Gastric cancer is a highly heterogeneous and aggressive malignancy,with conventional therapies often hampered by poor drug targeting and an immunosuppressive tumor microenvironment(TME).To address these limitations,we...Gastric cancer is a highly heterogeneous and aggressive malignancy,with conventional therapies often hampered by poor drug targeting and an immunosuppressive tumor microenvironment(TME).To address these limitations,we developed a biomimetic nanoplatform(PLGA-UA@MA)composed of poly(lactic-co-glycolic acid)(PLGA)nanoparticles encapsulating the natural antitumor agent ursolic acid(UA),further cloaked with homologous gastric cancer cell membranes doped with the immunoadjuvant monophosphoryl lipid A(MPLA).This engineered system synergistically combines tumor-specific targeting,immune modulation,and stimuliresponsive drug release,presenting a precision therapeutic strategy for gastric cancer.PLGA-UA@M-A exhibits selective homing to primary tumor sites,facilitated by membrane fusion-mediated enhanced cellular uptake.In vitro studies demonstrated potent inhibition of MFC gastric cancer cell proliferation,induction of apoptosis,and suppression of metastatic behavior,underscoring its enhanced antitumor efficacy.Moreover,the nanoplatform triggered immunogenic cell death(ICD),while MPLA acted as an immunostimulant to promote dendritic cell maturation and T-cell priming—effectively reprogramming the immunosuppressive TME.In vivo evaluations confirmed excellent tumor accumulation,robust antitumor activity,and negligible systemic toxicity,highlighting its favorable biosafety profile.Collectively,PLGA-UA@M-A represents a multifunctional biomimetic delivery system that integrates chemotherapy with immune activation,offering a promising therapeutic paradigm for gastric cancer treatment.展开更多
Background:Neutrophil-lymphocyte ratio(NLR)and platelet-lymphocyte ration(PLR)have been shown to contribute to tumour progression and response to therapy.Methods:We retrospectively counted NLR and PLR in 719 patients ...Background:Neutrophil-lymphocyte ratio(NLR)and platelet-lymphocyte ration(PLR)have been shown to contribute to tumour progression and response to therapy.Methods:We retrospectively counted NLR and PLR in 719 patients with advanced malignancies receiving chemo-and/or immuno-therapy.Results:Both the pretreatment NLR and PLR were significantly elevated in patients with progressive disease than in those without progressive disease.Compared to low groups,the high NLR and PLR groups showed significantly worse event free survival.Conclusion:We propose that NLR and PLR are not only effective blood markers for predicting therapeutic responses to chemo-and/or immuno-therapy,but also useful in detecting survival in diverse malignancies.展开更多
BACKGROUND Hepatocellular carcinoma(HCC)is a leading cause of cancer-related deaths worldwide and currently lacks effective treatment options.This is particularly true for advanced HCC,for which conventional therapies...BACKGROUND Hepatocellular carcinoma(HCC)is a leading cause of cancer-related deaths worldwide and currently lacks effective treatment options.This is particularly true for advanced HCC,for which conventional therapies often lead to a poor prognosis.AIM To assess the safety and efficacy of transarterial chemoembolization(TACE)with donafenib and immune checkpoint inhibitors(ICIs)for unresectable HCC.METHODS We retrospectively assessed the data of patients with HCC who underwent TACE combined with donafenib and an ICI(tislelizumab or cedilimumab).Patients received oral donafenib daily for 2 weeks before TACE,followed by tislelizumab or cedilimumab 200 mg intravenously on day 1 of a 21-day therapeutic cycle.The primary endpoints were objective response rate,disease control rate,and duration of response according to the modified RECIST criteria.The secondary endpoint was presence of treatment-related adverse events(TRAEs).RESULTS The median follow-up was 7.8 months(95%CI:5.0-11.8 months).The objective response rate was 60.0%(18/30),while the disease control rate was 93.3%.The median duration of response in confirmed responders was 6.6 months(95%CI:1.3-12.9 months).The median progression-free survival was 11.8 months(95%CI:8.3-15.4 months).More than half of the patients survived until the end of the study.Grade>3 TRAEs occurred in 40%of the patients with no grade 5 TRAEs reported.The most common grade 3/4 TRAE was palmar-plantar erythrodysesthesia,a dermatologic condition characterized by painful redness and swelling of the palms and soles,with an incidence of 56.7%.No ICI-related adverse effects were observed.CONCLUSION TACE combined with donafenib and ICI is a promising and safe therapeutic regimen for unresectable HCC.展开更多
Background:No clear evidence exists regarding the relationship between the systemic immune-inflammation index(SII)and the efficacy of first-line chemotherapy combined with immunotherapy in patients with advanced non-s...Background:No clear evidence exists regarding the relationship between the systemic immune-inflammation index(SII)and the efficacy of first-line chemotherapy combined with immunotherapy in patients with advanced non-small cell lung cancer(NSCLC).This study aimed to establish the relationship between the SII and survival of patients with advanced NSCLC.Methods:This study included 123 patients with advanced NSCLC.The cutoff value of the SII was determined to be 1172 using ROC curve analysis.We evaluated the relationship between the SII and progression-free survival(PFS)and overall survival(OS)using the Cox regression model and Kaplan-Meier(KM)curve analysis.We stratified patients into multiple subgroups based on covariates such as age,sex,and smoking history.Subgroup analysis was used to evaluate the relationship between high SII,disease progression,and mortality risk.Results:Univariate analysis indicated that no significant difference existed between SII and PFS,but univariate analysis showed a significant association between SII and OS(hazard ratio[HR]=1.93,95% confidence interval[CI]=1.14-3.29,p=0.015).The fully adjusted Cox regression analysis also showed a significant correlation between the SII and OS after adjustment for covariables(HR=1.76,95%CI=1.02-3.02,p=0.041).In some subgroups,a high SII positively correlated with the risk of disease progression,and the relationship between a high SII and the risk of mortality was consistent in almost all subgroups.Conclusions:These results indicate that pretreatment SII may be an independent predictivemarker for patients with advanced NSCLC undergoing first-line chemotherapy combined with immunotherapy.However,large-scale prospective studies are required to confirm our results.展开更多
Lung cancer is a common cause of cancer-related death globally.The majority of lung cancer patients initially benefit from chemotherapy and immunotherapy.However,as the treatment cycle progresses and the disease evolv...Lung cancer is a common cause of cancer-related death globally.The majority of lung cancer patients initially benefit from chemotherapy and immunotherapy.However,as the treatment cycle progresses and the disease evolves,the emergence of acquired resistance leads to treatment failure.Many researches have shown that non-coding RNAs(ncRNAs)not only influence lung cancer progression but also act as potential mediators of immunotherapy and chemotherapy resistance in lung cancer,mediating drug resistance by regulating multiple targets and pathways.In addition,the regulation of immune response by ncRNAs is dualistic,forming a microenvironment for inhibits/promotes immune escape through changes in the expression of immune checkpoints.The aim of this review is to understand the effects of ncRNAs on the occurrence and development of lung cancer,focusing on the role of ncRNAs in regulating drug resistance of lung cancer.展开更多
