Background:Gastric cancer(GC)continues to pose a significant global health challenge due to its high rates of incidence and mortality,with the majority of cases identified at advanced stages.Immunotherapy,particularly...Background:Gastric cancer(GC)continues to pose a significant global health challenge due to its high rates of incidence and mortality,with the majority of cases identified at advanced stages.Immunotherapy,particularly immune checkpoint blockades(ICBs),has demonstrated considerable therapeutic potential;however,many patients do not exhibit a favorable response.As a result,constructing a predictive model to assess ICBs'responsiveness is essential for enhancing treatment outcomes.Methods:Using consensus clustering based on anoikis-related gene expression,GC patients were stratified into two subclusters.Differences in tumor immune microenvironment,ICB resistance,genomic alterations,methylation profiles,and transcriptional networks were analyzed.A machine learning-based strategy was employed to develop a consensus anoikis-related gene signature(ARGS).Potential therapeutic targets were identified through single-cell RNA sequencing(scRNA-seq),and validation was conducted using multiplex immunofluorescence and immunohistochemistry in an in-house cohort(n=28),including 14 ICB responders and 14 nonresponders.Results:The anoikis-resistant cluster(Cluster A)was associated with poorer survival,immunosuppressive infiltration,lower tumor mutation burden,and ICB resistance.ScRNA-seq revealed high fibroblast and endothelial infiltration,with GLI3+cancer-associated fibroblasts suggesting Hedgehog pathway involvement.The ARGS model effectively stratified patients,with elevated scores associ-ated with immunotherapy resistance,enhanced AR characteristics,and poorer clinical outcomes.展开更多
Objectives:Immunotherapy based on immune checkpoint blockade(ICB)has become a key treatment for melanoma.However,the increasing number of cases of melanoma resistant to immunotherapy highlights the need to develop met...Objectives:Immunotherapy based on immune checkpoint blockade(ICB)has become a key treatment for melanoma.However,the increasing number of cases of melanoma resistant to immunotherapy highlights the need to develop methods to overcome this resistance.This study aims to collect the most recent information on melanoma immunotherapy,discuss potential strategies to overcome resistance to immunotherapy,and identify areas that require further analysis.Methods:To achieve this goal,scientific publications from 2021-2024 available in PubMed and Google Scholar databases were analyzed.The databases were searched using the following terms:“melanoma”,“immunotherapy”,“Immune Checkpoint Blockade”,and“immunoresistance”.Results:The results of preclinical and early-stage clinical research indicate the potential application of tank-binding kinase 1(TBK-1),fecal microbiota transplant(FMT),Toll-like Receptor 9(TLR9),lipid nanoparticles(LNPs)containing a stimulator of an interferon gene agonist(STING),BRAF inhibitors,Lymphocyte Activation Gene(LAG-3),T-Cell Immunoglobulin and ITIM Domain(TIGIT),and oncolytic viruses(OVs)as potential methods to enhance melanoma sensitivity to ICB.Discussion:To optimize immunotherapy,further research is needed to determine the detailed mechanisms of action,safety profiles,tolerability,and precise patient selection criteria for methods capable of overcoming melanoma’s immunoresistance.展开更多
Dear Editor,Lymphocyte activation gene 3(LAG3),the third established target for immune checkpoint blockade therapy,suppresses T cell function by binding to major histocompatibility complex classⅡ(MHCⅡ).Despite its s...Dear Editor,Lymphocyte activation gene 3(LAG3),the third established target for immune checkpoint blockade therapy,suppresses T cell function by binding to major histocompatibility complex classⅡ(MHCⅡ).Despite its significant therapeutic potential in cancer immunotherapy and the substantial attention it has received from academia and industry,the molecular mechanisms of LAG3-mediated immunosuppression remain poorly understood,primarily because of its unique ligand-binding characteristics and intracellular domains[1].展开更多
Early studies shed light on the immune suppression of immune checkpoint molecules in the cancer microenvironment,with later studies applying immune checkpoint blockade(ICB)in treatment of various malignancies.Despite ...Early studies shed light on the immune suppression of immune checkpoint molecules in the cancer microenvironment,with later studies applying immune checkpoint blockade(ICB)in treatment of various malignancies.Despite the encouraging efficacy of ICBs in a substantial subset of cancer patients,the treatment response varies.Gene mutations of both tumor cells and immune cells in the tumor microenvironment have recently been identified as potential predictors of the ICB response.Recent developments in gene expression profiling of tumors have allowed identification of a panel of mutated genes that may affect tumor cell response to ICB treatment.In this review,we discuss the association of the ICB response with gene expression and mutation profiles in tumor cells,which it is hoped will help to optimize the clinical application of ICBs in cancer patients.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
Objective:To investigate the anti-tumor effects of an E1B55KD-deleted oncolytic adenovirus,H101,in combination with a humanized anti-PD-1(Programmed cell death protein 1)monoclonal antibody,Camrelizumab.Methods:Anti-t...Objective:To investigate the anti-tumor effects of an E1B55KD-deleted oncolytic adenovirus,H101,in combination with a humanized anti-PD-1(Programmed cell death protein 1)monoclonal antibody,Camrelizumab.Methods:Anti-tumor efficacy of intratumoral injection of H101 or/and intraperitoneal injection of Camrelizumab were evaluated in an immune system humanized NOD Prkdc^(scid) Il2rg^(-/-)mice subcutaneous(S.C.)tumor model,established with human glioblastoma of unknown origin cell line U87-MG,and human bladder cancer cell line T24 and YTS-1.The mechanism by which H101 induced anti-tumor immunity were also investigated.Results:Combining H101 with Camrelizumab demonstrated more potent anti-tumor effects than monotherapy in mouse S.C.tumor model.Increased tumor-infiltrating T cells were observed in the combined treatment group.H101 infection decreased the expression of CD47 in cancer cells,thereby promoting macrophages to phagocytose cancer cells.Following the H101-mediated activation of macrophages,increased levels of cytokines,including TNF,IL-12 and IFN-γwere observed.Moreover,when induced THP-1 cells were co-cultured with H101-treated cancer cells,expression of IFN-γwas increased in T cells.Elimination of IL-12 using an anti-IL-12 antibody abolished IFN-γproduction from T cells.In addition,infection with H101 increased PD-L1 expression in YTS-1 cells.These results suggested that H101 may act synergistically to enhance the therapeutic efficacy of PD-1 blockade in cancer via suppressing CD47 signaling,which may promote macrophages to phagocytose tumor cells and activate CD8^(+)T cells.Conclusion:The combination of H101 with PD-1 blockade exhibits potential as a novel strategy for the treatment of cancer.展开更多
