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
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
Immune checkpoint inhibitors(ICIs)and cellular immunotherapy have revolutionized cancer treatment.Although these therapies have significantly improved cancer patients’survival,they are associated with a range of immu...Immune checkpoint inhibitors(ICIs)and cellular immunotherapy have revolutionized cancer treatment.Although these therapies have significantly improved cancer patients’survival,they are associated with a range of immunerelated adverse events(irAEs)that can affect patients’quality of life.Neuromuscular complications related to cancer immunotherapy are rare(<5%with monotherapy and up to 14%with combination therapy),but they can be fatal if not addressed promptly.Early diagnosis and intervention are crucial to improving the quality of life and survival of cancer patients affected by neuromuscular complications associated with immunotherapy.However,symptoms can be diverse and nonspecific,including weakness,numbness,imbalance,dysarthria,dysphagia,and even difficulty in breathing,which presents significant challenges for diagnosis and management.This review summarizes the current understanding of the mechanisms,clinical features,diagnostic challenges,and management strategies for neuromuscular complications related to cancer immunotherapy.Understanding the complex interplay between T cells,B cells,and cytokines in the pathogenesis of neuromuscular irAEs is essential for guiding their management.It is important for healthcare providers,including oncologists,neurologists,primary care physicians,and other practitioners,to be familiar with the multidisciplinary clinical management of neuromuscular irAEs.This knowledge will help reduce the mortality and morbidity associated with these complications.展开更多
Despite existing curative options like surgical removal,tissue destruction techniques,and liver transplantation for early-stage hepatocellular carcinoma(HCC),the rising incidence and mortality rates of this global hea...Despite existing curative options like surgical removal,tissue destruction techniques,and liver transplantation for early-stage hepatocellular carcinoma(HCC),the rising incidence and mortality rates of this global health burden necessitate continuous exploration of novel therapeutic strategies.This review critically assesses the dynamic treatment panorama for HCC,focusing specifically on the burgeoning role of immunotherapy in two key contexts:early-stage HCC and downstaging advanced HCC to facilitate liver transplant candidacy.It delves into the unique immunobiology of the liver and HCC,highlighting tumor-mediated immune evasion mechanisms.Analyzing the diverse immunothera-peutic approaches including checkpoint inhibitors,cytokine modulators,vaccines,oncolytic viruses,antigen-targeting antibodies,and adoptive cell therapy,this review acknowledges the limitations of current diagnostic markers alpha-fetoprotein and glypican-3 and emphasizes the need for novel biomarkers for patient selection and treatment monitoring.Exploring the rationale for neoadjuvant and adjuvant immunotherapy in early-stage HCC,current research is actively exploring the safety and effectiveness of diverse immunothera-peutic approaches through ongoing clinical trials.The review further explores the potential benefits and challenges of combining immunotherapy and liver transplant,highlighting the need for careful patient selection,meticulous monitoring,and novel strategies to mitigate post-transplant complications.Finally,this review delves into the latest findings from the clinical research landscape and future directions in HCC management,paving the way for optimizing treatment strategies and improving long-term survival rates for patients with this challenging malignancy.展开更多
Objective:Immune checkpoint inhibitors(ICIs)have demonstrated substantial efficacy in patients with advanced non-small cell lung cancer(NSCLC).However,the optimal duration of ICI therapy remains unclear,and limited re...Objective:Immune checkpoint inhibitors(ICIs)have demonstrated substantial efficacy in patients with advanced non-small cell lung cancer(NSCLC).However,the optimal duration of ICI therapy remains unclear,and limited real-world data are available.The aim of this study was to evaluate the relationship between ICI therapy duration and overall survival(OS)in patients who achieved varying best overall response(BOR)during ICI treatment,and to compare patients treated for 6 to 18 months vs.at least 18 months.Methods:This retrospective cohort study included adult patients diagnosed with advanced NSCLC who received ICI therapy at the Zhejiang Cancer Hospital between 2017 and 2022.Data collection ended on May 1,2024,and statistical analysis was performed between May and June 2024.Results:Using strict entry criteria,we screened 487 patients with advanced NSCLC and identified 134 eligible patients.Among these patients,the median durations of immunotherapy and follow-up were 24.57 months and 43.60 months,respectively.The objective response rate(ORR)was 58.2%,and the median progression-free survival(PFS)was 10.6 months.Median OS was not reached.At the last follow-up,54 patients had no disease progression,and 118 patients remained alive.Patients treated with ICI therapy for≥18 months had superior survival to those treated for 6 to 18 months(P=0.039).Further analysis revealed that the survival benefit was associated with BOR during ICI therapy.Specifically,patients achieving complete response/partial response(CR/PR)who received≥18 months of ICI therapy had a trend toward longer median OS than those treated for 6 to 18 months,but the difference did not reach statistical significance(P=0.177).Patients with stable disease(SD)who received≥18 months of ICI therapy had a statistically longer median OS than those treated for 6 to 18 months(P=0.019).Among patients treated with ICIs for≥18 months,24 continued with ICI-based therapy and achieved a median PFS2 of 6.67 months,an ORR of 33.3%,and a disease control rate(DCR)of 83.3%.Conclusions:This study provides real-world evidence and novel insights into the need for continuing ICI therapy beyond 18 months in patients with advanced NSCLC who do not exhibit progressive disease.For patients achieving SD during ICI therapy,a treatment duration of at least 18 months appears appropriate.For patients achieving CR/PR,treatment decisions should be individualized according to patient-specific circumstances.However,owing to the retrospective study design,potential selection bias and confounding factors might have influenced the results.Therefore,our findings require further validation in prospective clinical studies.展开更多