BACKGROUND Neutrophil extracellular traps(NETs)are associated with an immunosuppressive tumor microenvironment and may influence the efficacy of immune-based therapies.However,their role in neoadjuvant chemotherapy co...BACKGROUND Neutrophil extracellular traps(NETs)are associated with an immunosuppressive tumor microenvironment and may influence the efficacy of immune-based therapies.However,their role in neoadjuvant chemotherapy combined with immunotherapy(NACI)for locally advanced gastric cancer(LAGC)remains unclear.AIM To investigate the prognostic and predictive value of NET density in LAGC patients undergoing NACI.METHODS We enrolled 31 LAGC patients treated with NACI.NET density was assessed through dual immunofluorescence staining of citrullinated histone H3 and myeloperoxidase in pretreatment biopsy and post-treatment surgical specimens.Patients were stratified into high and low pre-NACI NET groups based on median NET density.Pathological complete response(pCR)and overall response rates were evaluated in relation to NET density.Logistic regression analyses were performed to identify independent predictors of treatment outcomes.Dynamic changes in NET density during NACI were also analyzed.RESULTS Patients with low pre-NACI NET density demonstrated significantly higher rates of pCR(40%vs 6%,P=0.037)and overall response(53%vs 12%,P=0.023)compared to those with high NET density.Low pre-NACI NET density and higher programmed death protein ligand 1 expression were identified as independent protective factors for achieving pCR and better response rates.NACI increased NET density;however,this increase was primarily observed in non-pCR and nonresponder groups.Patients in the pCR and responder groups showed stable NET density before and after treatment.Higher post-NACI NET density was associated with poorer respond to NACI.High post-NACI NET density was associated with increased infiltration of immunosuppressive FOXP3+T regulatory cells(P=0.025)and CD68+macrophages(P=0.038).CONCLUSION Pre-NACI NET density serves as a prognostic and predictive biomarker for NACI efficacy in LAGC patients.Low pretreatment NET density is associated with favorable outcomes,while increased post-treatment NET density correlates with poorer response.Targeting NET formation may represent a novel therapeutic strategy to enhance NACI efficacy in LAGC.展开更多
BACKGROUND Immunotherapy is an approved treatment for metastatic rectal cancer in patients with defective mismatch repair(MMR).AIM To examine the clinical efficacy of neoadjuvant immunotherapy combined with radiothera...BACKGROUND Immunotherapy is an approved treatment for metastatic rectal cancer in patients with defective mismatch repair(MMR).AIM To examine the clinical efficacy of neoadjuvant immunotherapy combined with radiotherapy and chemotherapy for the treatment of locally advanced rectal cancer(LARC),with a focus on patients with proficient MMR(pMMR)and mic-rosatellite stability.METHODS Two researchers searched multiple databases for publications up to September 2024.All included publications examined neoadjuvant immunotherapy for LARC,and reported major pathological response(MPR),pathological complete response(pCR),clinical complete response(CCR),and rates of R0 resection and anus-pre-serving surgery.Meta-analysis,subgroup analysis,sensitivity analysis,and ana-lysis of publication bias were performed.RESULTS We included 15 publications(796 patients).The MPR,pCR,and CCR were sig-nificantly better in the group that received immunotherapy(all P<0.05),espe-cially for patients with pMMR.In addition,the rate of R0 resection and anus-preserving surgery were also significantly greater in the group that received neoadjuvant immunotherapy(both P<0.05).Hematological toxicity and abnormal liver function were the most common clinical adverse events above grade 3.Most patients successfully completed the immunotherapy treatment.The incidence of immune-related adverse reactions was 0%-13.5%,and the severities of these events were generally considered acceptable.CONCLUSION The addition of neoadjuvant immunotherapy improved the clinical remission rate of patients who had LARC with pMMR,and the treatment-related adverse reactions were generally acceptable.Neoadjuvant immunotherapy combined with radiotherapy and chemotherapy should be considered for patients with LARC.展开更多
BACKGROUND The treatment of gastric cancer remains highly challenging,particularly in cases of unresectable locally advanced or metastatic disease.Although chemotherapy and immunotherapy have shown some efficacy in su...BACKGROUND The treatment of gastric cancer remains highly challenging,particularly in cases of unresectable locally advanced or metastatic disease.Although chemotherapy and immunotherapy have shown some efficacy in such patients,significant limitations persist in extending survival and enhancing safety.To address these challenges,we designed an innovative first-line quadruple conversion therapy regimen that integrates a programmed cell death protein 1(PD-1)inhibitor with chemotherapy,and we successfully implemented this therapy regimen in the treatment of a patient with unresectable locally advanced gastric adenocarcinoma.CASE SUMMARY We report the case of a 55-year-old male who was diagnosed with unresectable locally advanced gastric adenocarcinoma and presented with intermittent epigastric pain and multiple lymph node metastases in the abdominal cavity,with the metastasis being notably large in size.The tumor tissue was negative for human epidermal growth factor receptor 2 by immunohistochemistry.Considering the patient's status,the multidisciplinary team decided to administer sintilimab in combination with albumin-bound paclitaxel(nab-paclitaxel),S-1,and oxaliplatin as a quadruple drug conversion therapy.After 4 cycles of conversion therapy,the patient's epigastric pain was significantly alleviated,his stool color normalized,the volume of the primary tumor and lymph node metastases was markedly reduced,and the tumor marker levels decreased to within the normal range.The patient subsequently underwent laparoscopic total gastrectomy with abdominal lymph node dissection,and postoperative pathological biopsy revealed a pathological complete response and R0 resection,after which the patient recovered to an excellent physical status.CONCLUSION To the best of our knowledge,this is the first reported case of unresectable locally advanced gastric adenocar-cinoma successfully treated with quadruple therapy with a PD-1 inhibitor and chemotherapy as a first-line conversion regimen.This first-line conversion therapy with the quadruple regimen may be effective and safe for unresectable locally advanced gastric adenocarcinoma.展开更多
Background:Glioblastoma(GBM)prognosis has seen little improvement over the past two decades.While immunotherapy has revolutionized cancer treatment,its impact on GBM remains limited.To characterize the evolving resear...Background:Glioblastoma(GBM)prognosis has seen little improvement over the past two decades.While immunotherapy has revolutionized cancer treatment,its impact on GBM remains limited.To characterize the evolving research landscape and identify future directions in GBM immunotherapy,we conducted a comprehensive bibliometric review.Methods:All literature related to immunotherapy in GBM from 1999 to 2024 was collected from the Web of Science Core Collection.CtieSpace and VOSviewer were used to conduct bibliometric analysis and visualize the data.Results:Bibliometric analysis identified 5038 publications authored by 23,335 researchers from 4699 institutions across 96 countries/regions,published in 945 journals.The United States produced the highest number of publications,while Switzerland achieved the highest average citation rate.Duke University led in institutional output and citations.John H Sampson was the most productive author,and Roger Stupp was the most cited.Frontiers in Immunology published the most papers,while Clinical Cancer Research was the most cited journal.Research focus centered on adoptive T cell therapy,particularly chimeric antigen receptor(CAR)-T cells with 572 dedicated publications.Within CAR-T research for GBM,the University of Pennsylvania was the leading institution,Frontiers in Immunology the predominant journal,and Christine E Brown(City of Hope National Medical Center)was the most prolific and cited author.Conclusions:There has been a growing interest in GBM immunotherapy over past decades.The United States is the dominant contributor.CAR-T therapy represents the primary research focus.Emerging strategies like chimeric antigen receptor-modified natural killer(CAR-NK)cells,chimeric antigen receptor-engineered macrophages(CAR-M),and cytomegalovirus-specific T cell receptor(CMV-TCR)T cells are gaining prominence,aiming to address limitations in antigen recognition inherent to CAR-T therapy for GBM.展开更多
