Immunotherapy has brought unprecedented breakthroughs to advanced malignant tumors,yet the immune microenvironment shaped by the tumor stroma has often been underestimated in the traditional focus on the“immune check...Immunotherapy has brought unprecedented breakthroughs to advanced malignant tumors,yet the immune microenvironment shaped by the tumor stroma has often been underestimated in the traditional focus on the“immune checkpoint-T cell”axis.Collagen not only constitutes a mechanical barrier that distinguishes between the periphery and core of solid tumors but also systematically remodels the orientation of metabolism,vasculature,and immune cell phenotypic plasticity through its spatial density,fiber arrangement,and crosslinking patterns(F igure 1)[1,2].Abundant evidence suggests that over-accumulated types I and III collagen drive CD8+T cell exhaustion,NK cell functional inhibition,and tumor-associated macrophage polarization through ligand-receptor networks involving LAIR-1,DDR2,andβ1/β3 integrins[3-6].Mechanistically,collagen engagement of LAIR-1 delivers inhibitory signals in effector lymphocytes,promoting dysfunctional or exhausted states[7-9].In parallel,collagen-β1/β3 integrin signaling activates mechanotransduction pathways(e.g.,FAK/SRC),reducing T-cell motility and immune-tumor contact,while DDR2 activation supports matrix-remodeling programs that limit lymphocyte trafficking.展开更多
Post-translational modifications(PTMs)regulate the occurrence and development of cancer,and lactylation modification is a new form of PTMs.Recent studies have found that lactic acid modification can regulate the immun...Post-translational modifications(PTMs)regulate the occurrence and development of cancer,and lactylation modification is a new form of PTMs.Recent studies have found that lactic acid modification can regulate the immune tolerance of cancer cells.The classical theory holds that prostate apoptosis response-4(PAR-4)is a tumor suppressor protein.However,our recent research has found that PAR-4 has a biological function of promoting cancer in hepatocellular carcinoma(HCC),and our analysis shows that PAR-4 can be modified of lactic acid.These research evidences suggest that PAR-4 lactylation modification may drive immune tolerance in HCC.Therefore,inhibiting PAR-4 lactylation modification is very likely to increase the sensitivity of HCC to immunotherapy.展开更多
Background:Aberrant expression of transcription factors(TFs)is a key mechanism mediating tumor immune escape and therapeutic resistance.The involvement of E26 transformation-specific(ETS)family of TFs in immune regula...Background:Aberrant expression of transcription factors(TFs)is a key mechanism mediating tumor immune escape and therapeutic resistance.The involvement of E26 transformation-specific(ETS)family of TFs in immune regulation is not fully understood.The study aimed to elucidate the function of E-twenty-six variant 4(ETV4)in tumor immune evasion and its potential as a predictive biomarker for immunotherapy in melanoma.Methods:The expression patterns of ETS family TFs were analyzed in melanoma and hepatocellular carcinoma(HCC).Single-cell RNA sequencing(scRNA-seq)was used to dissect the cellular expression and function of ETV4 in the tumor microenvironment.Functional studies and murine models were employed to investigate the role of ETV4 in T cell-mediated tumor killing and tumor growth.The correlation between ETV4 expression level and patient responsiveness to programmed cell death protein 1(PD-1)blockade therapy was evaluated.Results:TFs in the ETS family were found to effectively stratify melanoma and HCC patients into prognostic subgroups.In melanoma,the polyoma enhancer activator 3(PEA3)subfamily,particularly ETV4 and ETV5,showed a negative correlation with immune infiltration.scRNA-seq analysis showed that ETV4 is preferentially expressed in melanoma cells and involves in mediating tumor-immunocyte interactions.Functional studies demonstrated that ETV4 impairs T cell-mediated tumor killing by transcriptionally upregulating programmed death-ligand 1(PD-L1).In immunocompetent murine models,ETV4 downregulation significantly suppressed tumor growth.Furthermore,high ETV4 expression correlated with poor responses to anti-PD-1 therapy.Conclusion:Our findings identify ETV4 as a key transcriptional regulator of immune evasion in melanoma by controlling PD-L1 expression.ETV4 may act as a predictive biomarker for immunotherapy outcomes.展开更多
Alzheimer’s disease,a devastating neurodegenerative disorder,is characterized by progressive cognitive decline,primarily due to amyloid-beta protein deposition and tau protein phosphorylation.Effectively reducing the...Alzheimer’s disease,a devastating neurodegenerative disorder,is characterized by progressive cognitive decline,primarily due to amyloid-beta protein deposition and tau protein phosphorylation.Effectively reducing the cytotoxicity of amyloid-beta42 aggregates and tau oligomers may help slow the progression of Alzheimer’s disease.Conventional drugs,such as donepezil,can only alleviate symptoms and are not able to prevent the underlying pathological processes or cognitive decline.Currently,active and passive immunotherapies targeting amyloid-beta and tau have shown some efficacy in mice with asymptomatic Alzheimer’s disease and other transgenic animal models,attracting considerable attention.However,the clinical application of these immunotherapies demonstrated only limited efficacy before the discovery of lecanemab and donanemab.This review first discusses the advancements in the pathogenesis of Alzheimer’s disease and active and passive immunotherapies targeting amyloid-beta and tau proteins.Furthermore,it reviews the advantages and disadvantages of various immunotherapies and considers their future prospects.Although some antibodies have shown promise in patients with mild Alzheimer’s disease,substantial clinical data are still lacking to validate their effectiveness in individuals with moderate Alzheimer’s disease.展开更多