Bladder cancer remains a significant global health challenge,requiring repeated treatments and surveillance and potentially morbid therapies,particularly in advanced and recurrent stages.Exosomes,small extracellular v...Bladder cancer remains a significant global health challenge,requiring repeated treatments and surveillance and potentially morbid therapies,particularly in advanced and recurrent stages.Exosomes,small extracellular vesicles central to intercellular communication,have emerged as innovative tools in cancer diagnostics,prognosis,and therapy.Their role in modulating the immune response and the tumor microenvironment makes them particularly attractive for cancer immunotherapy.This review provides a comprehensive overview of exosome biology,with a focus on their role in immune modulation and potential therapeutic applications.We explore the progress and challenges of exosome-based immunotherapy in cancer,followed by a discussion on the current state of bladder cancer immunotherapy.Additionally,we highlight the roles of exosomes in bladder cancer,emphasizing their diagnostic and prognostic applications.Despite promising preclinical studies and a growing number of clinical trials in other cancers,exosome-based therapies remain underexplored in bladder cancer.We discuss the current clinical trials related to exosomes in bladder cancer and propose their potential future role in immunotherapy.Finally,we address the challenges and opportunities in translating exosome-based therapies from bench to bedside,emphasizing the need for further preclinical and clinical investigations.This review emphasized the potential of exosome-based immunotherapy as a transformative approach for bladder cancer diagnosis and treatment.展开更多
Conventional therapies are primary cancer treatments that directly eliminate or inhibit the growth of tumor cells,reducing the overall tumor burden.Increasing evidence suggests that conventional therapies possess sign...Conventional therapies are primary cancer treatments that directly eliminate or inhibit the growth of tumor cells,reducing the overall tumor burden.Increasing evidence suggests that conventional therapies possess significant immunomodulatory properties in addition to their established direct tumoricidal effects.Emerging immunotherapies have revolutionized the clinical management of various cancer types.Conventional therapy and immunotherapy have demonstrated remarkable clinical efficacy,leading to numerous ongoing clinical investiga-tions exploring their potential synergistic effects.However,trials investigating the combination of conventional therapy and immunotherapy have shown limited synergistic therapeutic efficacy.This unsatisfactory clinical outcome may be attributed to the suboptimal design of the combination approach and the inadequate understanding of the mechanisms and impacts of radiotherapy,chemotherapy,targeted ther-apy regimens(including dosing,timing,and administration route),and surgery on both cancer cells and the host immune system.Here,we comprehensively review preclinical and clinical investigations exploring the therapeutic effects and mechanisms of conventional therapy alone or in combination with immunotherapy.We proposed that optimizing the dosing,timing,and route of administration of conventional therapies can enhance the synergistic efficacy of combination therapies,thus offering significant clinical advantages.展开更多
Cancer is a major global concern due to its high mortality rate.Tumor immunotherapy has revolutionized cancer treatment.However,low response rates and immune-related complications remain challenges.Extracellular vesic...Cancer is a major global concern due to its high mortality rate.Tumor immunotherapy has revolutionized cancer treatment.However,low response rates and immune-related complications remain challenges.Extracellular vesicles(EVs),including exosomes,have emerged as promising therapeutic tools for various pathological conditions,especially cancer.Evidence indicates that changes in the quantity and composition of EVs can influence the immunosuppressive tumor microenvironment,potentially affecting the effectiveness of immunotherapy.Exploiting EVs for immune sensitization has generated significant clinical interest.This review provides an in-depth understanding of the origin of EVs,their therapeutic applications(such as drug delivery nanoplatforms and cancer immunotherapies,including vaccines),diagnostic potential as tumor biomarkers,ongoing EV-based clinical trials,and the challenges encountered in EV-based cancer immunotherapy.展开更多
Objective:Cytotoxic T lymphocytes(CTLs)play a crucial role in the therapeutic approach to hepatocellular carcinoma(HCC).Recent research has indicated that junctional adhesion molecule-like protein(JAML)enhances the an...Objective:Cytotoxic T lymphocytes(CTLs)play a crucial role in the therapeutic approach to hepatocellular carcinoma(HCC).Recent research has indicated that junctional adhesion molecule-like protein(JAML)enhances the antitumor activity of CD8+T cells.Our study investigates the role of JAML+CD8+T cells in HCC.Methods:We utilized time-of-flight mass cytometry and an orthotopic mouse model of HCC to examine histone modifications in tumor-infiltrating immune cells undergoing immunotherapy.Flow cytometry was used to assess CD4+T cells differentiation and JAML expression in CD8+T cells infiltrating HCC.Correlation analysis revealed a strong positive correlation between lactate dehydrogenase A+(LDHA+)CD4+T cells and JAML+CD8+T cells.Subsequently,we evaluated the therapeutic effects of an agonistic anti-JAML antibody,both alone and combined with immunotherapy.Finally,RNA sequencing was conducted to identify potential regulatory mechanisms.Results:Immunotherapy significantly increased the percentage of CD8+T cells infiltrating HCC and induced histone modifications,such as H3K18 lactylation(H3K18la)in CD4+T cells.Flow cytometry analysis revealed that lactate promotes the differentiation of CD4+T cells into Th1 cells.LDHA,an enzyme that converts pyruvate to lactate,plays a key role in this process.Correlation analysis revealed a strong positive relationship between LDHA+CD4+T cells and JAML+CD8+T cells in patients who responded to immunotherapy.Moreover,high JAML expression in CD8+T cells was associated with a more favorable prognosis.In vivo experiments demonstrated that agonistic anti-JAML antibody therapy reduced tumor volume and significantly prolonged the survival of tumor-bearing mice,independent of the effects of anti-programmed cell death protein ligand-1 antibody(αPD-L1)-mediated immunotherapy.Pathway enrichment analysis further revealed that JAML enhances CTL responses through the oxidative phosphorylation pathway.Conclusions:Activation of JAML enhances CTL responses in HCC treatment,independent ofαPD-L1-mediated immunotherapy,providing a promising strategy for advanced HCC.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
The principal breast cancer treatment approach has long been surgical removal of the primary breast lesions and regional lymph nodes,particularly the axillary lymph nodes.However,the advent of minimally invasive diagn...The principal breast cancer treatment approach has long been surgical removal of the primary breast lesions and regional lymph nodes,particularly the axillary lymph nodes.However,the advent of minimally invasive diagnostic techniques,such as sentinel lymph node biopsy(SLNB),has markedly diminished the extent of surgery required for regional lymph nodes.展开更多