BACKGROUND The liver represents a common site of distant metastasis in patients with esophageal cancer(EC).Conventional chemotherapy(CMT)presents limited efficacy for EC,and EC patients with liver metastases typically...BACKGROUND The liver represents a common site of distant metastasis in patients with esophageal cancer(EC).Conventional chemotherapy(CMT)presents limited efficacy for EC,and EC patients with liver metastases typically experience a poor prognosis,highlighting an urgent need to explore novel treatment approaches.This study evaluated the overall efficacy and safety of CMT vs CMT combined with immune checkpoint inhibitors(ICIs)in the treatment of EC patients with liver metastases.Furthermore,prognostic factors influencing outcomes in this patient population were identified.AIM To evaluate the efficacy and safety of first-line chemoimmunotherapy for EC patients with liver metastases and to analyze prognostic factors.METHODS This retrospective study included 126 EC patients with liver metastases at Zhejiang Cancer Hospital between 2014 and 2024.Patients receiving CMT were compared with those receiving CMT+ICI.Analyzed variables included clinicopathological features,treatment history,characteristics of metastasis,systemic and local treatments,overall survival(OS),and treatment-related adverse events(TRAEs).Prognostic factors were evaluated using univariate and multivariate Cox proportional-hazards regression models.Finally,efficacy outcomes and TRAE profiles were compared between the two groups.RESULTS A significant difference in median OS was identified between the two groups(10.8 months in the CMT group vs 20.8 months in the CMT+ICI group,P=0.004).The CMT+ICI group also demonstrated a significantly longer median progression-free survival of 11.7 months(P<0.001).Patients receiving combination therapy exhibited significantly improved systemic objective response rate and disease control rate.Multivariate analysis identified key factors significantly influencing OS in EC patients with liver metastases:Karnofsky Performance Status score≥70,receipt of local therapy for liver metastases,and the number of cycles of CMT and immunotherapy received.Furthermore,the incidence of TRAEs did not significantly differ between the CMT+ICI and CMT groups.CONCLUSION For EC patients with liver metastases,the combination of CMT and ICIs demonstrates significantly superior efficacy compared with CMT alone,while maintaining manageable TRAEs.展开更多
Background:Aberrant expression of transcription factors(TFs)is a key mechanism mediating tumor immune escape and therapeutic resistance.The involvement of E26 transformation-specific(ETS)family of TFs in immune regula...Background:Aberrant expression of transcription factors(TFs)is a key mechanism mediating tumor immune escape and therapeutic resistance.The involvement of E26 transformation-specific(ETS)family of TFs in immune regulation is not fully understood.The study aimed to elucidate the function of E-twenty-six variant 4(ETV4)in tumor immune evasion and its potential as a predictive biomarker for immunotherapy in melanoma.Methods:The expression patterns of ETS family TFs were analyzed in melanoma and hepatocellular carcinoma(HCC).Single-cell RNA sequencing(scRNA-seq)was used to dissect the cellular expression and function of ETV4 in the tumor microenvironment.Functional studies and murine models were employed to investigate the role of ETV4 in T cell-mediated tumor killing and tumor growth.The correlation between ETV4 expression level and patient responsiveness to programmed cell death protein 1(PD-1)blockade therapy was evaluated.Results:TFs in the ETS family were found to effectively stratify melanoma and HCC patients into prognostic subgroups.In melanoma,the polyoma enhancer activator 3(PEA3)subfamily,particularly ETV4 and ETV5,showed a negative correlation with immune infiltration.scRNA-seq analysis showed that ETV4 is preferentially expressed in melanoma cells and involves in mediating tumor-immunocyte interactions.Functional studies demonstrated that ETV4 impairs T cell-mediated tumor killing by transcriptionally upregulating programmed death-ligand 1(PD-L1).In immunocompetent murine models,ETV4 downregulation significantly suppressed tumor growth.Furthermore,high ETV4 expression correlated with poor responses to anti-PD-1 therapy.Conclusion:Our findings identify ETV4 as a key transcriptional regulator of immune evasion in melanoma by controlling PD-L1 expression.ETV4 may act as a predictive biomarker for immunotherapy outcomes.展开更多
Alzheimer’s disease,a devastating neurodegenerative disorder,is characterized by progressive cognitive decline,primarily due to amyloid-beta protein deposition and tau protein phosphorylation.Effectively reducing the...Alzheimer’s disease,a devastating neurodegenerative disorder,is characterized by progressive cognitive decline,primarily due to amyloid-beta protein deposition and tau protein phosphorylation.Effectively reducing the cytotoxicity of amyloid-beta42 aggregates and tau oligomers may help slow the progression of Alzheimer’s disease.Conventional drugs,such as donepezil,can only alleviate symptoms and are not able to prevent the underlying pathological processes or cognitive decline.Currently,active and passive immunotherapies targeting amyloid-beta and tau have shown some efficacy in mice with asymptomatic Alzheimer’s disease and other transgenic animal models,attracting considerable attention.However,the clinical application of these immunotherapies demonstrated only limited efficacy before the discovery of lecanemab and donanemab.This review first discusses the advancements in the pathogenesis of Alzheimer’s disease and active and passive immunotherapies targeting amyloid-beta and tau proteins.Furthermore,it reviews the advantages and disadvantages of various immunotherapies and considers their future prospects.Although some antibodies have shown promise in patients with mild Alzheimer’s disease,substantial clinical data are still lacking to validate their effectiveness in individuals with moderate Alzheimer’s disease.展开更多
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
Gamma delta(γδ)T cells and invariant natural killer T(iNKT)cells are unconventional T cells with limited T cell receptor(TCR)diversity.Both can recognize lipid or non-peptide antigens,often through cluster of differ...Gamma delta(γδ)T cells and invariant natural killer T(iNKT)cells are unconventional T cells with limited T cell receptor(TCR)diversity.Both can recognize lipid or non-peptide antigens,often through cluster of differentiation 1d(CD1d),rapidly produce cytokines,express natural killer(NK)cell markers,and are mainly found in mucosal and barrier tissues.Acting as a bridge between innate and adaptive immunity,they show great promise for cancer immunotherapy.DevelopingγδT and iNKT cells for treatment involves shared features like thymic origin,MHC-independent recognition,rapid cytotoxicity,low graft-vs.-host disease(GvHD)risk,ex vivo expansion,and genetic modification,making them suitable for adoptive cell therapies.While their mechanisms are similar,iNKT cells rely on CD1d-mediated antigen presentation,provided by CD1d-expressing antigen-presenting cells(APCs)or engineered cell lines,to activate their invariant TCR and expand effectively.Chimeric antigen receptors(CAR)-induced functional activations make these cell types viable alternatives to conventional cell-based or CAR-T therapies with additional safety benefits.Early clinical trials have shown encouraging results,and their completion will confirm their potential for future treatments.This review explores the biology and mechanisms ofγδT and iNKT cells,focusing on how APCs,cytokines,feeder cells,and CARs contribute to boosting their cytotoxic function,cytokine production,and expansion,enhancing their promise as cancer immunotherapies.It also explores the advancements and challenges in developingγδT and iNKT cell-based immunotherapies,with preclinical and early clinical outcomes offering promising insights.展开更多
AIM: To investigate whether autologous dendritic cell (DC)-cytokine-induced killer (CIK) cell therapy is able to improve the therapeutic efficacy of chemotherapy in colon cancer.