Small intestinal villi are essential for nutrient absorption,and their impairment can lead to malabsorption.Small intestinal villous atrophy(VA)encompasses a heterogeneous group of disorders,including immune-mediated ...Small intestinal villi are essential for nutrient absorption,and their impairment can lead to malabsorption.Small intestinal villous atrophy(VA)encompasses a heterogeneous group of disorders,including immune-mediated conditions(e.g.,celiac disease,autoimmune enteropathy,inborn errors of immunity),lymphoproliferative disorders(e.g.,enteropathy-associated T-cell lymphoma),infectious causes(e.g.,tropical sprue,Whipple’s disease),iatrogenic factors(e.g.,Olmesartanassociated enteropathy,graft-vs-host disease),as well as inflammatory and idiopathic types.These disorders are often rare and challenging to distinguish due to overlapping clinical,serological,endoscopic,and histopathological features.Through a systematic literature search using keywords such as small intestinal VA,malabsorption,and specific enteropathies,this review provides a comprehensive overview of diagnostic clues for VA and malabsorption.We systematically summarize the pathological characteristics of each condition to assist pathologists and clinicians in accurately identifying the underlying etiologies.Current studies still have many limitations and lack broader and deeper investigations into these diseases.Therefore,future research should focus on the development of novel diagnostic tools,predictive models,therapeutic targets,and mechanistic molecular studies to refine both diagnosis and management strategies.展开更多
Liver diseases are of growing interest to clinicians and researchers due to their high prevalence,difficulty in early diagnosis,and limited treatment options.The liver is an important organ at the intersection of many...Liver diseases are of growing interest to clinicians and researchers due to their high prevalence,difficulty in early diagnosis,and limited treatment options.The liver is an important organ at the intersection of many metabolic and immune pathways.To this end,it contains a large number of immune cells of both the innate and adaptive immune system that perform multiple functions,detecting and destroying pathogens that enter the body through the intestine,as well as recognizing endogenous antigens.Immune cells in the liver have a complex regulation that can be impaired in various diseases such as metabolic dysfunctionassociated steatotic liver disease(MASLD),liver cancer,and biliary diseases.A growing body of evidence reinforces the realization that not only impaired metabolism but also many immune mechanisms underlie MASLD.The liver has complex bilateral immune and metabolic links with the gut microbiota,and disruptions of these links underlie the development and progression of both gastrointestinal and other organ diseases.In this regard,acting on immune mechanisms is a promising therapeutic target for liver diseases.展开更多
Dysfunction of anti-tumor immune responses is crucial for cancer progression. Immune checkpoint blockade(ICB), which can potentiate T cell responses, is an effective strategy for the normalization of host anti-tumor i...Dysfunction of anti-tumor immune responses is crucial for cancer progression. Immune checkpoint blockade(ICB), which can potentiate T cell responses, is an effective strategy for the normalization of host anti-tumor immunity. In recent years, immune checkpoints, expressed on both tumor cells and immune cells, have been identified;some of them have exhibited potential druggability and have been approved by the US Food and Drug Administration(FDA) for clinical treatment. However, limited responses and immune-related adverse events(ir AEs) cannot be ignored. This review outlines the development and applications of ICBs, potential strategies for overcoming resistance, and future directions for ICB-based cancer immunotherapy.展开更多
Hepatocellular carcinoma presents with three distinct immune phenotypes,including immune-desert,immune-excluded,and immune-inflamed,indicating various treatment responses and prognostic outcomes.The clinical applicati...Hepatocellular carcinoma presents with three distinct immune phenotypes,including immune-desert,immune-excluded,and immune-inflamed,indicating various treatment responses and prognostic outcomes.The clinical application of multi-omics parameters is still restricted by the expensive and less accessible assays,although they accurately reflect immune status.A comprehensive evaluation framework based on“easy-to-obtain”multi-model clinical parameters is urgently required,incorporating clinical features to establish baseline patient profiles and disease staging;routine blood tests assessing systemic metabolic and functional status;immune cell subsets quantifying subcluster dynamics;imaging features delineating tumor morphology,spatial configuration,and perilesional anatomical relationships;immunohistochemical markers positioning qualitative and quantitative detection of tumor antigens from the cellular and molecular level.This integrated phenomic approach aims to improve prognostic stratification and clinical decision-making in hepatocellular carcinoma management conveniently and practically.展开更多
Microglia are the resident macrophages of the central nervous system.They act as the first line of defense against pathogens and play essential roles in neuroinflammation and tissue repair after brain insult or in neu...Microglia are the resident macrophages of the central nervous system.They act as the first line of defense against pathogens and play essential roles in neuroinflammation and tissue repair after brain insult or in neurodegenerative and demyelinating diseases(Borst et al.,2021).Together with infiltrating monocyte-derived macrophages,microglia also play a critical role for brain tumor development,since immunosuppressive interactions between tumor cells and tumor-associated microglia and macrophages(TAM)are linked to malignant progression.This mechanism is of particular relevance in glioblastoma(GB),the deadliest form of brain cancer with a median overall survival of less than 15 months(Khan et al.,2023).Therefore,targeting microglia and macrophage activation is a promising strategy for therapeutic interference in brain disease.展开更多