Pancreatic cancer remains one of the most challenging malignancies to treat,with a poor prognosis and limited therapeutic options.Despite the success of immunotherapy and targeted therapies for other cancers,these app...Pancreatic cancer remains one of the most challenging malignancies to treat,with a poor prognosis and limited therapeutic options.Despite the success of immunotherapy and targeted therapies for other cancers,these approaches have not yet transformed the treatment landscape for pancreatic cancer.The unique tumor microenvironment(TME)of pancreatic cancer,characterized by dense fibrotic stroma and immunosuppressive myeloid cells,poses significant barriers to effective immunotherapy.Current research highlights the need for an in-depth understanding of the TME and the development of strategies to overcome its immunosuppressive properties.Recent studies have explored various immunotherapeutic approaches,including immune checkpoint inhibitors,cancer vaccines,and adoptive cell therapies,some of which have shown promising results in preclinical and early clinical trials.Furthermore,combining immunotherapy with traditional treatments,such as chemotherapy and radiotherapy,has shown potential for enhancing antitumor efficacy,although targeted therapies for pancreatic cancer are still in their early stages and are being investigated for their ability to disrupt specific molecular pathways involved in tumor growth and survival.This review provides a comprehensive overview of the advances in immunotherapy and targeted therapies for pancreatic cancer,discussing the current state of research,clinical outcomes,and future directions for improving patient prognosis.展开更多
BACKGROUND Mitochondrial genes are involved in tumor metabolism in ovarian cancer(OC)and affect immune cell infiltration and treatment responses.AIM To predict prognosis and immunotherapy response in patients diagnose...BACKGROUND Mitochondrial genes are involved in tumor metabolism in ovarian cancer(OC)and affect immune cell infiltration and treatment responses.AIM To predict prognosis and immunotherapy response in patients diagnosed with OC using mitochondrial genes and neural networks.METHODS Prognosis,immunotherapy efficacy,and next-generation sequencing data of patients with OC were downloaded from The Cancer Genome Atlas and Gene Expression Omnibus.Mitochondrial genes were sourced from the MitoCarta3.0 database.The discovery cohort for model construction was created from 70% of the patients,whereas the remaining 30% constituted the validation cohort.Using the expression of mitochondrial genes as the predictor variable and based on neural network algorithm,the overall survival time and immunotherapy efficacy(complete or partial response)of patients were predicted.RESULTS In total,375 patients with OC were included to construct the prognostic model,and 26 patients were included to construct the immune efficacy model.The average area under the receiver operating characteristic curve of the prognostic model was 0.7268[95% confidence interval(CI):0.7258-0.7278]in the discovery cohort and 0.6475(95%CI:0.6466-0.6484)in the validation cohort.The average area under the receiver operating characteristic curve of the immunotherapy efficacy model was 0.9444(95%CI:0.8333-1.0000)in the discovery cohort and 0.9167(95%CI:0.6667-1.0000)in the validation cohort.CONCLUSION The application of mitochondrial genes and neural networks has the potential to predict prognosis and immunotherapy response in patients with OC,providing valuable insights into personalized treatment strategies.展开更多
Primary liver cancer(PLC)is a prevalent malignancy with high incidence and mortality rates globally.Hepatocellular carcinoma(HCC),primarily resulting from hepatitis B virus infections in Asia,constitutes most PLC case...Primary liver cancer(PLC)is a prevalent malignancy with high incidence and mortality rates globally.Hepatocellular carcinoma(HCC),primarily resulting from hepatitis B virus infections in Asia,constitutes most PLC cases.Despite advancements in targeted therapies and localized treatments,the 5-year survival rate remains low,indicating limited efficacy of current approaches.The advent of immunotherapy,particularly immune checkpoint inhibitors(ICIs),has brought new hope for patients with PLC.However,the liver's unique immune microenvironment presents significant challenges to the effectiveness of immunotherapy in HCC.This article reviews recent research developments in liver cancer immunotherapy,focusing on ICIs,combination therapies,emerging treatments,and prospective future directions.展开更多
Allergen specific immunotherapy(AIT)has a history spanning over 110 years and represents the only diseasemodifying treatment for allergic diseases,with potential preventive effects.Nevertheless,the broader application...Allergen specific immunotherapy(AIT)has a history spanning over 110 years and represents the only diseasemodifying treatment for allergic diseases,with potential preventive effects.Nevertheless,the broader application of AIT is limited by the inherent drawbacks of natural allergen extracts,such as variability in composition,risk of side effects,and complex,lengthy treatment regimens.Advances in molecular allergology have enabled the development of novel vaccine strategies-including recombinant allergens,hypoallergenic derivatives,allergen-derived peptides,and nucleic acid-based vaccines-that aim to improve safety,efficacy,and precision.However,no molecule-based AIT product has yet achieved regulatory approval,largely due to technical and clinical trial challenges.In parallel,immunomodulatory adjuvants such as monophosphoryl lipid A,CpG oligodeoxynucleotides,flagellin and mannan have demonstrated promising properties.These innovations have the potential to enhance AIT outcomes by promoting immune tolerance,reducing IgE responses,and improving patient compliance.This review summarizes the current landscape of allergen vaccines and adjuvant technologies under investigation for AIT,highlighting key advances,clinical data,and future directions aimed at overcoming existing limitations and optimizing treatment strategies for allergic diseases.展开更多
Cerenkov radiation(CR)can serve as a source of internal light to overcome the limited tissue penetration of external light in conventional photodynamic therapy(PDT).However,insufficient luminescence intensity hinders ...Cerenkov radiation(CR)can serve as a source of internal light to overcome the limited tissue penetration of external light in conventional photodynamic therapy(PDT).However,insufficient luminescence intensity hinders the clinical application of CR-PDT.Here,we developed a glutathione-responsive biomimetic nanoplatform by fusing cancer cell membranes and liposomes loaded with photosensitizer hematoporphyrin monomethyl ether(HMME)and a radiation energy amplifier Eu^(3+),named HMME-Eu@LEV.Colloidal Eu^(3+)convertsγ-radiation and CR from radioisotopes into fluorescence to enhance antitumor effects.Sequential administration ensures co-localization of HMME-Eu@LEV and radiopharmaceutical^(18)F-fluorodeoxyglucose(FDG)at the tumor site,triggering enhanced CR-PDT and immunogenic cell death.Our observations indicated that luminescence resonance energy transfer between Eu^(3+)and HMME was efficient,and Cerenkov luminescence from Eu@LEV+FDG was approximately 5.6-fold higher in intensity than that from FDG alone.As a result,abundant ROS were generated,and macrophages in the tumor microenvironment were polarized from M2 to M1.In addition,the immunosuppressive tumor microenvironment could be reversed by promoting the maturation of dendritic cells and infiltration of cytotoxic T lymphocytes.The activated immune system effectively inhibited the growth of primary tumors and spread of distant metastases.Our work demonstrates the feasibility of CR-PDT without an external light source and the critical role of nanomaterials in personalized medicine.展开更多