In the past decade,immunotherapies targeting cytotoxic T-lymphocyte antigen-4(CTLA-4),programmed cell death 1(PD-1),and PD-1 ligand(PD-L1)have been approved for solid tumors.However,some patients demonstrate suboptima...In the past decade,immunotherapies targeting cytotoxic T-lymphocyte antigen-4(CTLA-4),programmed cell death 1(PD-1),and PD-1 ligand(PD-L1)have been approved for solid tumors.However,some patients demonstrate suboptimal clinical outcomes due to resistance.The tumor microenvironment(TME)significantly affects the efficiency of immunotherapy by mediating interactions between tumor and non-tumor cells,including dendritic cells,T cells,B cells,macrophages,neutrophils,NK cells,and myeloid-derived suppressor cells(MDSCs).These non-tumor cells often exhibit two phenotypes with altered functions,and tumor cells drives their transition towards tumor promotion through tumor-education.Tumor-educated cells(TECs)are cells influenced by tumor cells,which acquire immune-suppressive phenotypes and promote tumor progression through resistance to anticancer therapies.These cells undergo modifications in response to signals from the tumor,which can influence their roles in tumor progression.Their dynamic interactions with tumor cells contribute to the reshaping of the TME,facilitating cancer growth and immune modulation.This review summarizes research on TECs in TME,explores mechanisms related to tumor education,and discusses their role in tumor progression and immunotherapy resistance.Additionally,potential therapeutic approaches targeting these cells are also reviewed,which may complement current treatment strategies.展开更多
BACKGROUND Irreversible electroporation(IRE)is a novel local tumor ablation approach with the potential to activate the host’s immune system.However,this approach is insufficient to prevent cancer progression,and com...BACKGROUND Irreversible electroporation(IRE)is a novel local tumor ablation approach with the potential to activate the host’s immune system.However,this approach is insufficient to prevent cancer progression,and complementary approaches are required for effective immunotherapy.AIM To assess the immunomodulatory effects and mechanism of IRE combined antiprogrammed cell death protein 1(PD-1)treatment in subcutaneous pancreatic cancer models.METHODS C57BL-6 tumor-bearing mice were randomly divided into four groups:Control group;IRE group;anti-PD-1 group;and IRE+anti-PD-1 group.Tumor-infiltrating T,B,and natural killer cell levels and plasma concentrations of T helper type 1 cytokines(interleukin-2,interferon-γ,and tumor necrosis factor-α)were evaluated.Real-time PCR was used to determine the expression of CD8(marker of CD8+T cells)in tumor tissues of the mice of all groups at different points of time.The growth curves of tumors were drawn.RESULTS The results demonstrated that the IRE+anti-PD-1 group exhibited significantly higher percentages of T lymphocyte infiltration,including CD4+and CD8+T cells compared with the control group.Additionally,the IRE+anti-PD-1 group showed increased infiltration of natural killer and B cells,elevated cytokine levels,and higher CD8 mRNA expression.Tumor volume was significantly reduced in the IRE+anti-PD-1 group,indicating a more pronounced therapeutic effect.CONCLUSION The combination of IRE and anti-PD-1 therapy promotes CD8+T cell immunity responses,leading to a more effective reduction in tumor volume and improved therapeutic outcomes,which provides a new direction for ablation and immunotherapy of pancreatic cancer.展开更多
BACKGROUND Gastric cancer(GC)is one of the most common malignancies worldwide,and Helicobacter pylori(HP)infection is a well-established risk factor for its development.Programmed death-ligand 1(PD-L1)expression is a ...BACKGROUND Gastric cancer(GC)is one of the most common malignancies worldwide,and Helicobacter pylori(HP)infection is a well-established risk factor for its development.Programmed death-ligand 1(PD-L1)expression is a crucial biomarker for predicting the efficacy of immune checkpoint inhibitors in cancer treatment.While HP infection and PD-L1 expression in GC may be linked,the relationship between them remains unclear,in part because there have been conflicting results reported from various studies.AIM To perform a meta-analysis to assess the relationship between HP and PD-L1 expression in patients with GC.METHODS A systematic literature review was conducted using PubMed,Embase,Cochrane Library,and Web of Science databases.Observational studies that examined the association between HP infection and PD-L1 expression in patients with GC were included.Odds ratios and 95%confidence intervals were calculated to estimate the association.Heterogeneity was assessed using Cochrane’s Q test and I²statistic.A random-effects model was used due to significant heterogeneity across studies.RESULTS Fourteen studies involving a total of 3069 patients with GC were included.The pooled analysis showed a significant association between HP infection and increased PD-L1 expression in GC tissues(odd ratio=1.69,95%confidence interval:1.24-2.29,P<0.001,I^(2)=59%).Sensitivity analyses confirmed the robustness of these findings.Subgroup analyses did not show significant variation based on geographic region,sample size,or method of PD-L1 assessment.Publication bias was minimal,as shown by funnel plots and Egger’s regression test.CONCLUSION HP infection is associated with increased PD-L1 expression in GC,suggesting that HP status may influence the response to programmed cell death protein 1/PD-L1 blockade therapy.展开更多
BACKGROUND Since the advent of the 20th century,alongside the progression of medical science and technological advancements,immunotherapy has emerged as a pivotal thera-peutic approach for tumor patients subsequent to...BACKGROUND Since the advent of the 20th century,alongside the progression of medical science and technological advancements,immunotherapy has emerged as a pivotal thera-peutic approach for tumor patients subsequent to undergoing radiotherapy and chemotherapy.Arimab(camrelizumab),a flagship drug in the realm of immuno-therapy,functions as a monoclonal antibody specifically targeting the progra-mmed death protein 1(PD-1).This drug engages with the human PD-1 receptor,effectively inhibiting the PD-1/programmed death ligand 1 signaling pathway.This inhibition results in the restoration of T cell activity and the induction of an anti-tumour response.However,it is noteworthy that such interference could lead to immune-related adverse events resembling autoimmune reactions.The grow-ing availability and clinical use of immune checkpoint inhibitors have raised sig-nificant clinical concerns regarding their safety.Numerous instances of immune-related adverse reactions and the associated management strategies have been extensively reported.Timely identification and diagnosis,coupled with multidi-sciplinary consultation and the prompt administration of immunosuppressants,can effectively address severe immune-related adverse reactions.CASE SUMMARY Arimab(camrelizumab),a monoclonal antibody targeting programmed death protein 1(PD-1),disrupts the PD-1/programmed death ligand 1(PD-L1)inter-action,reactivating T cell function and triggering anti-tumor immunity.However,this disruption may trigger immune-mediated adverse events akin to autoim-mune disorders.Approximately 2.8%of such events manifest as immune-related dermatologic reactions,with 0.7%classified as grade 3,which are infrequently documented.Here,this study describes a case of grade 3 bullous dermatitis occur-ring 15 days after initiating camrelizumab therapy.The patient,a 67-year-old male with oesophageal squamous cell carcinoma,received camrelizumab plus paclitaxel alongside chemotherapy and radiotherapy in early 2022.Due to disease progression,maintenance monotherapy with camrelizumab(200 mg)commenced in June 2022.On the fourth cycle,15 days into treatment,the patient presented with an immune-checkpoint inhibitor-related rash,despite unremarkable test results.Dermatology and pharmacy consultations were conducted,leading to glucocorticoid therapy,topical