Metastatic melanoma has long been considered to have a very poor prognosis and to be chemo-resistant. However, a subgroup of patients with metastatic melanoma presents remarkable responses to chemotherapeutic agents, ...Metastatic melanoma has long been considered to have a very poor prognosis and to be chemo-resistant. However, a subgroup of patients with metastatic melanoma presents remarkable responses to chemotherapeutic agents, even in the absence of a response to modern targeted therapies and immunotherapies; accordingly, determining predictive biomarkers of the response to chemotherapies for metastatic melanoma remains a priority to guide treatment in these patients. We report a case study of a patient with B-Raf proto-oncogene serine/threonine kinase-mutated metastatic melanoma harbouring many genetic mutations. The patient did not respond to prior targeted therapies or immunotherapies but experienced a dramatic objective radiological and clinical response to subsequent dacarbazine-based chemotherapy. In the era of targeted therapies and immunotherapies for metastatic melanoma, cytotoxic chemotherapies may still represent an interesting therapeutic weapon in a well-deined subgroup of patients presenting with speciic genetic and molecular features.展开更多
Although notable progress has been made on novel cancer treatments,the overall survival rate and therapeutic effects are still unsatisfactory for cancer patients.Chemoimmunotherapy,combining chemotherapeutics and immu...Although notable progress has been made on novel cancer treatments,the overall survival rate and therapeutic effects are still unsatisfactory for cancer patients.Chemoimmunotherapy,combining chemotherapeutics and immunotherapeutic drugs,has emerged as a promising approach for cancer treatment,with the advantages of cooperating two kinds of treatment mechanism,reducing the dosage of the drug and enhancing therapeutic effect.Moreover,nano-based drug delivery system(NDDS)was applied to encapsulate chemotherapeutic agents and exhibited outstanding properties such as targeted delivery,tumor microenvironment response and site-specific release.Several nanocarriers have been approved in clinical cancer chemotherapy and showed significant improvement in therapeutic efficiency compared with traditional formulations,such as liposomes(Doxil R,Lipusu R),nanoparticles(Abraxane R)and micelles(Genexol-PM R).The applications of NDDS to chemoimmunotherapy would be a powerful strategy for future cancer treatment,which could greatly enhance the therapeutic efficacy,reduce the side effects and optimize the clinical outcomes of cancer patients.Herein,the current approaches of cancer immunotherapy and chemoimmunotherapy were discussed,and recent advances of NDDS applied for chemoimmunotherapy were further reviewed.展开更多
AIM: To evaluate the therapeutic efficacy of systemic chemo-immunotherapy for advanced hepatocellular carcinoma (HCC). METHODS: Twenty-six patients with advanced HCC were treated by using systemic chemo-immunotherapy ...AIM: To evaluate the therapeutic efficacy of systemic chemo-immunotherapy for advanced hepatocellular carcinoma (HCC). METHODS: Twenty-six patients with advanced HCC were treated by using systemic chemo-immunotherapy (PIAF regimen), which consisted of dsplatin (20 mg/m2) intravenously daily for 4 consecutive day, doxorubicin (40 mg/m2) intravenously on day 1, 5-fluorouracil (400 mg/m2) intravenously daily for 4 consecutive day, and human recombinant a-interferon-2a (5 Mu/m2) subcutaneous injection daily for 4 consecutive day. The treatment was repeated every 3 wk, with a maximum of six cycles. RESULTS: A total of 90 cycles of PIAF treatment were administered, with a mean number of 3.9 cycles per patient. Eight patients received six cycles of treatment (group A), and the remaining 18 were subjected to two to five cycles (group B). There were 0 complete response, 4 partial responses, 9 static diseases and 13 progressive diseases, with a disease control rate of 50% (13/26). The 1-year survival rate was 24.3%, with a median survival time of 6.0 mo. Group A had a remarkably better survival as compared with group B, the 1- and 2-year survival rates were 62.5% vs 6.1% and 32.3% vs 0%, and a median survival time was 12.5 mo vs5.0 mo (P= 0.001). CONCLUSION: Systemic chemo-immunotherapy using PIAF regimen represented an effective treatment and could improve the survival rate and prolong the survival time in selected patients with advanced HCC.展开更多
Colorectal cancer(CRC) is among the most prevalent and deadly neoplasms worldwide. According to GLOBOCAN predictions, its incidence will increase from 1.15 million CRC cases in 2020 to 1.92 million cases in 2040. Ther...Colorectal cancer(CRC) is among the most prevalent and deadly neoplasms worldwide. According to GLOBOCAN predictions, its incidence will increase from 1.15 million CRC cases in 2020 to 1.92 million cases in 2040. Therefore, a better understanding of the mechanisms involved in CRC development is necessary to improve strategies focused on reducing the incidence, prevalence,and mortality of this oncological pathology. Surgery, chemotherapy, and radiotherapy are the main strategies for treating CRC. The conventional chemotherapeutic agent utilized throughout the last four decades is 5-fluorouracil, notwithstanding its low efficiency as a single therapy. In contrast, combining 5-fluorouracil therapy with leucovorin and oxaliplatin or irinotecan increases its efficiency. However, these treatments have limited and temporary solutions and aggressive side effects. Additionally, most patients treated with these regimens develop drug resistance, which leads to disease progression. The immune response is considered a hallmark of cancer;thus, the use of new strategies and methodologies involving immune molecules, cells, and transcription factors has been suggested for CRC patients diagnosed in stages Ⅲ and Ⅳ. Despite the critical advances in immunotherapy, the development and impact of immune checkpoint inhibitors on CRC is still under investigation because less than 25% of CRC patients display an increased 5-year survival. The causes of CRC are diverse and include modifiable environmental factors(smoking, diet, obesity, and alcoholism), individual genetic mutations, and inflammation-associated bowel diseases. Due to these diverse causes, the solutions likely cannot be generalized. Interestingly, new strategies, such as single-cell multiomics, proteomics, genomics, flow cytometry, and massive sequencing for tumor microenvironment analysis, are beginning to clarify the way forward. Thus,the individual mechanisms involved in developing the CRC microenvironment, their causes, and their consequences need to be understood from a genetic and immunological perspective. This review highlighted the importance of altering the immune response in CRC. It focused on drugs that may modulate the immune response and show specific efficacy and contrasted with evidence that immunosuppression or the promotion of the immune response is the answer to generating effective treatments with combined chemotherapeutic drugs.展开更多
BACKGROUND The advent of cutting-edge systemic therapies has driven advances in the treatment of hepatocellular carcinoma(HCC),and therapeutic strategies with multiple modes of delivery have been shown to be more effi...BACKGROUND The advent of cutting-edge systemic therapies has driven advances in the treatment of hepatocellular carcinoma(HCC),and therapeutic strategies with multiple modes of delivery have been shown to be more efficacious than mono-therapy.However,the mechanisms underlying this innovative treatment modality have not been elucidated.AIM To evaluate the clinical efficacy of targeted therapy plus immunotherapy combined with hepatic arterial infusion chemotherapy(HAIC)of FOLFOX in patients with unresectable HCC.METHODS We enrolled 53 patients with unresectable HCC who received a combination of targeted therapy,immunotherapy,and HAIC of FOLFOX between December 2020 and June 2021 and assessed the efficacy and safety of the treatment regimen.RESULTS The objective response rate was 60.4%(32/53),complete response was 24.5%(13/53),partial response was 35.9%(19/53),and stable disease was 39.6%(21/53).The median duration of response and median progression-free survival were 9.1 and 13.9 months,respectively.The surgical conversion rate was 34.0%(18/53),and 1-year overall survival was 83.0%without critical complicating diseases or adverse events(AEs).CONCLUSION The regimen of HAIC of FOLFOX,targeted therapy,and immunotherapy was curative for patients with unresectable HCC,with no serious AEs and a high rate of surgical conversion.展开更多
基金supported by the National Natural Science Foundation of China(No.82360498)Gansu Joint Scientific Research Fund Major Project(No.23JRRA1537)+5 种基金the 2025 Central-Guided Local Science and Technology Development Found(No.25ZYJA003)Gansu Provincial Health Industry Science and Technology Innovation Major Project(No.GSWSZD2024-01)Gansu Province Key Talent Project(No.2025RCXM067)2024 Gansu Provincial Hospital Special Fund of NHC Key Laboratory of Diagnosis and Therapy of Gastrointestinal Tumor(No.23GSSYA-10)the 2021 Central-Guided Local Science and Technology Development Found(No.ZYYDDFFZZJ-1)Zhejiang Provincial Natural Science Foundation of China(No.LTGY23H160032).