TheγδT cells are an emerging class of immune effectors with potent antitumor activity,bridging innate and adaptive immunity.Their unique ability to recognise stress-induced ligands independently of major histocompat...TheγδT cells are an emerging class of immune effectors with potent antitumor activity,bridging innate and adaptive immunity.Their unique ability to recognise stress-induced ligands independently of major histocompatibility complex restriction makes them attractive candidates for cancer immunotherapy.However,the clinical application ofγδT cells requires efficient in vitro expansion strategies to generate large numbers of functional cells.This mini-review explores the latest advancements inγδT cell expansion protocols,focusing on key activation stimuli,cytokine support,and culture conditions that optimise proliferation and cytotoxicity.展开更多
Perioperative fluorouracil,leucovorin,oxaliplatin and docetaxel is currently the standard chemotherapy for resectable gastric and gastroesophageal junction adenocarcinomas,based on the results of FLOT4 and ESOPEC tria...Perioperative fluorouracil,leucovorin,oxaliplatin and docetaxel is currently the standard chemotherapy for resectable gastric and gastroesophageal junction adenocarcinomas,based on the results of FLOT4 and ESOPEC trials.This regimen has demonstrated efficacy in tumor downstaging,enhancing the chances of curative resection,and ultimately improving the overall survival.However,despite these advances,the complete response rate in the perioperative setting remains below 10%to 15%,highlighting the need for more effective treatment strategies.Recent studies evaluating immunotherapy,such as the KEYNOTE-585 trial with pembrolizumab and the MATTERHORN trial with durvalumab,have shown promising preliminary results,including improved response rates and event-free survival.Nevertheless,these regimens are not yet considered the standard of care.This article explores the current landscape of perioperative treatments for gastric cancer and discusses future directions in this field.展开更多
Hepatocellular carcinoma(HCC)is one of the most common malignant tumors globally and is the most prevalent type of primary liver cancer,posing a heavy burden on global health.Surgical resection and liver transplantati...Hepatocellular carcinoma(HCC)is one of the most common malignant tumors globally and is the most prevalent type of primary liver cancer,posing a heavy burden on global health.Surgical resection and liver transplantation are the gold standard for the radical treatment of HCC.However,due to the heterogeneity and high invasiveness of HCC,the rates of local and distant recurrence are extremely high,with over 70%of patients experiencing recurrence within 5 years after treatment,significantly impacting the long-term quality of life.Therefore,researchers are exploring other treatment methods to reduce tumor recurrence and improve patient survival.To date,extensive research has concentrated on new alternative therapies,including radiotherapy(e.g.,selective internal radiotherapy),targeted drug therapy(e.g.,sorafenib and lenvatinib),and immunotherapy(e.g.,immune checkpoint inhibitors),which have played an integral role in the comprehensive treatment of HCC.This review mainly focuses on the cutting-edge advancements in these treatment methods for HCC and their potential role in reducing HCC recurrence.展开更多
Background:The role of systemic tumor immune environment(STIE)is unclear in hepatocellular carcinoma(HCC).This study aimed to exam the cells in the STIE,their changes after transarterial chemoembolisation(TACE),stereo...Background:The role of systemic tumor immune environment(STIE)is unclear in hepatocellular carcinoma(HCC).This study aimed to exam the cells in the STIE,their changes after transarterial chemoembolisation(TACE),stereotactic body radiotherapy(SBRT),and immunotherapy(IO)and explore their significance in the treatment response of patients with unresectable HCC.Methods:This is a prospective biomarker study of patients with unresectable HCC.The treatment was sequential TACE,SBRT(27.5-40 Gy/5 fractions),and IO.The treatment response was assessed according to modified Re-sponse Evaluation Criteria in Solid Tumors(mRECIST)by magnetic resonance imaging(MRI)after 6 months of treatment.Longitudinal data of STIE cells was extracted from laboratory results of complete blood cell counts,in-cluding leukocytes,lymphocytes,neutrophils,monocytes,eosinophils,basophils,and platelets.Peripheral blood samples were collected at baseline and after TACE,SBRT,and IO for T-lymphocyte subtyping by flow cytometry.Generalized estimation equation was employed for longitudinal analyses.Results:A total of 35 patients with unresectable HCC were enrolled:23 patients in the exploratory cohort and 12 in the validation cohort.STIE circulating cells,especially lymphocytes,were heterogenous at baseline and changed differentially after TACE,SBRT,and IO in both cohorts.SBRT caused the greatest reduction of 0.7×10^(9)/L(95%CI:0.3×10^(9)/L-1.0×10^(9)/L,P<0.001)in lymphocytes;less reduction was associated with significantly better treatment response.The analysis of T-lymphocyte lineage revealed that the baseline levels of CD4+T cells(P=0.010),type 1 T helper(Th1)cells(P=0.007),and Th1/Th17 ratios(P=0.001)were significantly higher in responders,while regulatory T(Treg)cells(P=0.002),Th17 cells(P=0.047),and Th2/Th1 ratios(P=0.028)were significantly higher in non-responders.After treatment with TACE,SBRT and IO,T-lymphocyte lineage also changed differentially.More reductions were observed in CD25^(+)CD8^(+)T cells and CD127^(+)CD8^(+)T cells after SBRT in non-responders,while increases in natural killer T(NKT)cells after SBRT(10.4%vs.3.4%,P=0.001)and increases in the lymphocyte counts were noted during IO in responders.Conclusions:STIE cells are significant for treatment response,can be reshaped differentially after TACE,SBRT,and IO.The most significant changes of T-lymphocyte lineage are SBRT associated modulations in CD25^(+)CD8^(+)T cells,CD127^(+)CD8^(+)T cells,and NKT cells,which also have significant effects on the ultimate treatment response after TACE-SBRT-IO(ClinicalTrails.gov identifier:GCOG0001/NCT05061342).展开更多
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.