Background:While the treatment of metastatic renal cell carcinoma(mRCC)is evolving due to immune checkpoint inhibitors(ICIs),optimal strategies for later lines of therapy have yet to be defined.The combination of lenv...Background:While the treatment of metastatic renal cell carcinoma(mRCC)is evolving due to immune checkpoint inhibitors(ICIs),optimal strategies for later lines of therapy have yet to be defined.The combination of lenvatinib and everolimus represents a viable option,and the present review aimed to summarize its activity,effectiveness,and safety.Methods:A systematic review of the literature was conducted using PubMed,targeting studies published between 2018 and 2025.Eligible studies included English-language prospective and retrospective trials reporting survival outcomes in mRCC patients treated with lenvatinib and everolimus after at least one ICI-containing regimen.Results:Nine studies met the inclusion criteria,encompassing a total of 441 patients.The lenvatinib and everolimus combination was primarily used in the third and subsequent lines of therapy.Median overall survival ranged from 7.5 to 24.5 months,while median progression-free survival was more consistent,between 6.1 and 6.7 months,except for one study reporting 12.9 months.Objective response rates varied widely(14.0%–55.7%).Adverse events of grade≥3 did not exceed the expected rate,with diarrhoea and proteinuria as the most reported events.Dose reductions and treatment discontinuations due to toxicity occurred but were generally lower than in prior pivotal trials.Conclusions:Real-world evidence suggests that lenvatinib and everolimus represent an effective and safe option after ICI failure in mRCC patients.Nevertheless,the lack of randomized phase III trials and the heterogeneity of existing studies highlight the need for more robust prospective research to guide post-ICI therapeutic strategies.展开更多
Immunotherapy offers the promise of a potential cure for cancer,yet achieving the desired therapeutic effect can be challenging due to the immunosuppressive tumor microenvironments(TMEs) present in some tumors.Therefo...Immunotherapy offers the promise of a potential cure for cancer,yet achieving the desired therapeutic effect can be challenging due to the immunosuppressive tumor microenvironments(TMEs) present in some tumors.Therefore,robust immune system activation is crucial to enhance the efficacy of cancer immunotherapy in clinical applications.Bacteria have shown the ability to target the hypoxic TMEs while activating both innate and adaptive immune responses.Engineered bacteria,modified through chemical or biological methods,can be endowed with specific physiological properties,such as diverse surface antigens,metabolites,and improved biocompatibility.These unique characteristics give engineered bacteria distinct advantages in stimulating anti-cancer immune responses.This review explores the potential regulatory mechanisms of engineered bacteria in modulating both innate and adaptive immunity while also forecasting the future development and challenges of using engineered bacteria in clinical cancer immunotherapy.展开更多
CD8^(+)T cell exhaustion,a critical challenge in the immune response to cancer,is characterized by a profound decline in the functionality of effector CD8^(+)T cells.This state of exhaustion is accompanied by the upre...CD8^(+)T cell exhaustion,a critical challenge in the immune response to cancer,is characterized by a profound decline in the functionality of effector CD8^(+)T cells.This state of exhaustion is accompanied by the upregulation of various inhibitory receptors and significant shifts in both transcriptional and epigenetic profiles,thus ultimately leading to inadequate tumor control.Therapeutic strategies aimed at reversing CD8^(+)T cell exhaustion have the potential to rejuvenate immune responses and enhance treatment efficacy.This review compiles current knowledge regarding the molecular mechanisms underlying CD8^(+)T cell exhaustion,including the roles of immune checkpoint molecules,the tumor microenvironment,metabolic reprogramming,transcription factors,and epigenetic modifications.Emerging therapeutic approaches designed to combat CD8^(+)T cell exhaustion are evaluated,with emphasis on the modulation of immune checkpoints;targeting of metabolic and transcriptional changes;and exploration of other innovative strategies,such as epigenetic editing and engineered CAR-T cells.Importantly,we expand the exhaustion concept to immune cells beyond CD8^(+)T cells,such as CD4^(+)T cells,natural killer cells,and myeloid populations,thereby highlighting the broader implications of systemic immunosuppression in the cancer context.Finally,we propose avenues for future research aimed at further elucidating the factors and molecular mechanisms associated with CD8^(+)T cell exhaustion,thereby underscoring the critical need for strategies aimed at reversing this state to improve outcomes in cancer immunotherapy.展开更多
Polytrauma with significant bone and volumetric muscle loss presents substantial clinical challenges.Although immune responses significantly influence fracture healing post-polytrauma,the cellular and molecular underp...Polytrauma with significant bone and volumetric muscle loss presents substantial clinical challenges.Although immune responses significantly influence fracture healing post-polytrauma,the cellular and molecular underpinnings of polytrauma-induced immune dysregulation require further investigation.While previous studies examined either injury site tissue or systemic tissue(peripheral blood),our study uniquely investigated both systemic and local immune cells at the same time to better understand polytrauma-induced immune dysregulation and associated impaired bone healing.Using single-cell RNA sequencing(scRNA-seq)in a rat polytrauma model,we analyzed blood,bone marrow,and the local defect soft tissue to identify potential cellular and molecular targets involved in immune dysregulation.We identified a trauma-associated immunosuppressive myeloid(TIM)cell population that drives systemic immune dysregulation,immunosuppression,and potentially impaired bone healing.We found CD1d as a global marker for TIM cells in polytrauma.展开更多
Currently,the use of immune checkpoint inhibitors(ICIs)has shown notable clinical efficacy in treating various malignant tumors,significantly improving patient prognosis.However,while ICIs enhance the body’s anti-tum...Currently,the use of immune checkpoint inhibitors(ICIs)has shown notable clinical efficacy in treating various malignant tumors,significantly improving patient prognosis.However,while ICIs enhance the body’s anti-tumor effects,they can also trigger immune-related adverse events(irAEs),with ICI-associated colitis being one of the more prevalent forms.This condition can disrupt treatment,necessitate drug discontinuation,and adversely affect therapeutic outcomes.In severe cases,irAEs may even become life-threatening.A recent case report by Hong et al highlights the importance of vigilance for ICI-associated colitis in patients experiencing symptoms such as diarrhea and abdominal pain,which can arise both during and even after completion of ICI treatment.Early identification,multidisciplinary management,and continuous monitoring of patients are essential steps to further improve outcomes.展开更多