interventions,and supportive care.Gastric mucosal protection,nutritional supplementation,and other adjunctive treatments were also provided.The patient's symptoms resolved within 15 days post-discharge,resulting in discontinuation of camrelizumab.Like other PD-1 inhibitors,camrelizumab is associated with immune-mediated dermatitis.Thus,optimal management of these events requires a multidisciplinary approach,vigilant monitoring,regular evalua-tions,prompt glucocorticoid administration,and specialized dermatologic care.CONCLUSION The increasing adoption of immune checkpoint inhibitors in clinical practice has prompted substantial concerns about their safety profile.A wide range of immune-related adverse events and corresponding management stra-tegies have been well-documented.Early recognition and accurate diagnosis,combined with interdisciplinary collaboration and swift initiation of immunosuppressive therapy,are essential in managing severe immune-related adverse reactions effectively.This report details the treatment trajectory and outcome of a case involving immune-related cutaneous adverse reactions,providing pertinent clinical insights for future cases.展开更多
There is growing evidence that interleukin(IL)-6 plays an important role in neurological and psychiatric disorders.This editorial comments on the study published in the recent issue of the World Journal of Psychiatry,...There is growing evidence that interleukin(IL)-6 plays an important role in neurological and psychiatric disorders.This editorial comments on the study published in the recent issue of the World Journal of Psychiatry,which employed Mendelian randomization to identify a causal relationship between IL-6 receptor blockade and decreased epilepsy incidence.The purpose of this editorial is to highlight the dual effects of IL-6 in epilepsy and its related neuropsychiatric comorbidities.IL-6 plays a critical role in the facilitation of epileptogenesis and maintenance of epileptic seizures and is implicated in neuroinflammatory proce-sses associated with epilepsy.Furthermore,IL-6 significantly influences mood regulation and cognitive dysfunction in patients with epilepsy,highlighting its involvement in neuropsychiatric comorbidities.In summary,IL-6 is not only a pivotal factor in the pathogenesis of epilepsy but also significantly contributes to the emergence of epilepsy-related neuropsychiatric complications.Future resear-ch should prioritize elucidating the specific mechanisms by which IL-6 operates across different subtypes,stages and neuropsychiatric comorbidities of epilepsy,with the aim of developing more precise and effective interventions.Furthermore,the potential of IL-6 as a biomarker for the early diagnosis and prognosis of epile-psy warrants further investigation.展开更多
BACKGROUND Bradycardia,renal failure,atrioventricular nodal blockade,shock,and hyper-kalemia(BRASH)syndrome is an acronym used to describe a constellation of BRASH.It is an underrecognized phenomenon that can be deadl...BACKGROUND Bradycardia,renal failure,atrioventricular nodal blockade,shock,and hyper-kalemia(BRASH)syndrome is an acronym used to describe a constellation of BRASH.It is an underrecognized phenomenon that can be deadly if not appro-priately managed in a timely manner.This case highlights the importance of rapid diagnosis and reviews a multitude of treatment options in a uniquely severe case of BRASH syndrome.CASE SUMMARY We present a case of a 54-year-old male on a beta-blocker and angiotensin-con-verting enzyme inhibitor who presented with one day history of nausea,vomi-ting,and shortness of breath.Upon presentation,he was bradycardic and hypotensive,requiring transcutaneous pacing.Initial electrocardiogram showed atrial fibrillation with ventricular rate in 30’s.He was found to have acute kidney injury,hyperkalemia,and metabolic acidosis.He was successfully treated with multiple potassium lowering agents,continuous renal replacement therapy,four pressors,mechanical ventilation,and transvenous pacing with complete recovery prior to discharge.CONCLUSION Increased awareness of BRASH syndrome may improve outcomes through timely diagnosis and aggressive intervention.展开更多
Integrating photodynamic therapy(PDT)with immunosuppression reversal represents a promising synergistic approach to boost cancer immunotherapy.However,the complicated components and cumbersome preparation procedures o...Integrating photodynamic therapy(PDT)with immunosuppression reversal represents a promising synergistic approach to boost cancer immunotherapy.However,the complicated components and cumbersome preparation procedures of the currently developed nano drug delivery systems heavily hinder their further clinical translation.Herein,a reactive oxygen species(ROS)/photo dual-responsive amphipathic prodrug(denoted as PPTN)was designed and synthesized by linking NLG919,an indoleamine-2,3-dioxygenase(IDO)inhibitor,with the photosensitizer protoporphyrin IX(PpIX)by a thioketal moiety,and further modifying with mPEG2k.PPTN could self-assemble into nanoscale unimolecular micelles in aqueous solution without additional excipients,increasing tumor accumulation while effectively addressing the pronounced hydrophobicity challenge of PpIX.Upon light exposure,PPTN generated ROS,not only directly damaging cancer cells,but also trigger the breakage of thioketal bond to accelerate simultaneous release of NLG919.Therefore,PPTN potentially act as a promising ROS/photo dual-responsive carrier-free prodrug delivery system for controllable drug release and specific tumor therapy.Moreover,PPTN induced simultaneous PDT-triggered immunogenic cell death(ICD)effect and specific IDO blockade to boost immune response,exhibiting potent suppression efficacy against primary and distant tumors.Overall,with the superiorities of easily controllable preparation procedures,synchronous drug delivery and ROS/photo dual-responsiveness,such a prodrug unimolecular micelle may represent a promising nanoplatform for photoactivated-immunotherapy.展开更多
BACKGROUND:BRASH syndrome(Bradycardia,Renal failure,AV nodal blockade,Shock,and Hyperkalemia)is a recently described clinical entity characterized by synergistic interaction between AV nodal blocking medications and h...BACKGROUND:BRASH syndrome(Bradycardia,Renal failure,AV nodal blockade,Shock,and Hyperkalemia)is a recently described clinical entity characterized by synergistic interaction between AV nodal blocking medications and hyperkalemia.Despite increasing recognition,its clinical characteristics,risk factors,and outcomes remain poorly defined.The rationale of this review is to provide clinicians an upto-date overview of the most commonly encountered risk factors,triggers,clinical pictures,usual lab values,complications and outcomes,via the systemic analysis of currently published cases.METHODS:A systematic review was conducted using MEDLINE,Web of Science,and Cochrane Library databases through December 2024.Case reports,case series,and conference abstracts involving adult patients with BRASH syndrome were included.Data extraction focused on demographics,clinical presentations,laboratory findings,management strategies,and outcomes.RESULTS:Analysis included 131 patients from 111 published cases.Mean age was(71±13)years,with female predominance(58.1%).Hypertension(77.0%),chronic kidney disease(48.4%),and diabetes mellitus(46.7%)were the most common comorbidities.Beta-blockers were the predominant medication(76.5%).Most common presenting symptoms were syncope(17.9%),generalized weakness(16.2%),and altered mental status(11.9%).Mean potassium level was 6.6 mEq/L,with more than half of cases presenting with non-severe hyperkalemia(<6.5 mEq/L).Management often required multimodal therapy,with 50.8% of patients requiring vasopressors and 31.6% requiring hemodialysis.CONCLUSION:This systematic review provides the most comprehensive analysis of BRASH syndrome to date,demonstrating that while potentially serious,outcomes are generally favorable with appropriate recognition and management.The syndrome can develop even with modest hyperkalemia,particularly in elderly patients with multiple comorbidities.Early recognition and systematic management addressing all components of the syndrome appear crucial for optimal outcomes.展开更多