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 VA Merit Award(grant number:I01BX003895)National Cancer Institute R01(grant num-ber:AI154722)Personalized Cancer Therapy Gift Fund(T.L.).
文摘Immune checkpoint inhibitors(ICIs)and cellular immunotherapy have revolutionized cancer treatment.Although these therapies have significantly improved cancer patients’survival,they are associated with a range of immunerelated adverse events(irAEs)that can affect patients’quality of life.Neuromuscular complications related to cancer immunotherapy are rare(<5%with monotherapy and up to 14%with combination therapy),but they can be fatal if not addressed promptly.Early diagnosis and intervention are crucial to improving the quality of life and survival of cancer patients affected by neuromuscular complications associated with immunotherapy.However,symptoms can be diverse and nonspecific,including weakness,numbness,imbalance,dysarthria,dysphagia,and even difficulty in breathing,which presents significant challenges for diagnosis and management.This review summarizes the current understanding of the mechanisms,clinical features,diagnostic challenges,and management strategies for neuromuscular complications related to cancer immunotherapy.Understanding the complex interplay between T cells,B cells,and cytokines in the pathogenesis of neuromuscular irAEs is essential for guiding their management.It is important for healthcare providers,including oncologists,neurologists,primary care physicians,and other practitioners,to be familiar with the multidisciplinary clinical management of neuromuscular irAEs.This knowledge will help reduce the mortality and morbidity associated with these complications.
文摘Despite existing curative options like surgical removal,tissue destruction techniques,and liver transplantation for early-stage hepatocellular carcinoma(HCC),the rising incidence and mortality rates of this global health burden necessitate continuous exploration of novel therapeutic strategies.This review critically assesses the dynamic treatment panorama for HCC,focusing specifically on the burgeoning role of immunotherapy in two key contexts:early-stage HCC and downstaging advanced HCC to facilitate liver transplant candidacy.It delves into the unique immunobiology of the liver and HCC,highlighting tumor-mediated immune evasion mechanisms.Analyzing the diverse immunothera-peutic approaches including checkpoint inhibitors,cytokine modulators,vaccines,oncolytic viruses,antigen-targeting antibodies,and adoptive cell therapy,this review acknowledges the limitations of current diagnostic markers alpha-fetoprotein and glypican-3 and emphasizes the need for novel biomarkers for patient selection and treatment monitoring.Exploring the rationale for neoadjuvant and adjuvant immunotherapy in early-stage HCC,current research is actively exploring the safety and effectiveness of diverse immunothera-peutic approaches through ongoing clinical trials.The review further explores the potential benefits and challenges of combining immunotherapy and liver transplant,highlighting the need for careful patient selection,meticulous monitoring,and novel strategies to mitigate post-transplant complications.Finally,this review delves into the latest findings from the clinical research landscape and future directions in HCC management,paving the way for optimizing treatment strategies and improving long-term survival rates for patients with this challenging malignancy.
基金supported by the Natural Scientific Foundation of Zhejiang Province,China(Grant No.LTGY23H160007).
文摘Objective:Immune checkpoint inhibitors(ICIs)have demonstrated substantial efficacy in patients with advanced non-small cell lung cancer(NSCLC).However,the optimal duration of ICI therapy remains unclear,and limited real-world data are available.The aim of this study was to evaluate the relationship between ICI therapy duration and overall survival(OS)in patients who achieved varying best overall response(BOR)during ICI treatment,and to compare patients treated for 6 to 18 months vs.at least 18 months.Methods:This retrospective cohort study included adult patients diagnosed with advanced NSCLC who received ICI therapy at the Zhejiang Cancer Hospital between 2017 and 2022.Data collection ended on May 1,2024,and statistical analysis was performed between May and June 2024.Results:Using strict entry criteria,we screened 487 patients with advanced NSCLC and identified 134 eligible patients.Among these patients,the median durations of immunotherapy and follow-up were 24.57 months and 43.60 months,respectively.The objective response rate(ORR)was 58.2%,and the median progression-free survival(PFS)was 10.6 months.Median OS was not reached.At the last follow-up,54 patients had no disease progression,and 118 patients remained alive.Patients treated with ICI therapy for≥18 months had superior survival to those treated for 6 to 18 months(P=0.039).Further analysis revealed that the survival benefit was associated with BOR during ICI therapy.Specifically,patients achieving complete response/partial response(CR/PR)who received≥18 months of ICI therapy had a trend toward longer median OS than those treated for 6 to 18 months,but the difference did not reach statistical significance(P=0.177).Patients with stable disease(SD)who received≥18 months of ICI therapy had a statistically longer median OS than those treated for 6 to 18 months(P=0.019).Among patients treated with ICIs for≥18 months,24 continued with ICI-based therapy and achieved a median PFS2 of 6.67 months,an ORR of 33.3%,and a disease control rate(DCR)of 83.3%.Conclusions:This study provides real-world evidence and novel insights into the need for continuing ICI therapy beyond 18 months in patients with advanced NSCLC who do not exhibit progressive disease.For patients achieving SD during ICI therapy,a treatment duration of at least 18 months appears appropriate.For patients achieving CR/PR,treatment decisions should be individualized according to patient-specific circumstances.However,owing to the retrospective study design,potential selection bias and confounding factors might have influenced the results.Therefore,our findings require further validation in prospective clinical studies.