BACKGROUND Immune checkpoint inhibitors(ICIs)have revolutionized cancer therapy but are associated with immune-related adverse events,including ICIs hepatitis.Mycophenolate mofetil(MMF)is often used as a second-line i...BACKGROUND Immune checkpoint inhibitors(ICIs)have revolutionized cancer therapy but are associated with immune-related adverse events,including ICIs hepatitis.Mycophenolate mofetil(MMF)is often used as a second-line immunosuppressive agent for steroid-refractory cases.However,there is no standardized approach to MMF tapering,leading to uncertainties regarding relapse risk,optimal tapering strategies,and long-term outcomes.AIM To evaluate current evidence on MMF tapering in ICI hepatitis,focusing on strategies,clinical outcomes,and the risk of hepatitis recurrence.Additionally,we explore the feasibility of reintroducing ICI therapy after immunosuppression withdrawal.METHODS A comprehensive literature search was conducted in PubMed,EMBASE,and clinical trial registries to identify studies reporting MMF use and tapering strategies in ICI hepatitis.We extracted data from manuscripts including patient characteristics,MMF dosing regimens,tapering duration,relapse rates,and oncologic outcomes.Risk factors for recurrence and successful tapering were analyzed.RESULTS There was significant heterogeneity in the duration of MMF taper,which ranged from 4 weeks to greater than 6 months.The tapering schedules presented were individualized based on the severity of liver injury,patient response to treatment,and risk factors for relapse.We summarize current tapering approaches,including rapid vs slow withdrawal,predictors of successful tapering,and alternative immunosuppressive strategies.The impact of MMF duration on liver recovery,relapse risk,and cancer prognosis will be discussed.Evidence on ICI rechallenge post-taper will also be reviewed.CONCLUSION While MMF is effective in managing ICI hepatitis,tapering remains a clinical challenge with potential risks of hepatitis flare and disease progression.Standardized tapering protocols are needed to optimize immunosuppression while preserving anticancer efficacy.Future studies should focus on biomarker-driven tapering strategies and prospective trials to establish best practices.展开更多
Microbes play a critical role in shaping immune development,with growing interest in how rhinovirus(RV)interacts with the host immune system,particularly in individuals with asthma and chronic obstructive pul-monary d...Microbes play a critical role in shaping immune development,with growing interest in how rhinovirus(RV)interacts with the host immune system,particularly in individuals with asthma and chronic obstructive pul-monary disease(COPD).Disruptions in microbial balance during RV infections can impair immune homeostasis and worsen disease outcomes.Recent studies emphasize RV-induced regulation of antiviral defenses,cytokine production,and immune tolerance.This review explores the interplay between RV,the immune system,and microbiota,highlighting the importance of these interactions in guiding effective therapies for respiratory in-fections.It advances existing literature by considering microbiota-mediated therapies as a novel approach to managing RV exacerbations in respiratory diseases like asthma and COPD.展开更多
In 1891,a New York surgeon named William Coley injected cancer patients with live bacteria,observing with fascination as some tumors shrank amid raging fevers.His crude experiments-later deemed reckless-nonetheless re...In 1891,a New York surgeon named William Coley injected cancer patients with live bacteria,observing with fascination as some tumors shrank amid raging fevers.His crude experiments-later deemed reckless-nonetheless revealed a tantalizing truth:The immune system,when properly provoked,could attack cancer.Over a century later,researchers have transformed this observation into a precision strike force.展开更多
Glioblastoma(GBM)is one of the most aggressive and treatment-resistant brain cancers.Despite years of research and clinical trials,especially using immune checkpoint inhibitors,therapeutic gains remain minimal[1,2].A ...Glioblastoma(GBM)is one of the most aggressive and treatment-resistant brain cancers.Despite years of research and clinical trials,especially using immune checkpoint inhibitors,therapeutic gains remain minimal[1,2].A recent study published in Nature by Faust Akl and colleagues begins to lift the veil on this mystery,uncovering a previously unknown mechanism of immune evasion in GBM[3].展开更多
Sepsis is characterized by immune dysregulation that are responsible for an increase in secondary in-fections and mortality.Acupuncture is a potential alternative treatment for sepsis.In this comprehensive literature ...Sepsis is characterized by immune dysregulation that are responsible for an increase in secondary in-fections and mortality.Acupuncture is a potential alternative treatment for sepsis.In this comprehensive literature review,we found that acupuncture is beneficial in treating immune disorders associated with sepsis.Acupuncture can improve immune disorders associated with sepsis and regulate the functions of innate and adaptive immune cells.Specifically,acupuncture can reduce the number of neutrophils in sep-sis,promote the polarization of macrophages towards M2-like macrophages,and alleviate inflammation by reducing the activation of microglia and astrocytes.Furthermore,acupuncture can increase the per-centage of T cells and modulate the balance between T cell subsets.The immunomodulatory mechanism of acupuncture in sepsis may be attributed to the balance of the autonomic nervous system,including activation of the sympathetic-adrenal axis,vagal-cholinergic pathway,and vagal-adrenal axis.In addition,acupuncture can inhibit inflammation by preserving the integrity of the intestinal barrier and regulating the composition of the intestinal microbiota.Clinical studies have also demonstrated that acupuncture can enhance the number of peripheral natural killer(NK)cells and T cell subsets,as well as the expres-sion of human leukocyte antigen DR(HLA-DR).Moreover,acupuncture can decrease the ratio of white blood cells to neutrophils and reduce the levels of inflammatory factors.Therefore,acupuncture has the potential to improve immune function in sepsis.Further investigation of its mechanism is expected to provide a scientific and reliable foundation for the application of acupuncture in sepsis treatment.展开更多