Tumor blockade therapy inhibits tumor progression by cutting off essential supplies of nutrients,oxygen,and biomolecules from the surrounding microenvironments.Inspired by natural processes,tumor biomineralization has...Tumor blockade therapy inhibits tumor progression by cutting off essential supplies of nutrients,oxygen,and biomolecules from the surrounding microenvironments.Inspired by natural processes,tumor biomineralization has evolved due to its biocompatibility,self-reinforcing capability,and penetrationindependent mechanism.However,the selective induction of tumor biomineralization using synthetic tools presents a significant challenge.Herein,a metabolic glycoengineering-assistant tumor biomineralization strategy was developed.Specifically,the azido group(N_(3))was introduced onto the cytomembrane by incubating tumor cells with glycose analog Ac4ManNAz.In addition,a bisphosphonate-containing polymer,dibenzocyclooctyne-poly(ethylene glycol)-alendronate(DBCO-PEG-ALN,DBPA)was synthesized,which attached to the tumor cell surface via"click chemistry"reaction between DBCO and N_(3).Subsequently,the bisphosphonate group on the cell surface chelated with positively charged ions in the microenvironments,triggering a consecutive process of biomineralization.This physical barrier significantly reduced tumor cell viability and mobility in a calcium ion concentration-dependent manner,suggesting its potential as an effective anti-tumor strategy for in vivo applications.展开更多
Esophageal squamous cell carcinoma(ESCC)remains a daunting global health concern.It is marked by aggressive progression and poor survival.While immunotherapy has emerged as a promising treatment modality,both primary ...Esophageal squamous cell carcinoma(ESCC)remains a daunting global health concern.It is marked by aggressive progression and poor survival.While immunotherapy has emerged as a promising treatment modality,both primary and acquired resistance continue to limit its clinical impact,leaving many patients without durable benefits(e.g.,CheckMate-648,ESCORT-1st).This review explains resistance mechanisms and suggests new strategies to improve outcomes.These mechanisms include immunosuppressive cells(Treg cells,myeloid-derived suppressor cells),inhibitory cytokines,molecular alterations involving programmed death 1/programmed death-ligand 1 signaling,and impaired antigen presentation.We also highlight key clinical trials—for example,CheckMate-648 and ESCORT-1st—that reveal both the potential and pitfalls of current immune checkpoint blockade strategies,underscoring the need for robust predictive biomarkers.Moreover,we examine cutting-edge tactics to overcome resistance,including combination regimens,tumor microenvironment remodeling,and tailored treatment approaches rooted in the patient’s unique genomic and immunologic landscape.展开更多
Mitochondria provides adenosine triphosphate for multiple vital movements to ensure tumor cell proliferation.Compared to the broadly used method of inducing DNA replication arrest to kill cancer,inducing mitochondria ...Mitochondria provides adenosine triphosphate for multiple vital movements to ensure tumor cell proliferation.Compared to the broadly used method of inducing DNA replication arrest to kill cancer,inducing mitochondria damage to cause energy shortage is quite promising as it can inhibit tumor cell bioactivities,increase intracellular accumulation of toxic drugs,eventually sensitize chemotherapy and even reverse drug resistance.Breaking the balance of glutathione(GSH)and reactive oxygen species(ROS)contents have been proven efficient in destroying mitochondria respectively.Herein,apigenin,a GSH efflux reagent,and 2-deoxy-5-fluorouridine 5-monophosphate sodium salt(FdUMP)that could induce toxic ROS were co-delivered by constructed lipid nanoparticles,noted as Lip@AF.An immune-checkpoint inhibition reagent CD276 antibody was modified onto the surface of Lip@AF with high reaction specificity(noted asαCD276-Lip@AF)to enhance the recognition of immune cells to tumor.Results showed that the redox balancewas destroyed,leading to severe injury to mitochondria and cell membrane.Furthermore,synergistic DNA/RNA replication inhibition caused by inhibiting the function of thymidylate synthase were observed.Eventually,significantly enhanced cytotoxicity was achieved by combining multiple mechanisms including ferroptosis,apoptosis and pyroptosis.In vivo,strengthen tumor growth inhibitionwas achieved byαCD276-Lip@AF with high biosafety,providing new sights in enhancing chemotherapy sensitiveness and achieving high-performance chemo-immunotherapy.展开更多
Gastrointestinal(GI)cancers are prevalent globally,with leading incidence and mortality rates among malignant tumors.Despite notable advancements in surgical resection,radiotherapy,and chemotherapy,the overall surviva...Gastrointestinal(GI)cancers are prevalent globally,with leading incidence and mortality rates among malignant tumors.Despite notable advancements in surgical resection,radiotherapy,and chemotherapy,the overall survival rates remain low.Hence,it is imperative to explore alternative approaches that enhance patient outcomes.Cluster of differentiation 47(CD47),serving as an early diagnostic marker,is predominantly overexpressed in GI cancers and associated with poor prognosis.Targeting the CD47-signal regulatory protein alpha(SIRPa)signaling pathway may provide a novel strategy for GI cancers treatment.This study summarizes current knowledge of the structure and function of CD47 and SIRPa,their roles in signaling pathways,the prognostic significance of CD47,therapeutic strategies targeting the CD47-SIRPα signaling pathway in GI cancer,and highlights key issues for future investigations.展开更多
Melanoma,a common malignant skin tumor,faces challenges with multidrug resistance and high recurrence rates.Combining photodynamic therapy(PDT)and immunotherapy offers a promising personalized treatment approach.Howev...Melanoma,a common malignant skin tumor,faces challenges with multidrug resistance and high recurrence rates.Combining photodynamic therapy(PDT)and immunotherapy offers a promising personalized treatment approach.However,poor water solubility and significant side effects of photosensitizers and immune checkpoint inhibitors(ICIs)limit their application.Enhancing delivery efficiency while reducing adverse effects is crucial.Herein,we formulate BM@HSSC nanoparticles(NPs),which consist of a reduction-responsive hyaluronic acid(HA)backbone modified with photosensitizer chlorin e6(Ce6)and loaded with the programmed cell death-ligand 1(PD-L1)inhibitor BMS-1.This system synergistically integrates PDT,immunogenic cell death(ICD),and immunotherapy for melanoma treatment.BM@HSSC NPs target and accumulate at the tumor site via the CD44 receptor.The disulfide bonds(-S-S-)in the NPs react with high glutathione(GSH)concentrations in tumor cells,rapidly releasing Ce6 and BMS-1.Under 660 nm laser irradiation,BM@HSSC NPs generate cytotoxic reactive oxygen species(ROS),inducing cell apoptosis and triggering ICD via PDT damage-associated molecular patterns(DAMPs)and tumor-associated antigens(TAAs)released from ICD promote dendritic cell(DC)maturation,enhancing antigen presentation and activating cytotoxic T lymphocytes(CTLs).Meanwhile,BMS-1 blocks the programmed cell death-1(PD-1)/PD-L1 pathway,countering the immunosuppressive tumor microenvironment(iTME)and inhibiting tumor cell immune escape.This strategy amplifies antitumor immune responses by enhancing immunogenicity and synergizing with ICIs,resulting in robust antitumor efficacy.展开更多