基金funded by start-up funds from the University of Chicago.
文摘Bladder cancer remains a significant global health challenge,requiring repeated treatments and surveillance and potentially morbid therapies,particularly in advanced and recurrent stages.Exosomes,small extracellular vesicles central to intercellular communication,have emerged as innovative tools in cancer diagnostics,prognosis,and therapy.Their role in modulating the immune response and the tumor microenvironment makes them particularly attractive for cancer immunotherapy.This review provides a comprehensive overview of exosome biology,with a focus on their role in immune modulation and potential therapeutic applications.We explore the progress and challenges of exosome-based immunotherapy in cancer,followed by a discussion on the current state of bladder cancer immunotherapy.Additionally,we highlight the roles of exosomes in bladder cancer,emphasizing their diagnostic and prognostic applications.Despite promising preclinical studies and a growing number of clinical trials in other cancers,exosome-based therapies remain underexplored in bladder cancer.We discuss the current clinical trials related to exosomes in bladder cancer and propose their potential future role in immunotherapy.Finally,we address the challenges and opportunities in translating exosome-based therapies from bench to bedside,emphasizing the need for further preclinical and clinical investigations.This review emphasized the potential of exosome-based immunotherapy as a transformative approach for bladder cancer diagnosis and treatment.
基金supported by the National Science Foundation of China(No.82172726)the Youth Project of Science and Technology Department of Shanxi Province(No.202203021212105)the Research Project Supported by the Shanxi Scholarship Council of China(2021-156).
文摘Conventional therapies are primary cancer treatments that directly eliminate or inhibit the growth of tumor cells,reducing the overall tumor burden.Increasing evidence suggests that conventional therapies possess significant immunomodulatory properties in addition to their established direct tumoricidal effects.Emerging immunotherapies have revolutionized the clinical management of various cancer types.Conventional therapy and immunotherapy have demonstrated remarkable clinical efficacy,leading to numerous ongoing clinical investiga-tions exploring their potential synergistic effects.However,trials investigating the combination of conventional therapy and immunotherapy have shown limited synergistic therapeutic efficacy.This unsatisfactory clinical outcome may be attributed to the suboptimal design of the combination approach and the inadequate understanding of the mechanisms and impacts of radiotherapy,chemotherapy,targeted ther-apy regimens(including dosing,timing,and administration route),and surgery on both cancer cells and the host immune system.Here,we comprehensively review preclinical and clinical investigations exploring the therapeutic effects and mechanisms of conventional therapy alone or in combination with immunotherapy.We proposed that optimizing the dosing,timing,and route of administration of conventional therapies can enhance the synergistic efficacy of combination therapies,thus offering significant clinical advantages.
文摘Cancer is a major global concern due to its high mortality rate.Tumor immunotherapy has revolutionized cancer treatment.However,low response rates and immune-related complications remain challenges.Extracellular vesicles(EVs),including exosomes,have emerged as promising therapeutic tools for various pathological conditions,especially cancer.Evidence indicates that changes in the quantity and composition of EVs can influence the immunosuppressive tumor microenvironment,potentially affecting the effectiveness of immunotherapy.Exploiting EVs for immune sensitization has generated significant clinical interest.This review provides an in-depth understanding of the origin of EVs,their therapeutic applications(such as drug delivery nanoplatforms and cancer immunotherapies,including vaccines),diagnostic potential as tumor biomarkers,ongoing EV-based clinical trials,and the challenges encountered in EV-based cancer immunotherapy.
基金funded by the Major Research Plan of the National Natural Science Foundation of China(No.92159202)the National Key Research and Development Program of China(No.2021YFA1100500)+1 种基金the Leading Innovation Team Project of Hangzhou Medical College(No.CXLJ202401)the Key Research and Development Plan of Zhejiang Provincial Department of Science and Technology(No.2024C03051)。
文摘Objective:Cytotoxic T lymphocytes(CTLs)play a crucial role in the therapeutic approach to hepatocellular carcinoma(HCC).Recent research has indicated that junctional adhesion molecule-like protein(JAML)enhances the antitumor activity of CD8+T cells.Our study investigates the role of JAML+CD8+T cells in HCC.Methods:We utilized time-of-flight mass cytometry and an orthotopic mouse model of HCC to examine histone modifications in tumor-infiltrating immune cells undergoing immunotherapy.Flow cytometry was used to assess CD4+T cells differentiation and JAML expression in CD8+T cells infiltrating HCC.Correlation analysis revealed a strong positive correlation between lactate dehydrogenase A+(LDHA+)CD4+T cells and JAML+CD8+T cells.Subsequently,we evaluated the therapeutic effects of an agonistic anti-JAML antibody,both alone and combined with immunotherapy.Finally,RNA sequencing was conducted to identify potential regulatory mechanisms.Results:Immunotherapy significantly increased the percentage of CD8+T cells infiltrating HCC and induced histone modifications,such as H3K18 lactylation(H3K18la)in CD4+T cells.Flow cytometry analysis revealed that lactate promotes the differentiation of CD4+T cells into Th1 cells.LDHA,an enzyme that converts pyruvate to lactate,plays a key role in this process.Correlation analysis revealed a strong positive relationship between LDHA+CD4+T cells and JAML+CD8+T cells in patients who responded to immunotherapy.Moreover,high JAML expression in CD8+T cells was associated with a more favorable prognosis.In vivo experiments demonstrated that agonistic anti-JAML antibody therapy reduced tumor volume and significantly prolonged the survival of tumor-bearing mice,independent of the effects of anti-programmed cell death protein ligand-1 antibody(αPD-L1)-mediated immunotherapy.Pathway enrichment analysis further revealed that JAML enhances CTL responses through the oxidative phosphorylation pathway.Conclusions:Activation of JAML enhances CTL responses in HCC treatment,independent ofαPD-L1-mediated immunotherapy,providing a promising strategy for advanced HCC.