To the editor:The liver’s immune-privileged status allows for a unique microenvironment that supports tumour growth and metastasis.In hepatocellular carcinoma(HCC),the balance between cytotoxic T lymphocytes and regu...To the editor:The liver’s immune-privileged status allows for a unique microenvironment that supports tumour growth and metastasis.In hepatocellular carcinoma(HCC),the balance between cytotoxic T lymphocytes and regulatory T cells plays a crucial role in determining patient outcomes.The expression of programmed cell death ligand 1(PD-1)and other immune checkpoint molecules contributes to a pro-tumourigenic microenvironment and is associated with poor prognosis.Additionally,the heterogeneity of the immune microenvironment adds complexity to disease progression and treatment response.展开更多
文摘Immunotherapy has brought unprecedented breakthroughs to advanced malignant tumors,yet the immune microenvironment shaped by the tumor stroma has often been underestimated in the traditional focus on the“immune checkpoint-T cell”axis.Collagen not only constitutes a mechanical barrier that distinguishes between the periphery and core of solid tumors but also systematically remodels the orientation of metabolism,vasculature,and immune cell phenotypic plasticity through its spatial density,fiber arrangement,and crosslinking patterns(F igure 1)[1,2].Abundant evidence suggests that over-accumulated types I and III collagen drive CD8+T cell exhaustion,NK cell functional inhibition,and tumor-associated macrophage polarization through ligand-receptor networks involving LAIR-1,DDR2,andβ1/β3 integrins[3-6].Mechanistically,collagen engagement of LAIR-1 delivers inhibitory signals in effector lymphocytes,promoting dysfunctional or exhausted states[7-9].In parallel,collagen-β1/β3 integrin signaling activates mechanotransduction pathways(e.g.,FAK/SRC),reducing T-cell motility and immune-tumor contact,while DDR2 activation supports matrix-remodeling programs that limit lymphocyte trafficking.
基金supported by the National Natural Science Foundation of China(Nos.82573045,82460602,82560459)the Hainan Provincial Graduate Student Innovative Research Project(No.Qhys2024-440).
文摘Post-translational modifications(PTMs)regulate the occurrence and development of cancer,and lactylation modification is a new form of PTMs.Recent studies have found that lactic acid modification can regulate the immune tolerance of cancer cells.The classical theory holds that prostate apoptosis response-4(PAR-4)is a tumor suppressor protein.However,our recent research has found that PAR-4 has a biological function of promoting cancer in hepatocellular carcinoma(HCC),and our analysis shows that PAR-4 can be modified of lactic acid.These research evidences suggest that PAR-4 lactylation modification may drive immune tolerance in HCC.Therefore,inhibiting PAR-4 lactylation modification is very likely to increase the sensitivity of HCC to immunotherapy.
基金funded by the National Natural Science Foundation of China(Grant Nos.82204517 to T.Z.and 82404756 to J.Z.)the Science and Technology Program in Medicine and Health of Zhejiang Province(Grant No.2023KY726 to T.Z.).
文摘Background:Aberrant expression of transcription factors(TFs)is a key mechanism mediating tumor immune escape and therapeutic resistance.The involvement of E26 transformation-specific(ETS)family of TFs in immune regulation is not fully understood.The study aimed to elucidate the function of E-twenty-six variant 4(ETV4)in tumor immune evasion and its potential as a predictive biomarker for immunotherapy in melanoma.Methods:The expression patterns of ETS family TFs were analyzed in melanoma and hepatocellular carcinoma(HCC).Single-cell RNA sequencing(scRNA-seq)was used to dissect the cellular expression and function of ETV4 in the tumor microenvironment.Functional studies and murine models were employed to investigate the role of ETV4 in T cell-mediated tumor killing and tumor growth.The correlation between ETV4 expression level and patient responsiveness to programmed cell death protein 1(PD-1)blockade therapy was evaluated.Results:TFs in the ETS family were found to effectively stratify melanoma and HCC patients into prognostic subgroups.In melanoma,the polyoma enhancer activator 3(PEA3)subfamily,particularly ETV4 and ETV5,showed a negative correlation with immune infiltration.scRNA-seq analysis showed that ETV4 is preferentially expressed in melanoma cells and involves in mediating tumor-immunocyte interactions.Functional studies demonstrated that ETV4 impairs T cell-mediated tumor killing by transcriptionally upregulating programmed death-ligand 1(PD-L1).In immunocompetent murine models,ETV4 downregulation significantly suppressed tumor growth.Furthermore,high ETV4 expression correlated with poor responses to anti-PD-1 therapy.Conclusion:Our findings identify ETV4 as a key transcriptional regulator of immune evasion in melanoma by controlling PD-L1 expression.ETV4 may act as a predictive biomarker for immunotherapy outcomes.
基金supported by the Nature Science Foundation of Liaoning Province,Nos.2022-MS-211,2021-MS-064,and 2024-MS-048(all to YC).
文摘Alzheimer’s disease,a devastating neurodegenerative disorder,is characterized by progressive cognitive decline,primarily due to amyloid-beta protein deposition and tau protein phosphorylation.Effectively reducing the cytotoxicity of amyloid-beta42 aggregates and tau oligomers may help slow the progression of Alzheimer’s disease.Conventional drugs,such as donepezil,can only alleviate symptoms and are not able to prevent the underlying pathological processes or cognitive decline.Currently,active and passive immunotherapies targeting amyloid-beta and tau have shown some efficacy in mice with asymptomatic Alzheimer’s disease and other transgenic animal models,attracting considerable attention.However,the clinical application of these immunotherapies demonstrated only limited efficacy before the discovery of lecanemab and donanemab.This review first discusses the advancements in the pathogenesis of Alzheimer’s disease and active and passive immunotherapies targeting amyloid-beta and tau proteins.Furthermore,it reviews the advantages and disadvantages of various immunotherapies and considers their future prospects.Although some antibodies have shown promise in patients with mild Alzheimer’s disease,substantial clinical data are still lacking to validate their effectiveness in individuals with moderate Alzheimer’s disease.
