout the world.In clinical practice,the prognosis of liver cancer patients is poor,and the complex reasons contribute to treatment failures,including fibrosis,hepatitis viral infection,drug resistance and metastasis.Thus,screening novel prognostic biomarkers is of great importance for guiding liver cancer therapy.Orosomucoid genes(ORMs)encode acute phase plasma proteins,including orosomucoid 1(ORM1)and ORM2.Previous studies showed their upregulation upon inflammation,but the specific function of ORMs has not yet been determined,especially in the development of liver cancer.AIM To determine the expression of ORMs and their potential function in liver cancer.METHODS Analysis of the expression of ORMs in different human tissues was performed on data from the HPA RNA-seq normal tissues project.The expression ratio of ORMs was determined using the HCCDB database,including the ratio between liver cancer and other cancers,normal liver and other normal tissues,liver cancer and adjacent normal liver tissues.Analysis of ORM expression in different cancer types was performed using The Cancer Genome Atlas and TIMER database.The expression of ORMs in liver tumor tissues and adjacent normal tissues were further confirmed using Gene Expression Omnibus data,including GSE36376 and GSE14520.The 10-year overall survival(OS),progression-free survival(PFS)and relapse-free survival(RFS)rates between high and low ORM expression groups in liver cancer patients were determined using the Kaplan-Meier plotter tool.Gene Set Enrichment Analysis(GSEA)was employed to explore the ORM2-associated signaling network.Correlations between ORM2 expression and tumor purity or the infiltration level of macrophages in liver tumor tissues were determined using the TIMER database.The correlation between ORM2 gene levels,tumor-associated macrophage(TAM)markers(including CD68 and TGFβ1)and T cell immunosuppression(including CTLA4 and PD-1)in liver tumor tissues and liver GTEx was determined using the GEPIA database.RESULTS ORM1 and ORM2 were highly expressed in normal liver and liver tumor tissues.ORM1 and ORM2 expression was significantly decreased in liver tumor tissues compared with adjacent normal tissues,and similar results were also noted in cholangiocarcinoma,esophageal carcinoma,and lung squamous cell carcinoma.Further analysis of the Gene Expression Omnibus Database also confirmed the downregulation of ORM1 and ORM2 in liver tumors.Survival analysis showed that the high ORM2 group had better survival rates in OS,PFS and RFS.ORM1 only represented better performance in PFS,but not in OS or RFS.GSEA analysis of ORM2 from The Cancer Genome Atlas liver cancer data identified that ORM2 positively associated with the G2/M checkpoint,E2F target signaling,as well as Wnt/β-catenin and Hedgehog signaling.Moreover,apoptosis,IFN-αresponses,IFN-γresponses and humoral immune responses were upregulated in the ORM2 high group.ORM2 expression was negatively correlated with the macrophage infiltration level,CD68,TGFβ1,CTLA4 and PD-1 levels.CONCLUSION The results showed that ORM1 and ORM2 were highly expressed specifically in liver tissues,whereas ORM1 and ORM2 were downregulated in liver tumor tissues.ORM2 is a better prognostic factor for liver cancer.Furthermore,ORM2 is closely associated with cancer-promoting pathways.

Enhanced CD3^+/CD4^+ T Cell Activities and Modulation of Th1/Th2 Lineage Development in Irradiated Rats Due to Treatment with the Male Zooid of Antheraea Pernyi Extracts

Objective： Cancer patients undergoing large dose radiotherapy exhibit multifaceted defects in their immune capacity that are likely to contribute to an increased susceptibility to infections and disease progression. The immune impairment may also constitute a barrier to effective immunotherapeutic interventions. Here, we evaluate whether supplementation with the male zooid of Antheraea pernyi extracts could enhance immune function in irradiated rats. Methods： Fifty male Wistar rats were randomly divided into a control group, a simple radiation group and a treatment group. The mice in the simple irradiation and treatment groups were given whole-chest irradiation with 6Gy. In the treatment group, the male zooid of Antheraea pernyi extracts was gavaged at the doses of 16.53mg/kg （large dose group）, 2.62mg/kg （medium dose group）, and 0.564mg/kg （small dose group） once a day for 14 days. The thymus and spleen indices were calculated. T cell subsets in peripheral blood were determined by flow cytometry and the expressions of IL-2, IFN-γ, IL-4 and IL-10 in sera were determined by ELISA on the 15th day. Results： The thymus index and spleen index of the high dose treatment group were statistically lower than that of the control group and higher than that of the radiation group （P〈0.01）. CD3＋ and CD4＋ T cells in the peripheral blood were increased in the high dose treatment group and decreased in the radiation group （P〈0.01）. Expression of IL-2 and INF-T in the radiation group was lower than that in control, and significantly increased during therapy. The production of IL-4 and IL-10 could be induced by radiation and was inhibited in the high dose treatment group （P〈0.01）. Conclusion： Our data indicate that the male zooid of Antheraea pernyi extracts may be administrated to improve immune function in irradiated rats and reverse the radial immune inhibition of rats by stimulating the proliferation of Th ceils and inducing the differentiation of Th2 to Th1.