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supported by grants from the National Natural Science Foundation of China(Grant Nos.81672638 and W2421095)National Natural Science Foundation of Shandong Province(Grant No.ZR2024LMB011)Collaborative Academic Innovation Project of Shandong Cancer Hospital(Grant No.GF003)。
文摘The principal breast cancer treatment approach has long been surgical removal of the primary breast lesions and regional lymph nodes,particularly the axillary lymph nodes.However,the advent of minimally invasive diagnostic techniques,such as sentinel lymph node biopsy(SLNB),has markedly diminished the extent of surgery required for regional lymph nodes.
文摘Pancreatic cancer remains one of the most challenging malignancies to treat,with a poor prognosis and limited therapeutic options.Despite the success of immunotherapy and targeted therapies for other cancers,these approaches have not yet transformed the treatment landscape for pancreatic cancer.The unique tumor microenvironment(TME)of pancreatic cancer,characterized by dense fibrotic stroma and immunosuppressive myeloid cells,poses significant barriers to effective immunotherapy.Current research highlights the need for an in-depth understanding of the TME and the development of strategies to overcome its immunosuppressive properties.Recent studies have explored various immunotherapeutic approaches,including immune checkpoint inhibitors,cancer vaccines,and adoptive cell therapies,some of which have shown promising results in preclinical and early clinical trials.Furthermore,combining immunotherapy with traditional treatments,such as chemotherapy and radiotherapy,has shown potential for enhancing antitumor efficacy,although targeted therapies for pancreatic cancer are still in their early stages and are being investigated for their ability to disrupt specific molecular pathways involved in tumor growth and survival.This review provides a comprehensive overview of the advances in immunotherapy and targeted therapies for pancreatic cancer,discussing the current state of research,clinical outcomes,and future directions for improving patient prognosis.
基金Supported by National Key Technology Research and Developmental Program of China,No.2022YFC2704400 and No.2022YFC2704405.
文摘BACKGROUND Mitochondrial genes are involved in tumor metabolism in ovarian cancer(OC)and affect immune cell infiltration and treatment responses.AIM To predict prognosis and immunotherapy response in patients diagnosed with OC using mitochondrial genes and neural networks.METHODS Prognosis,immunotherapy efficacy,and next-generation sequencing data of patients with OC were downloaded from The Cancer Genome Atlas and Gene Expression Omnibus.Mitochondrial genes were sourced from the MitoCarta3.0 database.The discovery cohort for model construction was created from 70% of the patients,whereas the remaining 30% constituted the validation cohort.Using the expression of mitochondrial genes as the predictor variable and based on neural network algorithm,the overall survival time and immunotherapy efficacy(complete or partial response)of patients were predicted.RESULTS In total,375 patients with OC were included to construct the prognostic model,and 26 patients were included to construct the immune efficacy model.The average area under the receiver operating characteristic curve of the prognostic model was 0.7268[95% confidence interval(CI):0.7258-0.7278]in the discovery cohort and 0.6475(95%CI:0.6466-0.6484)in the validation cohort.The average area under the receiver operating characteristic curve of the immunotherapy efficacy model was 0.9444(95%CI:0.8333-1.0000)in the discovery cohort and 0.9167(95%CI:0.6667-1.0000)in the validation cohort.CONCLUSION The application of mitochondrial genes and neural networks has the potential to predict prognosis and immunotherapy response in patients with OC,providing valuable insights into personalized treatment strategies.
文摘Primary liver cancer(PLC)is a prevalent malignancy with high incidence and mortality rates globally.Hepatocellular carcinoma(HCC),primarily resulting from hepatitis B virus infections in Asia,constitutes most PLC cases.Despite advancements in targeted therapies and localized treatments,the 5-year survival rate remains low,indicating limited efficacy of current approaches.The advent of immunotherapy,particularly immune checkpoint inhibitors(ICIs),has brought new hope for patients with PLC.However,the liver's unique immune microenvironment presents significant challenges to the effectiveness of immunotherapy in HCC.This article reviews recent research developments in liver cancer immunotherapy,focusing on ICIs,combination therapies,emerging treatments,and prospective future directions.
文摘Allergen specific immunotherapy(AIT)has a history spanning over 110 years and represents the only diseasemodifying treatment for allergic diseases,with potential preventive effects.Nevertheless,the broader application of AIT is limited by the inherent drawbacks of natural allergen extracts,such as variability in composition,risk of side effects,and complex,lengthy treatment regimens.Advances in molecular allergology have enabled the development of novel vaccine strategies-including recombinant allergens,hypoallergenic derivatives,allergen-derived peptides,and nucleic acid-based vaccines-that aim to improve safety,efficacy,and precision.However,no molecule-based AIT product has yet achieved regulatory approval,largely due to technical and clinical trial challenges.In parallel,immunomodulatory adjuvants such as monophosphoryl lipid A,CpG oligodeoxynucleotides,flagellin and mannan have demonstrated promising properties.These innovations have the potential to enhance AIT outcomes by promoting immune tolerance,reducing IgE responses,and improving patient compliance.This review summarizes the current landscape of allergen vaccines and adjuvant technologies under investigation for AIT,highlighting key advances,clinical data,and future directions aimed at overcoming existing limitations and optimizing treatment strategies for allergic diseases.
基金supported by the Major Science and Technology Special Projects in Henan Province(No.221100310100)co-construction Project of Henan Medical Science and Technology(LHGJ20230286).
文摘Cerenkov radiation(CR)can serve as a source of internal light to overcome the limited tissue penetration of external light in conventional photodynamic therapy(PDT).However,insufficient luminescence intensity hinders the clinical application of CR-PDT.Here,we developed a glutathione-responsive biomimetic nanoplatform by fusing cancer cell membranes and liposomes loaded with photosensitizer hematoporphyrin monomethyl ether(HMME)and a radiation energy amplifier Eu^(3+),named HMME-Eu@LEV.Colloidal Eu^(3+)convertsγ-radiation and CR from radioisotopes into fluorescence to enhance antitumor effects.Sequential administration ensures co-localization of HMME-Eu@LEV and radiopharmaceutical^(18)F-fluorodeoxyglucose(FDG)at the tumor site,triggering enhanced CR-PDT and immunogenic cell death.Our observations indicated that luminescence resonance energy transfer between Eu^(3+)and HMME was efficient,and Cerenkov luminescence from Eu@LEV+FDG was approximately 5.6-fold higher in intensity than that from FDG alone.As a result,abundant ROS were generated,and macrophages in the tumor microenvironment were polarized from M2 to M1.In addition,the immunosuppressive tumor microenvironment could be reversed by promoting the maturation of dendritic cells and infiltration of cytotoxic T lymphocytes.The activated immune system effectively inhibited the growth of primary tumors and spread of distant metastases.Our work demonstrates the feasibility of CR-PDT without an external light source and the critical role of nanomaterials in personalized medicine.