基金Supported by National High-Level Hospital Clinical Research Funding,No.2022-PUMCH-B-022,and No.2022-PUMCH-D-002CAMS Innovation Fund for Medical Sciences,No.CIFMS 2021-1-I2M-003Undergraduate Innovation Program,No.2024dcxm025.
文摘Small intestinal villi are essential for nutrient absorption,and their impairment can lead to malabsorption.Small intestinal villous atrophy(VA)encompasses a heterogeneous group of disorders,including immune-mediated conditions(e.g.,celiac disease,autoimmune enteropathy,inborn errors of immunity),lymphoproliferative disorders(e.g.,enteropathy-associated T-cell lymphoma),infectious causes(e.g.,tropical sprue,Whipple’s disease),iatrogenic factors(e.g.,Olmesartanassociated enteropathy,graft-vs-host disease),as well as inflammatory and idiopathic types.These disorders are often rare and challenging to distinguish due to overlapping clinical,serological,endoscopic,and histopathological features.Through a systematic literature search using keywords such as small intestinal VA,malabsorption,and specific enteropathies,this review provides a comprehensive overview of diagnostic clues for VA and malabsorption.We systematically summarize the pathological characteristics of each condition to assist pathologists and clinicians in accurately identifying the underlying etiologies.Current studies still have many limitations and lack broader and deeper investigations into these diseases.Therefore,future research should focus on the development of novel diagnostic tools,predictive models,therapeutic targets,and mechanistic molecular studies to refine both diagnosis and management strategies.
文摘Liver diseases are of growing interest to clinicians and researchers due to their high prevalence,difficulty in early diagnosis,and limited treatment options.The liver is an important organ at the intersection of many metabolic and immune pathways.To this end,it contains a large number of immune cells of both the innate and adaptive immune system that perform multiple functions,detecting and destroying pathogens that enter the body through the intestine,as well as recognizing endogenous antigens.Immune cells in the liver have a complex regulation that can be impaired in various diseases such as metabolic dysfunctionassociated steatotic liver disease(MASLD),liver cancer,and biliary diseases.A growing body of evidence reinforces the realization that not only impaired metabolism but also many immune mechanisms underlie MASLD.The liver has complex bilateral immune and metabolic links with the gut microbiota,and disruptions of these links underlie the development and progression of both gastrointestinal and other organ diseases.In this regard,acting on immune mechanisms is a promising therapeutic target for liver diseases.
基金supported by the National Key Research and Development Program of China(No.2022YFE0102100)the National Natural Science Foundation of China(Nos.U22A20307 and 81930041)。
文摘Dysfunction of anti-tumor immune responses is crucial for cancer progression. Immune checkpoint blockade(ICB), which can potentiate T cell responses, is an effective strategy for the normalization of host anti-tumor immunity. In recent years, immune checkpoints, expressed on both tumor cells and immune cells, have been identified;some of them have exhibited potential druggability and have been approved by the US Food and Drug Administration(FDA) for clinical treatment. However, limited responses and immune-related adverse events(ir AEs) cannot be ignored. This review outlines the development and applications of ICBs, potential strategies for overcoming resistance, and future directions for ICB-based cancer immunotherapy.
文摘Hepatocellular carcinoma presents with three distinct immune phenotypes,including immune-desert,immune-excluded,and immune-inflamed,indicating various treatment responses and prognostic outcomes.The clinical application of multi-omics parameters is still restricted by the expensive and less accessible assays,although they accurately reflect immune status.A comprehensive evaluation framework based on“easy-to-obtain”multi-model clinical parameters is urgently required,incorporating clinical features to establish baseline patient profiles and disease staging;routine blood tests assessing systemic metabolic and functional status;immune cell subsets quantifying subcluster dynamics;imaging features delineating tumor morphology,spatial configuration,and perilesional anatomical relationships;immunohistochemical markers positioning qualitative and quantitative detection of tumor antigens from the cellular and molecular level.This integrated phenomic approach aims to improve prognostic stratification and clinical decision-making in hepatocellular carcinoma management conveniently and practically.
基金Deutsche Forschungsgemeinschaft(DFG,German Research Foundation),project numbers 324633948 and 409784463(DFG grants Hi 678/9-3 and Hi 678/10-2,FOR2953)to HHBundesministerium für Bildung und Forschung-BMBF,project number 16LW0463K to HT.
文摘Microglia are the resident macrophages of the central nervous system.They act as the first line of defense against pathogens and play essential roles in neuroinflammation and tissue repair after brain insult or in neurodegenerative and demyelinating diseases(Borst et al.,2021).Together with infiltrating monocyte-derived macrophages,microglia also play a critical role for brain tumor development,since immunosuppressive interactions between tumor cells and tumor-associated microglia and macrophages(TAM)are linked to malignant progression.This mechanism is of particular relevance in glioblastoma(GB),the deadliest form of brain cancer with a median overall survival of less than 15 months(Khan et al.,2023).Therefore,targeting microglia and macrophage activation is a promising strategy for therapeutic interference in brain disease.