文摘Gastric cancer is a highly heterogeneous and aggressive malignancy,with conventional therapies often hampered by poor drug targeting and an immunosuppressive tumor microenvironment(TME).To address these limitations,we developed a biomimetic nanoplatform(PLGA-UA@MA)composed of poly(lactic-co-glycolic acid)(PLGA)nanoparticles encapsulating the natural antitumor agent ursolic acid(UA),further cloaked with homologous gastric cancer cell membranes doped with the immunoadjuvant monophosphoryl lipid A(MPLA).This engineered system synergistically combines tumor-specific targeting,immune modulation,and stimuliresponsive drug release,presenting a precision therapeutic strategy for gastric cancer.PLGA-UA@M-A exhibits selective homing to primary tumor sites,facilitated by membrane fusion-mediated enhanced cellular uptake.In vitro studies demonstrated potent inhibition of MFC gastric cancer cell proliferation,induction of apoptosis,and suppression of metastatic behavior,underscoring its enhanced antitumor efficacy.Moreover,the nanoplatform triggered immunogenic cell death(ICD),while MPLA acted as an immunostimulant to promote dendritic cell maturation and T-cell priming—effectively reprogramming the immunosuppressive TME.In vivo evaluations confirmed excellent tumor accumulation,robust antitumor activity,and negligible systemic toxicity,highlighting its favorable biosafety profile.Collectively,PLGA-UA@M-A represents a multifunctional biomimetic delivery system that integrates chemotherapy with immune activation,offering a promising therapeutic paradigm for gastric cancer treatment.
基金supported by the project of Young Technical Talents of Tianjin Medical University General Hospital(GG-2021-08).
文摘Background:Neutrophil-lymphocyte ratio(NLR)and platelet-lymphocyte ration(PLR)have been shown to contribute to tumour progression and response to therapy.Methods:We retrospectively counted NLR and PLR in 719 patients with advanced malignancies receiving chemo-and/or immuno-therapy.Results:Both the pretreatment NLR and PLR were significantly elevated in patients with progressive disease than in those without progressive disease.Compared to low groups,the high NLR and PLR groups showed significantly worse event free survival.Conclusion:We propose that NLR and PLR are not only effective blood markers for predicting therapeutic responses to chemo-and/or immuno-therapy,but also useful in detecting survival in diverse malignancies.
文摘BACKGROUND Hepatocellular carcinoma(HCC)is a leading cause of cancer-related deaths worldwide and currently lacks effective treatment options.This is particularly true for advanced HCC,for which conventional therapies often lead to a poor prognosis.AIM To assess the safety and efficacy of transarterial chemoembolization(TACE)with donafenib and immune checkpoint inhibitors(ICIs)for unresectable HCC.METHODS We retrospectively assessed the data of patients with HCC who underwent TACE combined with donafenib and an ICI(tislelizumab or cedilimumab).Patients received oral donafenib daily for 2 weeks before TACE,followed by tislelizumab or cedilimumab 200 mg intravenously on day 1 of a 21-day therapeutic cycle.The primary endpoints were objective response rate,disease control rate,and duration of response according to the modified RECIST criteria.The secondary endpoint was presence of treatment-related adverse events(TRAEs).RESULTS The median follow-up was 7.8 months(95%CI:5.0-11.8 months).The objective response rate was 60.0%(18/30),while the disease control rate was 93.3%.The median duration of response in confirmed responders was 6.6 months(95%CI:1.3-12.9 months).The median progression-free survival was 11.8 months(95%CI:8.3-15.4 months).More than half of the patients survived until the end of the study.Grade>3 TRAEs occurred in 40%of the patients with no grade 5 TRAEs reported.The most common grade 3/4 TRAE was palmar-plantar erythrodysesthesia,a dermatologic condition characterized by painful redness and swelling of the palms and soles,with an incidence of 56.7%.No ICI-related adverse effects were observed.CONCLUSION TACE combined with donafenib and ICI is a promising and safe therapeutic regimen for unresectable HCC.
基金supported by grants from the“Joint Project on Regional High-Incidence Diseases Research of Guangxi Natural Science Foundation”under Grant No.2023JJA141341the“Guangxi Medical and Health Key Discipline Construction Project.”。
文摘Background:No clear evidence exists regarding the relationship between the systemic immune-inflammation index(SII)and the efficacy of first-line chemotherapy combined with immunotherapy in patients with advanced non-small cell lung cancer(NSCLC).This study aimed to establish the relationship between the SII and survival of patients with advanced NSCLC.Methods:This study included 123 patients with advanced NSCLC.The cutoff value of the SII was determined to be 1172 using ROC curve analysis.We evaluated the relationship between the SII and progression-free survival(PFS)and overall survival(OS)using the Cox regression model and Kaplan-Meier(KM)curve analysis.We stratified patients into multiple subgroups based on covariates such as age,sex,and smoking history.Subgroup analysis was used to evaluate the relationship between high SII,disease progression,and mortality risk.Results:Univariate analysis indicated that no significant difference existed between SII and PFS,but univariate analysis showed a significant association between SII and OS(hazard ratio[HR]=1.93,95% confidence interval[CI]=1.14-3.29,p=0.015).The fully adjusted Cox regression analysis also showed a significant correlation between the SII and OS after adjustment for covariables(HR=1.76,95%CI=1.02-3.02,p=0.041).In some subgroups,a high SII positively correlated with the risk of disease progression,and the relationship between a high SII and the risk of mortality was consistent in almost all subgroups.Conclusions:These results indicate that pretreatment SII may be an independent predictivemarker for patients with advanced NSCLC undergoing first-line chemotherapy combined with immunotherapy.However,large-scale prospective studies are required to confirm our results.
文摘Lung cancer is a common cause of cancer-related death globally.The majority of lung cancer patients initially benefit from chemotherapy and immunotherapy.However,as the treatment cycle progresses and the disease evolves,the emergence of acquired resistance leads to treatment failure.Many researches have shown that non-coding RNAs(ncRNAs)not only influence lung cancer progression but also act as potential mediators of immunotherapy and chemotherapy resistance in lung cancer,mediating drug resistance by regulating multiple targets and pathways.In addition,the regulation of immune response by ncRNAs is dualistic,forming a microenvironment for inhibits/promotes immune escape through changes in the expression of immune checkpoints.The aim of this review is to understand the effects of ncRNAs on the occurrence and development of lung cancer,focusing on the role of ncRNAs in regulating drug resistance of lung cancer.