Therapeutic antibodies of targeting the programmed cell death protein 1(PD-1)/programmed death-ligand 1(PD-L1)pathway are used in hepatocellular carcinoma(HCC)treatment,but are limited by low response rates and immune...Therapeutic antibodies of targeting the programmed cell death protein 1(PD-1)/programmed death-ligand 1(PD-L1)pathway are used in hepatocellular carcinoma(HCC)treatment,but are limited by low response rates and immune-related toxicity[1].Searching for treatment approaches to combine with PD-1/PD-L1 blockade may potentially enhance the efficacy of PD-1/PD-L1 blockade and reduce its side effects.展开更多
基金National Science and Technology Major Project,Grant/Award Number:2024ZD0533300Excellent Doctor Program of Zhongnan Hospital of Wuhan University,Grant/Award Number:ZNYB2021009。
文摘Background:Gastric cancer(GC)continues to pose a significant global health challenge due to its high rates of incidence and mortality,with the majority of cases identified at advanced stages.Immunotherapy,particularly immune checkpoint blockades(ICBs),has demonstrated considerable therapeutic potential;however,many patients do not exhibit a favorable response.As a result,constructing a predictive model to assess ICBs'responsiveness is essential for enhancing treatment outcomes.Methods:Using consensus clustering based on anoikis-related gene expression,GC patients were stratified into two subclusters.Differences in tumor immune microenvironment,ICB resistance,genomic alterations,methylation profiles,and transcriptional networks were analyzed.A machine learning-based strategy was employed to develop a consensus anoikis-related gene signature(ARGS).Potential therapeutic targets were identified through single-cell RNA sequencing(scRNA-seq),and validation was conducted using multiplex immunofluorescence and immunohistochemistry in an in-house cohort(n=28),including 14 ICB responders and 14 nonresponders.Results:The anoikis-resistant cluster(Cluster A)was associated with poorer survival,immunosuppressive infiltration,lower tumor mutation burden,and ICB resistance.ScRNA-seq revealed high fibroblast and endothelial infiltration,with GLI3+cancer-associated fibroblasts suggesting Hedgehog pathway involvement.The ARGS model effectively stratified patients,with elevated scores associ-ated with immunotherapy resistance,enhanced AR characteristics,and poorer clinical outcomes.
文摘Objectives:Immunotherapy based on immune checkpoint blockade(ICB)has become a key treatment for melanoma.However,the increasing number of cases of melanoma resistant to immunotherapy highlights the need to develop methods to overcome this resistance.This study aims to collect the most recent information on melanoma immunotherapy,discuss potential strategies to overcome resistance to immunotherapy,and identify areas that require further analysis.Methods:To achieve this goal,scientific publications from 2021-2024 available in PubMed and Google Scholar databases were analyzed.The databases were searched using the following terms:“melanoma”,“immunotherapy”,“Immune Checkpoint Blockade”,and“immunoresistance”.Results:The results of preclinical and early-stage clinical research indicate the potential application of tank-binding kinase 1(TBK-1),fecal microbiota transplant(FMT),Toll-like Receptor 9(TLR9),lipid nanoparticles(LNPs)containing a stimulator of an interferon gene agonist(STING),BRAF inhibitors,Lymphocyte Activation Gene(LAG-3),T-Cell Immunoglobulin and ITIM Domain(TIGIT),and oncolytic viruses(OVs)as potential methods to enhance melanoma sensitivity to ICB.Discussion:To optimize immunotherapy,further research is needed to determine the detailed mechanisms of action,safety profiles,tolerability,and precise patient selection criteria for methods capable of overcoming melanoma’s immunoresistance.
文摘Dear Editor,Lymphocyte activation gene 3(LAG3),the third established target for immune checkpoint blockade therapy,suppresses T cell function by binding to major histocompatibility complex classⅡ(MHCⅡ).Despite its significant therapeutic potential in cancer immunotherapy and the substantial attention it has received from academia and industry,the molecular mechanisms of LAG3-mediated immunosuppression remain poorly understood,primarily because of its unique ligand-binding characteristics and intracellular domains[1].
基金This work is supported by the National Natural Science Foundation of China(No.81602492)the National Key Research and Development Program of China(No.2016YFA0201402).
文摘Early studies shed light on the immune suppression of immune checkpoint molecules in the cancer microenvironment,with later studies applying immune checkpoint blockade(ICB)in treatment of various malignancies.Despite the encouraging efficacy of ICBs in a substantial subset of cancer patients,the treatment response varies.Gene mutations of both tumor cells and immune cells in the tumor microenvironment have recently been identified as potential predictors of the ICB response.Recent developments in gene expression profiling of tumors have allowed identification of a panel of mutated genes that may affect tumor cell response to ICB treatment.In this review,we discuss the association of the ICB response with gene expression and mutation profiles in tumor cells,which it is hoped will help to optimize the clinical application of ICBs in cancer patients.
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.
基金supported by Techpool Bio-Pharma Co.,Ltd.(grant no.AKR-S005).
文摘Objective:To investigate the anti-tumor effects of an E1B55KD-deleted oncolytic adenovirus,H101,in combination with a humanized anti-PD-1(Programmed cell death protein 1)monoclonal antibody,Camrelizumab.Methods:Anti-tumor efficacy of intratumoral injection of H101 or/and intraperitoneal injection of Camrelizumab were evaluated in an immune system humanized NOD Prkdc^(scid) Il2rg^(-/-)mice subcutaneous(S.C.)tumor model,established with human glioblastoma of unknown origin cell line U87-MG,and human bladder cancer cell line T24 and YTS-1.The mechanism by which H101 induced anti-tumor immunity were also investigated.Results:Combining H101 with Camrelizumab demonstrated more potent anti-tumor effects than monotherapy in mouse S.C.tumor model.Increased tumor-infiltrating T cells were observed in the combined treatment group.H101 infection decreased the expression of CD47 in cancer cells,thereby promoting macrophages to phagocytose cancer cells.Following the H101-mediated activation of macrophages,increased levels of cytokines,including TNF,IL-12 and IFN-γwere observed.Moreover,when induced THP-1 cells were co-cultured with H101-treated cancer cells,expression of IFN-γwas increased in T cells.Elimination of IL-12 using an anti-IL-12 antibody abolished IFN-γproduction from T cells.In addition,infection with H101 increased PD-L1 expression in YTS-1 cells.These results suggested that H101 may act synergistically to enhance the therapeutic efficacy of PD-1 blockade in cancer via suppressing CD47 signaling,which may promote macrophages to phagocytose tumor cells and activate CD8^(+)T cells.Conclusion:The combination of H101 with PD-1 blockade exhibits potential as a novel strategy for the treatment of cancer.