Prevalence of diverticulosis in recurrent Clostridium difficile infection

AIM:To re-evaluate the theory that colonic diverticulosis is associated with relapse of Clostridium difficile associated disease (CDAD) in light of data suggesting increasing rates of CDAD infection and relapse.METHODS: Charts were reviewed for patients with recurrent CDAD who had also had a prior colonoscopy or flexible sigmoidoscopy. An age and gender matched control group was used to compare the prevalence of diverticulosis.RESULTS: Twenty-two patients met the study criteria, and the prevalence of diverticulosis in patients with CDAD relapse was 23% compared to 32% in age and sex matched controls (P=0.44). A significant proportion of patients with CDAD relapse had comorbidities associated with immune suppression.CONCLUSION: Diverticulosis does not appear to be associated with CDAD relapse.

The inhibitory effect of adenosine on tumor adaptive immunity and intervention strategies

Adenosine(Ado)is significantly elevated in the tumor microenvironment(TME)compared to normal tissues.It binds to adenosine receptors(AdoRs),suppressing tumor antigen presentation and immune cell activation,thereby inhibiting tumor adaptive immunity.Ado downregulates major histocompatibility complex II(MHC II)and co-stimulatory factors on dendritic cells(DCs)and macrophages,inhibiting antigen presentation.It suppresses anti-tumor cytokine secretion and T cell activation by disrupting T cell receptor(TCR)binding and signal transduction.Ado also inhibits chemokine secretion and KCa3.1 channel activity,impeding effector T cell trafficking and infiltration into the tumor site.Furthermore,Ado diminishes T cell cytotoxicity against tumor cells by promoting immune-suppressive cytokine secretion,upregulating immune checkpoint proteins,and enhancing immune-suppressive cell activity.Reducing Ado production in the TME can significantly enhance anti-tumor immune responses and improve the efficacy of other immunotherapies.Preclinical and clinical development of inhibitors targeting Ado generation or AdoRs is underway.Therefore,this article will summarize and analyze the inhibitory effects and molecular mechanisms of Ado on tumor adaptive immunity,as well as provide an overview of the latest advancements in targeting Ado pathways in anti-tumor immune responses.

Intercellular Trogocytosis Plays an Important Role in Modulation of Immune Responses

Intercellular communication is an important means of molecular information transfer through exchange of membrane proteins from cells to cells. Advent of the latest analytical and imaging tools has allowed us to enhance our understanding of the cellular communication through the intercellular exchange of intact membrane patches, also called trogocytosis, which is a ubiquitous phenomenon. Immune responses against pathogens or any foreign antigens require fine immune regulation, where cellular communications are mediated by either soluble or cell surface molecules. It has been demonstrated that the membrane molecule transfer between immune cells such as dendritic and T cells can be derived through internalization/recycling pathway, dissociation-associated pathway, uptake of exosomes and membrane nanotube formations. Recent evidence implicates the trogocytosis as an important mechanism of the immune system to modulate immune responses. Exchange of membrane molecules/ antigens between immune cells has been observed for a long time, but the mechanisms and functional consequences of these transfers remain unclear. In this review, we discuss the possible mechanisms of trogocytosis and its physiological relevance to immune system, with special reference to T cells and the stimulatory or suppressive immune responses derived from T cells with acquired dendritic cell membrane molecules. Cellular ＆ Molecular Immunology. 2008;5（4）：261-269.

Erythroid Lineage Cells in the Liver:Novel Immune Regulators and Beyond

The lineage of the erythroid cell has been revisited in recent years. Instead of being classified as simply inert oxygen carriers, emerging evidence has shown that they are a tightly regulated in immune potent population with potential devel-opmental plasticity for lineage crossing. Erythroid cells have been reported to exert immune regulatory function through secreted cytokines, or cell-cell contact, depending on the conditions of the microenvironment and disease models. In this review, we explain the natural history of erythroid cells in the liver through a developmental lens, as it offers perspec-tives into newly recognized roles of this lineage in liver biology. Here, we review the known immune roles of erythroid cells and discuss the mechanisms in the context of disease models and stages. Then, we explore the capability of erythroid lineage as a cell source for regenerative medicine. We propose that the versatile lineage of erythroid cells provides an underappreciated and potentially promising area for basic and translational research in the field of liver disease.

Dynamic Behavior and Function of Foxp3^+ Regulatory T Cells in Tumor Bearing Host

Regulatory T cells （Tregs） expressing forkhead/winged-helix transcription factor Foxp3 represent a distinct lineage of lymphocytes which play a central role in protecting the host from autoimmune diseases. However, Tregs also pose a major problem to anti-tumor immunity. Growing body of evidence from both laboratory and clinical investigations has demonstrated that expansion and accumulation of these immunosuppressive cells correlates with advanced tumor growth and predicts poor disease prognosis. How tumor development subverts normal self-tolerance function of Tregs thereby thwarts host anti-tumor immunity remains elusive. This review will discuss our current knowledge in understanding the dynamics and plasticity of Foxp3~ Treg activation and induction in tumor bearing hosts and their interaction with various antigen presenting cells （APCs） in tumor microenvironment leading to the establishment of active local and systemic immune suppression. Cellular ＆ Molecular Immunology.