文摘BACKGROUND Neutrophil extracellular traps(NETs)are associated with an immunosuppressive tumor microenvironment and may influence the efficacy of immune-based therapies.However,their role in neoadjuvant chemotherapy combined with immunotherapy(NACI)for locally advanced gastric cancer(LAGC)remains unclear.AIM To investigate the prognostic and predictive value of NET density in LAGC patients undergoing NACI.METHODS We enrolled 31 LAGC patients treated with NACI.NET density was assessed through dual immunofluorescence staining of citrullinated histone H3 and myeloperoxidase in pretreatment biopsy and post-treatment surgical specimens.Patients were stratified into high and low pre-NACI NET groups based on median NET density.Pathological complete response(pCR)and overall response rates were evaluated in relation to NET density.Logistic regression analyses were performed to identify independent predictors of treatment outcomes.Dynamic changes in NET density during NACI were also analyzed.RESULTS Patients with low pre-NACI NET density demonstrated significantly higher rates of pCR(40%vs 6%,P=0.037)and overall response(53%vs 12%,P=0.023)compared to those with high NET density.Low pre-NACI NET density and higher programmed death protein ligand 1 expression were identified as independent protective factors for achieving pCR and better response rates.NACI increased NET density;however,this increase was primarily observed in non-pCR and nonresponder groups.Patients in the pCR and responder groups showed stable NET density before and after treatment.Higher post-NACI NET density was associated with poorer respond to NACI.High post-NACI NET density was associated with increased infiltration of immunosuppressive FOXP3+T regulatory cells(P=0.025)and CD68+macrophages(P=0.038).CONCLUSION Pre-NACI NET density serves as a prognostic and predictive biomarker for NACI efficacy in LAGC patients.Low pretreatment NET density is associated with favorable outcomes,while increased post-treatment NET density correlates with poorer response.Targeting NET formation may represent a novel therapeutic strategy to enhance NACI efficacy in LAGC.
基金Supported by Start-up Fund for Doctor's Scientific Research in Shanxi Cancer Hospital,No.Dr202314and Natural Exploration Category of Shanxi Basic Research Plan,No.202203021221284.
文摘BACKGROUND Immunotherapy is an approved treatment for metastatic rectal cancer in patients with defective mismatch repair(MMR).AIM To examine the clinical efficacy of neoadjuvant immunotherapy combined with radiotherapy and chemotherapy for the treatment of locally advanced rectal cancer(LARC),with a focus on patients with proficient MMR(pMMR)and mic-rosatellite stability.METHODS Two researchers searched multiple databases for publications up to September 2024.All included publications examined neoadjuvant immunotherapy for LARC,and reported major pathological response(MPR),pathological complete response(pCR),clinical complete response(CCR),and rates of R0 resection and anus-pre-serving surgery.Meta-analysis,subgroup analysis,sensitivity analysis,and ana-lysis of publication bias were performed.RESULTS We included 15 publications(796 patients).The MPR,pCR,and CCR were sig-nificantly better in the group that received immunotherapy(all P<0.05),espe-cially for patients with pMMR.In addition,the rate of R0 resection and anus-preserving surgery were also significantly greater in the group that received neoadjuvant immunotherapy(both P<0.05).Hematological toxicity and abnormal liver function were the most common clinical adverse events above grade 3.Most patients successfully completed the immunotherapy treatment.The incidence of immune-related adverse reactions was 0%-13.5%,and the severities of these events were generally considered acceptable.CONCLUSION The addition of neoadjuvant immunotherapy improved the clinical remission rate of patients who had LARC with pMMR,and the treatment-related adverse reactions were generally acceptable.Neoadjuvant immunotherapy combined with radiotherapy and chemotherapy should be considered for patients with LARC.
基金Supported by the Health Industry Research Program of Gansu Province,No.GSWSKY2021-043the Youth Science and Technology Foundation of Gansu Province,No.22JR11RA002the Natural Science Foundation of Gansu Province,No.22JR5RA008.
文摘BACKGROUND The treatment of gastric cancer remains highly challenging,particularly in cases of unresectable locally advanced or metastatic disease.Although chemotherapy and immunotherapy have shown some efficacy in such patients,significant limitations persist in extending survival and enhancing safety.To address these challenges,we designed an innovative first-line quadruple conversion therapy regimen that integrates a programmed cell death protein 1(PD-1)inhibitor with chemotherapy,and we successfully implemented this therapy regimen in the treatment of a patient with unresectable locally advanced gastric adenocarcinoma.CASE SUMMARY We report the case of a 55-year-old male who was diagnosed with unresectable locally advanced gastric adenocarcinoma and presented with intermittent epigastric pain and multiple lymph node metastases in the abdominal cavity,with the metastasis being notably large in size.The tumor tissue was negative for human epidermal growth factor receptor 2 by immunohistochemistry.Considering the patient's status,the multidisciplinary team decided to administer sintilimab in combination with albumin-bound paclitaxel(nab-paclitaxel),S-1,and oxaliplatin as a quadruple drug conversion therapy.After 4 cycles of conversion therapy,the patient's epigastric pain was significantly alleviated,his stool color normalized,the volume of the primary tumor and lymph node metastases was markedly reduced,and the tumor marker levels decreased to within the normal range.The patient subsequently underwent laparoscopic total gastrectomy with abdominal lymph node dissection,and postoperative pathological biopsy revealed a pathological complete response and R0 resection,after which the patient recovered to an excellent physical status.CONCLUSION To the best of our knowledge,this is the first reported case of unresectable locally advanced gastric adenocar-cinoma successfully treated with quadruple therapy with a PD-1 inhibitor and chemotherapy as a first-line conversion regimen.This first-line conversion therapy with the quadruple regimen may be effective and safe for unresectable locally advanced gastric adenocarcinoma.
基金supported by Key Research and Development Plan of Hunan Province(2024DK2006)the Fundamental Research Funds for the Central Universities of Central South University(1053320221769)+2 种基金Hunan Provincial Respiratory Disease Rehabilitation and Nursing Engineering Research Center Innovation Capacity Building Project(No.202012)the Zhangjiajie Science and Technology Development Key Special Project(No.202304)the National Key Clinical Specialty Major Scientific Research Project(No.20230382).
文摘Background:Glioblastoma(GBM)prognosis has seen little improvement over the past two decades.While immunotherapy has revolutionized cancer treatment,its impact on GBM remains limited.To characterize the evolving research landscape and identify future directions in GBM immunotherapy,we conducted a comprehensive bibliometric review.Methods:All literature related to immunotherapy in GBM from 1999 to 2024 was collected from the Web of Science Core Collection.CtieSpace and VOSviewer were used to conduct bibliometric analysis and visualize the data.Results:Bibliometric analysis identified 5038 publications authored by 23,335 researchers from 4699 institutions across 96 countries/regions,published in 945 journals.The United States produced the highest number of publications,while Switzerland achieved the highest average citation rate.Duke University led in institutional output and citations.John H Sampson was the most productive author,and Roger Stupp was the most cited.Frontiers in Immunology published the most papers,while Clinical Cancer Research was the most cited journal.Research focus centered on adoptive T cell therapy,particularly chimeric antigen receptor(CAR)-T cells with 572 dedicated publications.Within CAR-T research for GBM,the University of Pennsylvania was the leading institution,Frontiers in Immunology the predominant journal,and Christine E Brown(City of Hope National Medical Center)was the most prolific and cited author.Conclusions:There has been a growing interest in GBM immunotherapy over past decades.The United States is the dominant contributor.CAR-T therapy represents the primary research focus.Emerging strategies like chimeric antigen receptor-modified natural killer(CAR-NK)cells,chimeric antigen receptor-engineered macrophages(CAR-M),and cytomegalovirus-specific T cell receptor(CMV-TCR)T cells are gaining prominence,aiming to address limitations in antigen recognition inherent to CAR-T therapy for GBM.