基金supported by the NIH/NCI grants(No.P01CA257907)the Educational Department of Hunan Province for Excellent Youth Scholars(No.23B0011)。
文摘In the past decade,immunotherapies targeting cytotoxic T-lymphocyte antigen-4(CTLA-4),programmed cell death 1(PD-1),and PD-1 ligand(PD-L1)have been approved for solid tumors.However,some patients demonstrate suboptimal clinical outcomes due to resistance.The tumor microenvironment(TME)significantly affects the efficiency of immunotherapy by mediating interactions between tumor and non-tumor cells,including dendritic cells,T cells,B cells,macrophages,neutrophils,NK cells,and myeloid-derived suppressor cells(MDSCs).These non-tumor cells often exhibit two phenotypes with altered functions,and tumor cells drives their transition towards tumor promotion through tumor-education.Tumor-educated cells(TECs)are cells influenced by tumor cells,which acquire immune-suppressive phenotypes and promote tumor progression through resistance to anticancer therapies.These cells undergo modifications in response to signals from the tumor,which can influence their roles in tumor progression.Their dynamic interactions with tumor cells contribute to the reshaping of the TME,facilitating cancer growth and immune modulation.This review summarizes research on TECs in TME,explores mechanisms related to tumor education,and discusses their role in tumor progression and immunotherapy resistance.Additionally,potential therapeutic approaches targeting these cells are also reviewed,which may complement current treatment strategies.
基金Science and Technology Program of Guangzhou,No.202102010077International Science Foundation of Guangzhou Fuda Cancer Hospital,No.Y2020-ZD-03.
文摘BACKGROUND Irreversible electroporation(IRE)is a novel local tumor ablation approach with the potential to activate the host’s immune system.However,this approach is insufficient to prevent cancer progression,and complementary approaches are required for effective immunotherapy.AIM To assess the immunomodulatory effects and mechanism of IRE combined antiprogrammed cell death protein 1(PD-1)treatment in subcutaneous pancreatic cancer models.METHODS C57BL-6 tumor-bearing mice were randomly divided into four groups:Control group;IRE group;anti-PD-1 group;and IRE+anti-PD-1 group.Tumor-infiltrating T,B,and natural killer cell levels and plasma concentrations of T helper type 1 cytokines(interleukin-2,interferon-γ,and tumor necrosis factor-α)were evaluated.Real-time PCR was used to determine the expression of CD8(marker of CD8+T cells)in tumor tissues of the mice of all groups at different points of time.The growth curves of tumors were drawn.RESULTS The results demonstrated that the IRE+anti-PD-1 group exhibited significantly higher percentages of T lymphocyte infiltration,including CD4+and CD8+T cells compared with the control group.Additionally,the IRE+anti-PD-1 group showed increased infiltration of natural killer and B cells,elevated cytokine levels,and higher CD8 mRNA expression.Tumor volume was significantly reduced in the IRE+anti-PD-1 group,indicating a more pronounced therapeutic effect.CONCLUSION The combination of IRE and anti-PD-1 therapy promotes CD8+T cell immunity responses,leading to a more effective reduction in tumor volume and improved therapeutic outcomes,which provides a new direction for ablation and immunotherapy of pancreatic cancer.
文摘BACKGROUND Gastric cancer(GC)is one of the most common malignancies worldwide,and Helicobacter pylori(HP)infection is a well-established risk factor for its development.Programmed death-ligand 1(PD-L1)expression is a crucial biomarker for predicting the efficacy of immune checkpoint inhibitors in cancer treatment.While HP infection and PD-L1 expression in GC may be linked,the relationship between them remains unclear,in part because there have been conflicting results reported from various studies.AIM To perform a meta-analysis to assess the relationship between HP and PD-L1 expression in patients with GC.METHODS A systematic literature review was conducted using PubMed,Embase,Cochrane Library,and Web of Science databases.Observational studies that examined the association between HP infection and PD-L1 expression in patients with GC were included.Odds ratios and 95%confidence intervals were calculated to estimate the association.Heterogeneity was assessed using Cochrane’s Q test and I²statistic.A random-effects model was used due to significant heterogeneity across studies.RESULTS Fourteen studies involving a total of 3069 patients with GC were included.The pooled analysis showed a significant association between HP infection and increased PD-L1 expression in GC tissues(odd ratio=1.69,95%confidence interval:1.24-2.29,P<0.001,I^(2)=59%).Sensitivity analyses confirmed the robustness of these findings.Subgroup analyses did not show significant variation based on geographic region,sample size,or method of PD-L1 assessment.Publication bias was minimal,as shown by funnel plots and Egger’s regression test.CONCLUSION HP infection is associated with increased PD-L1 expression in GC,suggesting that HP status may influence the response to programmed cell death protein 1/PD-L1 blockade therapy.
文摘BACKGROUND Since the advent of the 20th century,alongside the progression of medical science and technological advancements,immunotherapy has emerged as a pivotal thera-peutic approach for tumor patients subsequent to undergoing radiotherapy and chemotherapy.Arimab(camrelizumab),a flagship drug in the realm of immuno-therapy,functions as a monoclonal antibody specifically targeting the progra-mmed death protein 1(PD-1).This drug engages with the human PD-1 receptor,effectively inhibiting the PD-1/programmed death ligand 1 signaling pathway.This inhibition results in the restoration of T cell activity and the induction of an anti-tumour response.However,it is noteworthy that such interference could lead to immune-related adverse events resembling autoimmune reactions.The grow-ing availability and clinical use of immune checkpoint inhibitors have raised sig-nificant clinical concerns regarding their safety.Numerous instances of immune-related adverse reactions and the associated management strategies have been extensively reported.Timely identification and diagnosis,coupled with multidi-sciplinary consultation and the prompt administration of immunosuppressants,can effectively address severe immune-related adverse reactions.CASE SUMMARY Arimab(camrelizumab),a monoclonal antibody targeting programmed death protein 1(PD-1),disrupts the PD-1/programmed death ligand 1(PD-L1)inter-action,reactivating T cell function and triggering anti-tumor immunity.However,this disruption may trigger immune-mediated adverse events akin to autoim-mune disorders.Approximately 2.8%of such events manifest as immune-related dermatologic reactions,with 0.7%classified as grade 3,which are infrequently documented.Here,this study describes a case of grade 3 bullous dermatitis occur-ring 15 days after initiating camrelizumab therapy.The patient,a 67-year-old male with oesophageal squamous cell carcinoma,received camrelizumab plus paclitaxel alongside chemotherapy and radiotherapy in early 2022.Due to disease progression,maintenance monotherapy with camrelizumab(200 mg)commenced in June 2022.On the fourth cycle,15 days into treatment,the patient presented with an immune-checkpoint inhibitor-related rash,despite unremarkable test results.Dermatology and pharmacy consultations were conducted,leading to glucocorticoid therapy,topical interventions,and supportive care.Gastric mucosal protection,nutritional supplementation,and other adjunctive treatments were also provided.The patient's symptoms resolved within 15 days post-discharge,resulting in discontinuation of camrelizumab.Like other PD-1 inhibitors,camrelizumab is associated with immune-mediated dermatitis.Thus,optimal management of these events requires a multidisciplinary approach,vigilant monitoring,regular evalua-tions,prompt glucocorticoid administration,and specialized dermatologic care.CONCLUSION The increasing adoption of immune checkpoint inhibitors in clinical practice has prompted substantial concerns about their safety profile.A wide range of immune-related adverse events and corresponding management stra-tegies have been well-documented.Early recognition and accurate diagnosis,combined with interdisciplinary collaboration and swift initiation of immunosuppressive therapy,are essential in managing severe immune-related adverse reactions effectively.This report details the treatment trajectory and outcome of a case involving immune-related cutaneous adverse reactions,providing pertinent clinical insights for future cases.