文摘Background:While the treatment of metastatic renal cell carcinoma(mRCC)is evolving due to immune checkpoint inhibitors(ICIs),optimal strategies for later lines of therapy have yet to be defined.The combination of lenvatinib and everolimus represents a viable option,and the present review aimed to summarize its activity,effectiveness,and safety.Methods:A systematic review of the literature was conducted using PubMed,targeting studies published between 2018 and 2025.Eligible studies included English-language prospective and retrospective trials reporting survival outcomes in mRCC patients treated with lenvatinib and everolimus after at least one ICI-containing regimen.Results:Nine studies met the inclusion criteria,encompassing a total of 441 patients.The lenvatinib and everolimus combination was primarily used in the third and subsequent lines of therapy.Median overall survival ranged from 7.5 to 24.5 months,while median progression-free survival was more consistent,between 6.1 and 6.7 months,except for one study reporting 12.9 months.Objective response rates varied widely(14.0%–55.7%).Adverse events of grade≥3 did not exceed the expected rate,with diarrhoea and proteinuria as the most reported events.Dose reductions and treatment discontinuations due to toxicity occurred but were generally lower than in prior pivotal trials.Conclusions:Real-world evidence suggests that lenvatinib and everolimus represent an effective and safe option after ICI failure in mRCC patients.Nevertheless,the lack of randomized phase III trials and the heterogeneity of existing studies highlight the need for more robust prospective research to guide post-ICI therapeutic strategies.
基金supported by the Science and Technology Research Project of Jilin Education Bureau(No.JJKH20230804KJ)。
文摘Immunotherapy offers the promise of a potential cure for cancer,yet achieving the desired therapeutic effect can be challenging due to the immunosuppressive tumor microenvironments(TMEs) present in some tumors.Therefore,robust immune system activation is crucial to enhance the efficacy of cancer immunotherapy in clinical applications.Bacteria have shown the ability to target the hypoxic TMEs while activating both innate and adaptive immune responses.Engineered bacteria,modified through chemical or biological methods,can be endowed with specific physiological properties,such as diverse surface antigens,metabolites,and improved biocompatibility.These unique characteristics give engineered bacteria distinct advantages in stimulating anti-cancer immune responses.This review explores the potential regulatory mechanisms of engineered bacteria in modulating both innate and adaptive immunity while also forecasting the future development and challenges of using engineered bacteria in clinical cancer immunotherapy.
基金supported by grants from the National Natural Science Foundation of China(Grant No.82171810)the Program of Shandong Provincial Scientific and Technological Development of Traditional Chinese Medicine(Grant No.M-2023210)。
文摘CD8^(+)T cell exhaustion,a critical challenge in the immune response to cancer,is characterized by a profound decline in the functionality of effector CD8^(+)T cells.This state of exhaustion is accompanied by the upregulation of various inhibitory receptors and significant shifts in both transcriptional and epigenetic profiles,thus ultimately leading to inadequate tumor control.Therapeutic strategies aimed at reversing CD8^(+)T cell exhaustion have the potential to rejuvenate immune responses and enhance treatment efficacy.This review compiles current knowledge regarding the molecular mechanisms underlying CD8^(+)T cell exhaustion,including the roles of immune checkpoint molecules,the tumor microenvironment,metabolic reprogramming,transcription factors,and epigenetic modifications.Emerging therapeutic approaches designed to combat CD8^(+)T cell exhaustion are evaluated,with emphasis on the modulation of immune checkpoints;targeting of metabolic and transcriptional changes;and exploration of other innovative strategies,such as epigenetic editing and engineered CAR-T cells.Importantly,we expand the exhaustion concept to immune cells beyond CD8^(+)T cells,such as CD4^(+)T cells,natural killer cells,and myeloid populations,thereby highlighting the broader implications of systemic immunosuppression in the cancer context.Finally,we propose avenues for future research aimed at further elucidating the factors and molecular mechanisms associated with CD8^(+)T cell exhaustion,thereby underscoring the critical need for strategies aimed at reversing this state to improve outcomes in cancer immunotherapy.
文摘Polytrauma with significant bone and volumetric muscle loss presents substantial clinical challenges.Although immune responses significantly influence fracture healing post-polytrauma,the cellular and molecular underpinnings of polytrauma-induced immune dysregulation require further investigation.While previous studies examined either injury site tissue or systemic tissue(peripheral blood),our study uniquely investigated both systemic and local immune cells at the same time to better understand polytrauma-induced immune dysregulation and associated impaired bone healing.Using single-cell RNA sequencing(scRNA-seq)in a rat polytrauma model,we analyzed blood,bone marrow,and the local defect soft tissue to identify potential cellular and molecular targets involved in immune dysregulation.We identified a trauma-associated immunosuppressive myeloid(TIM)cell population that drives systemic immune dysregulation,immunosuppression,and potentially impaired bone healing.We found CD1d as a global marker for TIM cells in polytrauma.
基金Supported by 2021 Key Topic of Qinghai Provincial Health System–Guiding Plan Topic,No.2021-WJZDX-43.
文摘Currently,the use of immune checkpoint inhibitors(ICIs)has shown notable clinical efficacy in treating various malignant tumors,significantly improving patient prognosis.However,while ICIs enhance the body’s anti-tumor effects,they can also trigger immune-related adverse events(irAEs),with ICI-associated colitis being one of the more prevalent forms.This condition can disrupt treatment,necessitate drug discontinuation,and adversely affect therapeutic outcomes.In severe cases,irAEs may even become life-threatening.A recent case report by Hong et al highlights the importance of vigilance for ICI-associated colitis in patients experiencing symptoms such as diarrhea and abdominal pain,which can arise both during and even after completion of ICI treatment.Early identification,multidisciplinary management,and continuous monitoring of patients are essential steps to further improve outcomes.