The cellular metabolic landscape in the tumor milieu regulates the activity of myeloid infiltrates

Malignant cells upregulate distinct energy metabolism programs that support their proliferation,migration,and adaptation to the stressful tumor microenvironment(TME).Additionally,this exaggerated metabolic activity allows cancer cells to hijack essential nutrients and outcompete neighboring infiltrating immune cells,thereby impairing antitumor immunity.During recent years,there has been great interest in the field to understand the tumor-induced energy metabolism signals that regulate the function of immune cells in individuals with cancer.Accordingly,it is now well accepted that uncovering the mechanisms that instruct the metabolic behavior of cancer cells and tumor-associated immune cells is an indispensable strategy for the development of new approaches to overcome immune suppression in tumors.Thus,in this minireview,we briefly discuss the interaction between particular metabolic signaling pathways and immunosuppressive activity in different subsets of myeloid cells within the TME.Additionally,we illustrate potential central mechanisms controlling the metabolic reprogramming of myeloid cells in response to tumor-derived factors.

Pathological conditions re-shape physiological Tregs into pathological Tregs

CD4^(+)FOXP3^(+)regulatory T cells(Tregs)are a subset of CD4 T cells that play an essential role in maintaining peripheral immune tolerance,controlling acute and chronic inflammation,allergy,autoimmune diseases,and anti-cancer immune responses.Over the past 20 years,a significant progress has been made since Tregs were first characterized in 1995.Many concepts and principles regarding Tregs generation,phenotypic features,subsets(tTregs,pTregs,iTregs,and iTreg35),tissue specificity(central Tregs,effector Tregs,and tissue resident Tregs),homeostasis(highly dynamic and apoptotic),regulation of Tregs by receptors for PAMPs and DAMPs,Treg plasticity(re-differentiation to other CD4 T helper cell subsets,Th1,Th2,Tfh,and Th17),and epigenetic regulation of Tregs phenotypes and functions have been innovated.In this concise review,we want to briefly analyze these eight new progresses in the study of Tregs.We have also proposed for the first time a novel concept that“physiological Tregs”have been re-shaped into“pathological Tregs”in various pathological environments.Continuing of the improvement in our understanding on this important cellular component about the immune tolerance and immune suppression would lead to the future development of novel therapeutics approaches for acute and chronic inflammatory diseases,allergy,allogeneic transplantation-related immunity,sepsis,autoimmune diseases,and cancers.

The tumor immunosuppressive microenvironment impairs the therapy of anti-HER2/neu antibody

It has been well established that immune surveillance plays critical roles in preventing the occurrence and prog-ression of tumor.More and more evidence in recent years showed the host anti-tumor immune responses also play important roles in the chemotherapy and radiotherapy of cancers.Our previous study found that tumor-targeting therapy of anti-HER2/neu mAb is mediated by CD8+T cell responses.However,we found here that enhancement of CD8+T cell responses by combination therapy with IL-15R/IL-15 fusion protein or anti-CD40,which are strong stimultors for T cell responses,failed to promote the tumor therapeutic effects of anti-HER2/neu mAb.Analysis of tumor microenviornment showed that tumor tissues were heavily infiltrated with the immunosuppressive macrophages and most tumor infiltrating T cells,especially CD8^(+)T cells,expressed high level of inhibitory co-signaling receptor PD-1.These data suggest that tumor microenvironment is dominated by the immunosuppressive strategies,which thwart anti-tumor immune responses.Therefore,the successful tumor therapy should be the removal of inhibitory signals in the tumor microenvir-onment in combination with other therapeutic strategies.

HIF1α epigenetically repressed macrophages via CRISPR/Cas9-EZH2 system for enhanced cancer immunotherapy

Immune suppressive microenvironment in tumor emerges as the main obstacle for cancer immunotherapy.In this study,we identified that HIF1α was activated in the tumor associated macrophages and acted as an important factor for the immune suppressive microenvironment.Epigenetically silencing of Hif1αvia histone H3 methylation in the promoter region was achieved by CRISPR/dCas9-EZH2 system,in which histone H3 methylase EZH2 was recruited to the promoter region specifically.The Hif1αsilenced macrophage,namely HERM(Hif1αEpigenetically Repressed Macrophage)manifested as inheritable tumor suppressing phenotype.In the subcutaneous B16-F10 melanoma syngeneic model,intratumoral injection of HERMs reprogrammed the immune suppressive microenvironment to the active one,reducing tumor burden and prolonging overall survival.Additionally,HERMs therapy remarkably inhibited tumor angiogenesis.Together,our study has not only identified a promising cellular and molecular target for reverting immune suppressive microenvironment,but also provided a potent strategy for reprogramming tumor microenvironment via epigenetically reprogrammed macrophages.