文摘There is growing evidence that interleukin(IL)-6 plays an important role in neurological and psychiatric disorders.This editorial comments on the study published in the recent issue of the World Journal of Psychiatry,which employed Mendelian randomization to identify a causal relationship between IL-6 receptor blockade and decreased epilepsy incidence.The purpose of this editorial is to highlight the dual effects of IL-6 in epilepsy and its related neuropsychiatric comorbidities.IL-6 plays a critical role in the facilitation of epileptogenesis and maintenance of epileptic seizures and is implicated in neuroinflammatory proce-sses associated with epilepsy.Furthermore,IL-6 significantly influences mood regulation and cognitive dysfunction in patients with epilepsy,highlighting its involvement in neuropsychiatric comorbidities.In summary,IL-6 is not only a pivotal factor in the pathogenesis of epilepsy but also significantly contributes to the emergence of epilepsy-related neuropsychiatric complications.Future resear-ch should prioritize elucidating the specific mechanisms by which IL-6 operates across different subtypes,stages and neuropsychiatric comorbidities of epilepsy,with the aim of developing more precise and effective interventions.Furthermore,the potential of IL-6 as a biomarker for the early diagnosis and prognosis of epile-psy warrants further investigation.
文摘BACKGROUND Bradycardia,renal failure,atrioventricular nodal blockade,shock,and hyper-kalemia(BRASH)syndrome is an acronym used to describe a constellation of BRASH.It is an underrecognized phenomenon that can be deadly if not appro-priately managed in a timely manner.This case highlights the importance of rapid diagnosis and reviews a multitude of treatment options in a uniquely severe case of BRASH syndrome.CASE SUMMARY We present a case of a 54-year-old male on a beta-blocker and angiotensin-con-verting enzyme inhibitor who presented with one day history of nausea,vomi-ting,and shortness of breath.Upon presentation,he was bradycardic and hypotensive,requiring transcutaneous pacing.Initial electrocardiogram showed atrial fibrillation with ventricular rate in 30’s.He was found to have acute kidney injury,hyperkalemia,and metabolic acidosis.He was successfully treated with multiple potassium lowering agents,continuous renal replacement therapy,four pressors,mechanical ventilation,and transvenous pacing with complete recovery prior to discharge.CONCLUSION Increased awareness of BRASH syndrome may improve outcomes through timely diagnosis and aggressive intervention.
基金supported by the National Natural Science Foundation of China(82373811,82574333,82504683)Natural Science Foundation of Guangdong Province(2024A1515012132).
文摘Integrating photodynamic therapy(PDT)with immunosuppression reversal represents a promising synergistic approach to boost cancer immunotherapy.However,the complicated components and cumbersome preparation procedures of the currently developed nano drug delivery systems heavily hinder their further clinical translation.Herein,a reactive oxygen species(ROS)/photo dual-responsive amphipathic prodrug(denoted as PPTN)was designed and synthesized by linking NLG919,an indoleamine-2,3-dioxygenase(IDO)inhibitor,with the photosensitizer protoporphyrin IX(PpIX)by a thioketal moiety,and further modifying with mPEG2k.PPTN could self-assemble into nanoscale unimolecular micelles in aqueous solution without additional excipients,increasing tumor accumulation while effectively addressing the pronounced hydrophobicity challenge of PpIX.Upon light exposure,PPTN generated ROS,not only directly damaging cancer cells,but also trigger the breakage of thioketal bond to accelerate simultaneous release of NLG919.Therefore,PPTN potentially act as a promising ROS/photo dual-responsive carrier-free prodrug delivery system for controllable drug release and specific tumor therapy.Moreover,PPTN induced simultaneous PDT-triggered immunogenic cell death(ICD)effect and specific IDO blockade to boost immune response,exhibiting potent suppression efficacy against primary and distant tumors.Overall,with the superiorities of easily controllable preparation procedures,synchronous drug delivery and ROS/photo dual-responsiveness,such a prodrug unimolecular micelle may represent a promising nanoplatform for photoactivated-immunotherapy.
文摘BACKGROUND:BRASH syndrome(Bradycardia,Renal failure,AV nodal blockade,Shock,and Hyperkalemia)is a recently described clinical entity characterized by synergistic interaction between AV nodal blocking medications and hyperkalemia.Despite increasing recognition,its clinical characteristics,risk factors,and outcomes remain poorly defined.The rationale of this review is to provide clinicians an upto-date overview of the most commonly encountered risk factors,triggers,clinical pictures,usual lab values,complications and outcomes,via the systemic analysis of currently published cases.METHODS:A systematic review was conducted using MEDLINE,Web of Science,and Cochrane Library databases through December 2024.Case reports,case series,and conference abstracts involving adult patients with BRASH syndrome were included.Data extraction focused on demographics,clinical presentations,laboratory findings,management strategies,and outcomes.RESULTS:Analysis included 131 patients from 111 published cases.Mean age was(71±13)years,with female predominance(58.1%).Hypertension(77.0%),chronic kidney disease(48.4%),and diabetes mellitus(46.7%)were the most common comorbidities.Beta-blockers were the predominant medication(76.5%).Most common presenting symptoms were syncope(17.9%),generalized weakness(16.2%),and altered mental status(11.9%).Mean potassium level was 6.6 mEq/L,with more than half of cases presenting with non-severe hyperkalemia(<6.5 mEq/L).Management often required multimodal therapy,with 50.8% of patients requiring vasopressors and 31.6% requiring hemodialysis.CONCLUSION:This systematic review provides the most comprehensive analysis of BRASH syndrome to date,demonstrating that while potentially serious,outcomes are generally favorable with appropriate recognition and management.The syndrome can develop even with modest hyperkalemia,particularly in elderly patients with multiple comorbidities.Early recognition and systematic management addressing all components of the syndrome appear crucial for optimal outcomes.
基金supported by the National Natural Science Foundation of China(Nos.U23A20591 and 52273158)the Science and Technology Development Program of Jilin Province(Nos.20240101002JJ and 20210504001GH).
文摘Tumor blockade therapy inhibits tumor progression by cutting off essential supplies of nutrients,oxygen,and biomolecules from the surrounding microenvironments.Inspired by natural processes,tumor biomineralization has evolved due to its biocompatibility,self-reinforcing capability,and penetrationindependent mechanism.However,the selective induction of tumor biomineralization using synthetic tools presents a significant challenge.Herein,a metabolic glycoengineering-assistant tumor biomineralization strategy was developed.Specifically,the azido group(N_(3))was introduced onto the cytomembrane by incubating tumor cells with glycose analog Ac4ManNAz.In addition,a bisphosphonate-containing polymer,dibenzocyclooctyne-poly(ethylene glycol)-alendronate(DBCO-PEG-ALN,DBPA)was synthesized,which attached to the tumor cell surface via"click chemistry"reaction between DBCO and N_(3).Subsequently,the bisphosphonate group on the cell surface chelated with positively charged ions in the microenvironments,triggering a consecutive process of biomineralization.This physical barrier significantly reduced tumor cell viability and mobility in a calcium ion concentration-dependent manner,suggesting its potential as an effective anti-tumor strategy for in vivo applications.