基金Supported by National Science Center of Poland,No.2019/35/N/NZ6/02973.
文摘TheγδT cells are an emerging class of immune effectors with potent antitumor activity,bridging innate and adaptive immunity.Their unique ability to recognise stress-induced ligands independently of major histocompatibility complex restriction makes them attractive candidates for cancer immunotherapy.However,the clinical application ofγδT cells requires efficient in vitro expansion strategies to generate large numbers of functional cells.This mini-review explores the latest advancements inγδT cell expansion protocols,focusing on key activation stimuli,cytokine support,and culture conditions that optimise proliferation and cytotoxicity.
文摘Perioperative fluorouracil,leucovorin,oxaliplatin and docetaxel is currently the standard chemotherapy for resectable gastric and gastroesophageal junction adenocarcinomas,based on the results of FLOT4 and ESOPEC trials.This regimen has demonstrated efficacy in tumor downstaging,enhancing the chances of curative resection,and ultimately improving the overall survival.However,despite these advances,the complete response rate in the perioperative setting remains below 10%to 15%,highlighting the need for more effective treatment strategies.Recent studies evaluating immunotherapy,such as the KEYNOTE-585 trial with pembrolizumab and the MATTERHORN trial with durvalumab,have shown promising preliminary results,including improved response rates and event-free survival.Nevertheless,these regimens are not yet considered the standard of care.This article explores the current landscape of perioperative treatments for gastric cancer and discusses future directions in this field.
基金Supported by the National Natural Science Foundation of China,No.82270634Third Affiliated Hospital of Naval Medical University,No.tf2024yzyy01.
文摘Hepatocellular carcinoma(HCC)is one of the most common malignant tumors globally and is the most prevalent type of primary liver cancer,posing a heavy burden on global health.Surgical resection and liver transplantation are the gold standard for the radical treatment of HCC.However,due to the heterogeneity and high invasiveness of HCC,the rates of local and distant recurrence are extremely high,with over 70%of patients experiencing recurrence within 5 years after treatment,significantly impacting the long-term quality of life.Therefore,researchers are exploring other treatment methods to reduce tumor recurrence and improve patient survival.To date,extensive research has concentrated on new alternative therapies,including radiotherapy(e.g.,selective internal radiotherapy),targeted drug therapy(e.g.,sorafenib and lenvatinib),and immunotherapy(e.g.,immune checkpoint inhibitors),which have played an integral role in the comprehensive treatment of HCC.This review mainly focuses on the cutting-edge advancements in these treatment methods for HCC and their potential role in reducing HCC recurrence.
基金supported by the Shenzhen Science and Technology Program(grant number:KQTD20180411185028798).
文摘Background:The role of systemic tumor immune environment(STIE)is unclear in hepatocellular carcinoma(HCC).This study aimed to exam the cells in the STIE,their changes after transarterial chemoembolisation(TACE),stereotactic body radiotherapy(SBRT),and immunotherapy(IO)and explore their significance in the treatment response of patients with unresectable HCC.Methods:This is a prospective biomarker study of patients with unresectable HCC.The treatment was sequential TACE,SBRT(27.5-40 Gy/5 fractions),and IO.The treatment response was assessed according to modified Re-sponse Evaluation Criteria in Solid Tumors(mRECIST)by magnetic resonance imaging(MRI)after 6 months of treatment.Longitudinal data of STIE cells was extracted from laboratory results of complete blood cell counts,in-cluding leukocytes,lymphocytes,neutrophils,monocytes,eosinophils,basophils,and platelets.Peripheral blood samples were collected at baseline and after TACE,SBRT,and IO for T-lymphocyte subtyping by flow cytometry.Generalized estimation equation was employed for longitudinal analyses.Results:A total of 35 patients with unresectable HCC were enrolled:23 patients in the exploratory cohort and 12 in the validation cohort.STIE circulating cells,especially lymphocytes,were heterogenous at baseline and changed differentially after TACE,SBRT,and IO in both cohorts.SBRT caused the greatest reduction of 0.7×10^(9)/L(95%CI:0.3×10^(9)/L-1.0×10^(9)/L,P<0.001)in lymphocytes;less reduction was associated with significantly better treatment response.The analysis of T-lymphocyte lineage revealed that the baseline levels of CD4+T cells(P=0.010),type 1 T helper(Th1)cells(P=0.007),and Th1/Th17 ratios(P=0.001)were significantly higher in responders,while regulatory T(Treg)cells(P=0.002),Th17 cells(P=0.047),and Th2/Th1 ratios(P=0.028)were significantly higher in non-responders.After treatment with TACE,SBRT and IO,T-lymphocyte lineage also changed differentially.More reductions were observed in CD25^(+)CD8^(+)T cells and CD127^(+)CD8^(+)T cells after SBRT in non-responders,while increases in natural killer T(NKT)cells after SBRT(10.4%vs.3.4%,P=0.001)and increases in the lymphocyte counts were noted during IO in responders.Conclusions:STIE cells are significant for treatment response,can be reshaped differentially after TACE,SBRT,and IO.The most significant changes of T-lymphocyte lineage are SBRT associated modulations in CD25^(+)CD8^(+)T cells,CD127^(+)CD8^(+)T cells,and NKT cells,which also have significant effects on the ultimate treatment response after TACE-SBRT-IO(ClinicalTrails.gov identifier:GCOG0001/NCT05061342).