文摘BACKGROUND Immune checkpoint inhibitors(ICIs)have revolutionized cancer therapy but are associated with immune-related adverse events,including ICIs hepatitis.Mycophenolate mofetil(MMF)is often used as a second-line immunosuppressive agent for steroid-refractory cases.However,there is no standardized approach to MMF tapering,leading to uncertainties regarding relapse risk,optimal tapering strategies,and long-term outcomes.AIM To evaluate current evidence on MMF tapering in ICI hepatitis,focusing on strategies,clinical outcomes,and the risk of hepatitis recurrence.Additionally,we explore the feasibility of reintroducing ICI therapy after immunosuppression withdrawal.METHODS A comprehensive literature search was conducted in PubMed,EMBASE,and clinical trial registries to identify studies reporting MMF use and tapering strategies in ICI hepatitis.We extracted data from manuscripts including patient characteristics,MMF dosing regimens,tapering duration,relapse rates,and oncologic outcomes.Risk factors for recurrence and successful tapering were analyzed.RESULTS There was significant heterogeneity in the duration of MMF taper,which ranged from 4 weeks to greater than 6 months.The tapering schedules presented were individualized based on the severity of liver injury,patient response to treatment,and risk factors for relapse.We summarize current tapering approaches,including rapid vs slow withdrawal,predictors of successful tapering,and alternative immunosuppressive strategies.The impact of MMF duration on liver recovery,relapse risk,and cancer prognosis will be discussed.Evidence on ICI rechallenge post-taper will also be reviewed.CONCLUSION While MMF is effective in managing ICI hepatitis,tapering remains a clinical challenge with potential risks of hepatitis flare and disease progression.Standardized tapering protocols are needed to optimize immunosuppression while preserving anticancer efficacy.Future studies should focus on biomarker-driven tapering strategies and prospective trials to establish best practices.
文摘Microbes play a critical role in shaping immune development,with growing interest in how rhinovirus(RV)interacts with the host immune system,particularly in individuals with asthma and chronic obstructive pul-monary disease(COPD).Disruptions in microbial balance during RV infections can impair immune homeostasis and worsen disease outcomes.Recent studies emphasize RV-induced regulation of antiviral defenses,cytokine production,and immune tolerance.This review explores the interplay between RV,the immune system,and microbiota,highlighting the importance of these interactions in guiding effective therapies for respiratory in-fections.It advances existing literature by considering microbiota-mediated therapies as a novel approach to managing RV exacerbations in respiratory diseases like asthma and COPD.
文摘In 1891,a New York surgeon named William Coley injected cancer patients with live bacteria,observing with fascination as some tumors shrank amid raging fevers.His crude experiments-later deemed reckless-nonetheless revealed a tantalizing truth:The immune system,when properly provoked,could attack cancer.Over a century later,researchers have transformed this observation into a precision strike force.
文摘Glioblastoma(GBM)is one of the most aggressive and treatment-resistant brain cancers.Despite years of research and clinical trials,especially using immune checkpoint inhibitors,therapeutic gains remain minimal[1,2].A recent study published in Nature by Faust Akl and colleagues begins to lift the veil on this mystery,uncovering a previously unknown mechanism of immune evasion in GBM[3].
基金Supported by the National Natural Science Foundation of China:No.82374563,82004467,82305370China Postdoctoral Science Foundation:No.2022M721536+1 种基金Tianjin Graduate Research Innovation Project:2022BKY177TUTCM Graduate Research Innovation Project:YJSKC-20221016。
文摘Sepsis is characterized by immune dysregulation that are responsible for an increase in secondary in-fections and mortality.Acupuncture is a potential alternative treatment for sepsis.In this comprehensive literature review,we found that acupuncture is beneficial in treating immune disorders associated with sepsis.Acupuncture can improve immune disorders associated with sepsis and regulate the functions of innate and adaptive immune cells.Specifically,acupuncture can reduce the number of neutrophils in sep-sis,promote the polarization of macrophages towards M2-like macrophages,and alleviate inflammation by reducing the activation of microglia and astrocytes.Furthermore,acupuncture can increase the per-centage of T cells and modulate the balance between T cell subsets.The immunomodulatory mechanism of acupuncture in sepsis may be attributed to the balance of the autonomic nervous system,including activation of the sympathetic-adrenal axis,vagal-cholinergic pathway,and vagal-adrenal axis.In addition,acupuncture can inhibit inflammation by preserving the integrity of the intestinal barrier and regulating the composition of the intestinal microbiota.Clinical studies have also demonstrated that acupuncture can enhance the number of peripheral natural killer(NK)cells and T cell subsets,as well as the expres-sion of human leukocyte antigen DR(HLA-DR).Moreover,acupuncture can decrease the ratio of white blood cells to neutrophils and reduce the levels of inflammatory factors.Therefore,acupuncture has the potential to improve immune function in sepsis.Further investigation of its mechanism is expected to provide a scientific and reliable foundation for the application of acupuncture in sepsis treatment.
基金supported by Jiangsu Commission of Health(No.x202308)The Suzhou Gusu Health Talents Scientific Research Project(No.GSWS2021052).
文摘To the editor:The liver’s immune-privileged status allows for a unique microenvironment that supports tumour growth and metastasis.In hepatocellular carcinoma(HCC),the balance between cytotoxic T lymphocytes and regulatory T cells plays a crucial role in determining patient outcomes.The expression of programmed cell death ligand 1(PD-1)and other immune checkpoint molecules contributes to a pro-tumourigenic microenvironment and is associated with poor prognosis.Additionally,the heterogeneity of the immune microenvironment adds complexity to disease progression and treatment response.