文摘Esophageal squamous cell carcinoma(ESCC)remains a daunting global health concern.It is marked by aggressive progression and poor survival.While immunotherapy has emerged as a promising treatment modality,both primary and acquired resistance continue to limit its clinical impact,leaving many patients without durable benefits(e.g.,CheckMate-648,ESCORT-1st).This review explains resistance mechanisms and suggests new strategies to improve outcomes.These mechanisms include immunosuppressive cells(Treg cells,myeloid-derived suppressor cells),inhibitory cytokines,molecular alterations involving programmed death 1/programmed death-ligand 1 signaling,and impaired antigen presentation.We also highlight key clinical trials—for example,CheckMate-648 and ESCORT-1st—that reveal both the potential and pitfalls of current immune checkpoint blockade strategies,underscoring the need for robust predictive biomarkers.Moreover,we examine cutting-edge tactics to overcome resistance,including combination regimens,tumor microenvironment remodeling,and tailored treatment approaches rooted in the patient’s unique genomic and immunologic landscape.
基金financially supported by the National Natural Science Foundation of China(82173769)Tianjin Science Foundation for Distinguished Young Scholars(24JCJQJC00050)+2 种基金Applied Basic Research Multi-Investment Foundation of Tianjin(21JCYBJC01540)the National Natural Science Foundation of China(82300336)the Science&Technology Development Fund of Tianjin Education Commission for Higher Education(2019KJ178).
文摘Mitochondria provides adenosine triphosphate for multiple vital movements to ensure tumor cell proliferation.Compared to the broadly used method of inducing DNA replication arrest to kill cancer,inducing mitochondria damage to cause energy shortage is quite promising as it can inhibit tumor cell bioactivities,increase intracellular accumulation of toxic drugs,eventually sensitize chemotherapy and even reverse drug resistance.Breaking the balance of glutathione(GSH)and reactive oxygen species(ROS)contents have been proven efficient in destroying mitochondria respectively.Herein,apigenin,a GSH efflux reagent,and 2-deoxy-5-fluorouridine 5-monophosphate sodium salt(FdUMP)that could induce toxic ROS were co-delivered by constructed lipid nanoparticles,noted as Lip@AF.An immune-checkpoint inhibition reagent CD276 antibody was modified onto the surface of Lip@AF with high reaction specificity(noted asαCD276-Lip@AF)to enhance the recognition of immune cells to tumor.Results showed that the redox balancewas destroyed,leading to severe injury to mitochondria and cell membrane.Furthermore,synergistic DNA/RNA replication inhibition caused by inhibiting the function of thymidylate synthase were observed.Eventually,significantly enhanced cytotoxicity was achieved by combining multiple mechanisms including ferroptosis,apoptosis and pyroptosis.In vivo,strengthen tumor growth inhibitionwas achieved byαCD276-Lip@AF with high biosafety,providing new sights in enhancing chemotherapy sensitiveness and achieving high-performance chemo-immunotherapy.
基金supported by the Fundamental Research Funds for the Central Universities,China(Grant Nos.:2023CDJXY-009 and 2023CDJYGRH-YB07)the National Natural Science Foundation of China(Grant No.:82172888)the Natural Science Foundation Project of Chongqing Science and Technology Commission(Grant No.:cstc2020jcyj-msxmX0154).
文摘Gastrointestinal(GI)cancers are prevalent globally,with leading incidence and mortality rates among malignant tumors.Despite notable advancements in surgical resection,radiotherapy,and chemotherapy,the overall survival rates remain low.Hence,it is imperative to explore alternative approaches that enhance patient outcomes.Cluster of differentiation 47(CD47),serving as an early diagnostic marker,is predominantly overexpressed in GI cancers and associated with poor prognosis.Targeting the CD47-signal regulatory protein alpha(SIRPa)signaling pathway may provide a novel strategy for GI cancers treatment.This study summarizes current knowledge of the structure and function of CD47 and SIRPa,their roles in signaling pathways,the prognostic significance of CD47,therapeutic strategies targeting the CD47-SIRPα signaling pathway in GI cancer,and highlights key issues for future investigations.
基金supported by the National Natural Sciences Foundation of China(Grant Nos.:31971308 and 81960769)Science and Technology Plan Project of Shihezi University,China(Grant No.:2023AB047)+2 种基金National S&T Major Project,China(Grant No.:2019ZX09301-147)Luzhou Science and Technology Plan,China(Grant No.:2018CDLZ-10)Sichuan Science and Technology Program,China(Grant No.:2021YFS0081).
文摘Melanoma,a common malignant skin tumor,faces challenges with multidrug resistance and high recurrence rates.Combining photodynamic therapy(PDT)and immunotherapy offers a promising personalized treatment approach.However,poor water solubility and significant side effects of photosensitizers and immune checkpoint inhibitors(ICIs)limit their application.Enhancing delivery efficiency while reducing adverse effects is crucial.Herein,we formulate BM@HSSC nanoparticles(NPs),which consist of a reduction-responsive hyaluronic acid(HA)backbone modified with photosensitizer chlorin e6(Ce6)and loaded with the programmed cell death-ligand 1(PD-L1)inhibitor BMS-1.This system synergistically integrates PDT,immunogenic cell death(ICD),and immunotherapy for melanoma treatment.BM@HSSC NPs target and accumulate at the tumor site via the CD44 receptor.The disulfide bonds(-S-S-)in the NPs react with high glutathione(GSH)concentrations in tumor cells,rapidly releasing Ce6 and BMS-1.Under 660 nm laser irradiation,BM@HSSC NPs generate cytotoxic reactive oxygen species(ROS),inducing cell apoptosis and triggering ICD via PDT damage-associated molecular patterns(DAMPs)and tumor-associated antigens(TAAs)released from ICD promote dendritic cell(DC)maturation,enhancing antigen presentation and activating cytotoxic T lymphocytes(CTLs).Meanwhile,BMS-1 blocks the programmed cell death-1(PD-1)/PD-L1 pathway,countering the immunosuppressive tumor microenvironment(iTME)and inhibiting tumor cell immune escape.This strategy amplifies antitumor immune responses by enhancing immunogenicity and synergizing with ICIs,resulting in robust antitumor efficacy.
基金National Natural Science Foundation of China(Grant Nos.:82274154,82304792)Natural Science Foundation of Tianjin Municipality(GrantNos.:23JCzXJC00150+1 种基金23JCJQjC00040)China Postdoctoral Science Foundation(Grant Nos.:2023M732627,2024T170657).
文摘Therapeutic antibodies of targeting the programmed cell death protein 1(PD-1)/programmed death-ligand 1(PD-L1)pathway are used in hepatocellular carcinoma(HCC)treatment,but are limited by low response rates and immune-related toxicity[1].Searching for treatment approaches to combine with PD-1/PD-L1 blockade may potentially enhance the efficacy of PD-1/PD-L1 blockade and reduce its side effects.