基金Supported by National Natural Science Foundation of China,No.82303672Zhejiang Provincial Health Commission and Zhejiang Provincial Administration of Traditional Chinese Medicine through the Targeted Project for Medical and Health Research,No.2025ZL017and China Primary Health Care Foundation,No.ZLMY20240311001ZJ.
文摘BACKGROUND The liver represents a common site of distant metastasis in patients with esophageal cancer(EC).Conventional chemotherapy(CMT)presents limited efficacy for EC,and EC patients with liver metastases typically experience a poor prognosis,highlighting an urgent need to explore novel treatment approaches.This study evaluated the overall efficacy and safety of CMT vs CMT combined with immune checkpoint inhibitors(ICIs)in the treatment of EC patients with liver metastases.Furthermore,prognostic factors influencing outcomes in this patient population were identified.AIM To evaluate the efficacy and safety of first-line chemoimmunotherapy for EC patients with liver metastases and to analyze prognostic factors.METHODS This retrospective study included 126 EC patients with liver metastases at Zhejiang Cancer Hospital between 2014 and 2024.Patients receiving CMT were compared with those receiving CMT+ICI.Analyzed variables included clinicopathological features,treatment history,characteristics of metastasis,systemic and local treatments,overall survival(OS),and treatment-related adverse events(TRAEs).Prognostic factors were evaluated using univariate and multivariate Cox proportional-hazards regression models.Finally,efficacy outcomes and TRAE profiles were compared between the two groups.RESULTS A significant difference in median OS was identified between the two groups(10.8 months in the CMT group vs 20.8 months in the CMT+ICI group,P=0.004).The CMT+ICI group also demonstrated a significantly longer median progression-free survival of 11.7 months(P<0.001).Patients receiving combination therapy exhibited significantly improved systemic objective response rate and disease control rate.Multivariate analysis identified key factors significantly influencing OS in EC patients with liver metastases:Karnofsky Performance Status score≥70,receipt of local therapy for liver metastases,and the number of cycles of CMT and immunotherapy received.Furthermore,the incidence of TRAEs did not significantly differ between the CMT+ICI and CMT groups.CONCLUSION For EC patients with liver metastases,the combination of CMT and ICIs demonstrates significantly superior efficacy compared with CMT alone,while maintaining manageable TRAEs.
基金funded by the National Natural Science Foundation of China(Grant Nos.82204517 to T.Z.and 82404756 to J.Z.)the Science and Technology Program in Medicine and Health of Zhejiang Province(Grant No.2023KY726 to T.Z.).
文摘Background:Aberrant expression of transcription factors(TFs)is a key mechanism mediating tumor immune escape and therapeutic resistance.The involvement of E26 transformation-specific(ETS)family of TFs in immune regulation is not fully understood.The study aimed to elucidate the function of E-twenty-six variant 4(ETV4)in tumor immune evasion and its potential as a predictive biomarker for immunotherapy in melanoma.Methods:The expression patterns of ETS family TFs were analyzed in melanoma and hepatocellular carcinoma(HCC).Single-cell RNA sequencing(scRNA-seq)was used to dissect the cellular expression and function of ETV4 in the tumor microenvironment.Functional studies and murine models were employed to investigate the role of ETV4 in T cell-mediated tumor killing and tumor growth.The correlation between ETV4 expression level and patient responsiveness to programmed cell death protein 1(PD-1)blockade therapy was evaluated.Results:TFs in the ETS family were found to effectively stratify melanoma and HCC patients into prognostic subgroups.In melanoma,the polyoma enhancer activator 3(PEA3)subfamily,particularly ETV4 and ETV5,showed a negative correlation with immune infiltration.scRNA-seq analysis showed that ETV4 is preferentially expressed in melanoma cells and involves in mediating tumor-immunocyte interactions.Functional studies demonstrated that ETV4 impairs T cell-mediated tumor killing by transcriptionally upregulating programmed death-ligand 1(PD-L1).In immunocompetent murine models,ETV4 downregulation significantly suppressed tumor growth.Furthermore,high ETV4 expression correlated with poor responses to anti-PD-1 therapy.Conclusion:Our findings identify ETV4 as a key transcriptional regulator of immune evasion in melanoma by controlling PD-L1 expression.ETV4 may act as a predictive biomarker for immunotherapy outcomes.
基金supported by the Nature Science Foundation of Liaoning Province,Nos.2022-MS-211,2021-MS-064,and 2024-MS-048(all to YC).
文摘Alzheimer’s disease,a devastating neurodegenerative disorder,is characterized by progressive cognitive decline,primarily due to amyloid-beta protein deposition and tau protein phosphorylation.Effectively reducing the cytotoxicity of amyloid-beta42 aggregates and tau oligomers may help slow the progression of Alzheimer’s disease.Conventional drugs,such as donepezil,can only alleviate symptoms and are not able to prevent the underlying pathological processes or cognitive decline.Currently,active and passive immunotherapies targeting amyloid-beta and tau have shown some efficacy in mice with asymptomatic Alzheimer’s disease and other transgenic animal models,attracting considerable attention.However,the clinical application of these immunotherapies demonstrated only limited efficacy before the discovery of lecanemab and donanemab.This review first discusses the advancements in the pathogenesis of Alzheimer’s disease and active and passive immunotherapies targeting amyloid-beta and tau proteins.Furthermore,it reviews the advantages and disadvantages of various immunotherapies and considers their future prospects.Although some antibodies have shown promise in patients with mild Alzheimer’s disease,substantial clinical data are still lacking to validate their effectiveness in individuals with moderate Alzheimer’s disease.
基金supported by the National Natural Science Foundation of China(82472842 and 82473350)and Wuxi Double-Hundred Talent Fund Project(BJ2023075).
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.
文摘Gamma delta(γδ)T cells and invariant natural killer T(iNKT)cells are unconventional T cells with limited T cell receptor(TCR)diversity.Both can recognize lipid or non-peptide antigens,often through cluster of differentiation 1d(CD1d),rapidly produce cytokines,express natural killer(NK)cell markers,and are mainly found in mucosal and barrier tissues.Acting as a bridge between innate and adaptive immunity,they show great promise for cancer immunotherapy.DevelopingγδT and iNKT cells for treatment involves shared features like thymic origin,MHC-independent recognition,rapid cytotoxicity,low graft-vs.-host disease(GvHD)risk,ex vivo expansion,and genetic modification,making them suitable for adoptive cell therapies.While their mechanisms are similar,iNKT cells rely on CD1d-mediated antigen presentation,provided by CD1d-expressing antigen-presenting cells(APCs)or engineered cell lines,to activate their invariant TCR and expand effectively.Chimeric antigen receptors(CAR)-induced functional activations make these cell types viable alternatives to conventional cell-based or CAR-T therapies with additional safety benefits.Early clinical trials have shown encouraging results,and their completion will confirm their potential for future treatments.This review explores the biology and mechanisms ofγδT and iNKT cells,focusing on how APCs,cytokines,feeder cells,and CARs contribute to boosting their cytotoxic function,cytokine production,and expansion,enhancing their promise as cancer immunotherapies.It also explores the advancements and challenges in developingγδT and iNKT cell-based immunotherapies,with preclinical and early clinical outcomes offering promising insights.
基金Supported by National Natural Science Foundation of China,No.31171427 and No.30971651 to Wang ZXNational Natural Science Foundation of China,No.30700974 to Cao JXPostdoctoral Foundation of China,No.20060400775 to Cao JX
文摘AIM: To investigate whether autologous dendritic cell (DC)-cytokine-induced killer (CIK) cell therapy is able to improve the therapeutic efficacy of chemotherapy in colon cancer.
文摘Metastatic melanoma has long been considered to have a very poor prognosis and to be chemo-resistant. However, a subgroup of patients with metastatic melanoma presents remarkable responses to chemotherapeutic agents, even in the absence of a response to modern targeted therapies and immunotherapies; accordingly, determining predictive biomarkers of the response to chemotherapies for metastatic melanoma remains a priority to guide treatment in these patients. We report a case study of a patient with B-Raf proto-oncogene serine/threonine kinase-mutated metastatic melanoma harbouring many genetic mutations. The patient did not respond to prior targeted therapies or immunotherapies but experienced a dramatic objective radiological and clinical response to subsequent dacarbazine-based chemotherapy. In the era of targeted therapies and immunotherapies for metastatic melanoma, cytotoxic chemotherapies may still represent an interesting therapeutic weapon in a well-deined subgroup of patients presenting with speciic genetic and molecular features.
基金supported by the National Natural Science Foundation of China(No.81974498,No.81773652)。
文摘Although notable progress has been made on novel cancer treatments,the overall survival rate and therapeutic effects are still unsatisfactory for cancer patients.Chemoimmunotherapy,combining chemotherapeutics and immunotherapeutic drugs,has emerged as a promising approach for cancer treatment,with the advantages of cooperating two kinds of treatment mechanism,reducing the dosage of the drug and enhancing therapeutic effect.Moreover,nano-based drug delivery system(NDDS)was applied to encapsulate chemotherapeutic agents and exhibited outstanding properties such as targeted delivery,tumor microenvironment response and site-specific release.Several nanocarriers have been approved in clinical cancer chemotherapy and showed significant improvement in therapeutic efficiency compared with traditional formulations,such as liposomes(Doxil R,Lipusu R),nanoparticles(Abraxane R)and micelles(Genexol-PM R).The applications of NDDS to chemoimmunotherapy would be a powerful strategy for future cancer treatment,which could greatly enhance the therapeutic efficacy,reduce the side effects and optimize the clinical outcomes of cancer patients.Herein,the current approaches of cancer immunotherapy and chemoimmunotherapy were discussed,and recent advances of NDDS applied for chemoimmunotherapy were further reviewed.
文摘AIM: To evaluate the therapeutic efficacy of systemic chemo-immunotherapy for advanced hepatocellular carcinoma (HCC). METHODS: Twenty-six patients with advanced HCC were treated by using systemic chemo-immunotherapy (PIAF regimen), which consisted of dsplatin (20 mg/m2) intravenously daily for 4 consecutive day, doxorubicin (40 mg/m2) intravenously on day 1, 5-fluorouracil (400 mg/m2) intravenously daily for 4 consecutive day, and human recombinant a-interferon-2a (5 Mu/m2) subcutaneous injection daily for 4 consecutive day. The treatment was repeated every 3 wk, with a maximum of six cycles. RESULTS: A total of 90 cycles of PIAF treatment were administered, with a mean number of 3.9 cycles per patient. Eight patients received six cycles of treatment (group A), and the remaining 18 were subjected to two to five cycles (group B). There were 0 complete response, 4 partial responses, 9 static diseases and 13 progressive diseases, with a disease control rate of 50% (13/26). The 1-year survival rate was 24.3%, with a median survival time of 6.0 mo. Group A had a remarkably better survival as compared with group B, the 1- and 2-year survival rates were 62.5% vs 6.1% and 32.3% vs 0%, and a median survival time was 12.5 mo vs5.0 mo (P= 0.001). CONCLUSION: Systemic chemo-immunotherapy using PIAF regimen represented an effective treatment and could improve the survival rate and prolong the survival time in selected patients with advanced HCC.
文摘Colorectal cancer(CRC) is among the most prevalent and deadly neoplasms worldwide. According to GLOBOCAN predictions, its incidence will increase from 1.15 million CRC cases in 2020 to 1.92 million cases in 2040. Therefore, a better understanding of the mechanisms involved in CRC development is necessary to improve strategies focused on reducing the incidence, prevalence,and mortality of this oncological pathology. Surgery, chemotherapy, and radiotherapy are the main strategies for treating CRC. The conventional chemotherapeutic agent utilized throughout the last four decades is 5-fluorouracil, notwithstanding its low efficiency as a single therapy. In contrast, combining 5-fluorouracil therapy with leucovorin and oxaliplatin or irinotecan increases its efficiency. However, these treatments have limited and temporary solutions and aggressive side effects. Additionally, most patients treated with these regimens develop drug resistance, which leads to disease progression. The immune response is considered a hallmark of cancer;thus, the use of new strategies and methodologies involving immune molecules, cells, and transcription factors has been suggested for CRC patients diagnosed in stages Ⅲ and Ⅳ. Despite the critical advances in immunotherapy, the development and impact of immune checkpoint inhibitors on CRC is still under investigation because less than 25% of CRC patients display an increased 5-year survival. The causes of CRC are diverse and include modifiable environmental factors(smoking, diet, obesity, and alcoholism), individual genetic mutations, and inflammation-associated bowel diseases. Due to these diverse causes, the solutions likely cannot be generalized. Interestingly, new strategies, such as single-cell multiomics, proteomics, genomics, flow cytometry, and massive sequencing for tumor microenvironment analysis, are beginning to clarify the way forward. Thus,the individual mechanisms involved in developing the CRC microenvironment, their causes, and their consequences need to be understood from a genetic and immunological perspective. This review highlighted the importance of altering the immune response in CRC. It focused on drugs that may modulate the immune response and show specific efficacy and contrasted with evidence that immunosuppression or the promotion of the immune response is the answer to generating effective treatments with combined chemotherapeutic drugs.
基金This study was reviewed and approved by the Ethics Committee of Zhongshan People’s Hospital(Approval No.2022-029).
文摘BACKGROUND The advent of cutting-edge systemic therapies has driven advances in the treatment of hepatocellular carcinoma(HCC),and therapeutic strategies with multiple modes of delivery have been shown to be more efficacious than mono-therapy.However,the mechanisms underlying this innovative treatment modality have not been elucidated.AIM To evaluate the clinical efficacy of targeted therapy plus immunotherapy combined with hepatic arterial infusion chemotherapy(HAIC)of FOLFOX in patients with unresectable HCC.METHODS We enrolled 53 patients with unresectable HCC who received a combination of targeted therapy,immunotherapy,and HAIC of FOLFOX between December 2020 and June 2021 and assessed the efficacy and safety of the treatment regimen.RESULTS The objective response rate was 60.4%(32/53),complete response was 24.5%(13/53),partial response was 35.9%(19/53),and stable disease was 39.6%(21/53).The median duration of response and median progression-free survival were 9.1 and 13.9 months,respectively.The surgical conversion rate was 34.0%(18/53),and 1-year overall survival was 83.0%without critical complicating diseases or adverse events(AEs).CONCLUSION The regimen of HAIC of FOLFOX,targeted therapy,and immunotherapy was curative for patients with unresectable HCC,with no serious AEs and a high rate of surgical conversion.
