Microglia are the resident macrophages of the central nervous system.They act as the first line of defense against pathogens and play essential roles in neuroinflammation and tissue repair after brain insult or in neu...Microglia are the resident macrophages of the central nervous system.They act as the first line of defense against pathogens and play essential roles in neuroinflammation and tissue repair after brain insult or in neurodegenerative and demyelinating diseases(Borst et al.,2021).Together with infiltrating monocyte-derived macrophages,microglia also play a critical role for brain tumor development,since immunosuppressive interactions between tumor cells and tumor-associated microglia and macrophages(TAM)are linked to malignant progression.This mechanism is of particular relevance in glioblastoma(GB),the deadliest form of brain cancer with a median overall survival of less than 15 months(Khan et al.,2023).Therefore,targeting microglia and macrophage activation is a promising strategy for therapeutic interference in brain disease.展开更多
Currently,the use of immune checkpoint inhibitors(ICIs)has shown notable clinical efficacy in treating various malignant tumors,significantly improving patient prognosis.However,while ICIs enhance the body’s anti-tum...Currently,the use of immune checkpoint inhibitors(ICIs)has shown notable clinical efficacy in treating various malignant tumors,significantly improving patient prognosis.However,while ICIs enhance the body’s anti-tumor effects,they can also trigger immune-related adverse events(irAEs),with ICI-associated colitis being one of the more prevalent forms.This condition can disrupt treatment,necessitate drug discontinuation,and adversely affect therapeutic outcomes.In severe cases,irAEs may even become life-threatening.A recent case report by Hong et al highlights the importance of vigilance for ICI-associated colitis in patients experiencing symptoms such as diarrhea and abdominal pain,which can arise both during and even after completion of ICI treatment.Early identification,multidisciplinary management,and continuous monitoring of patients are essential steps to further improve outcomes.展开更多
Hepatocellular carcinoma(HCC)is a primary malignant tumor of the liver and one of the most common malignant tumors,as well as the third leading cause of cancer-related death.In recent years,immune checkpoint inhibitor...Hepatocellular carcinoma(HCC)is a primary malignant tumor of the liver and one of the most common malignant tumors,as well as the third leading cause of cancer-related death.In recent years,immune checkpoint inhibitors have emerged as a key strategy in cancer treatment.However,anti-programmed cell death 1/programmed death ligand 1 therapies,one of the main immunotherapeutic approaches,only elicit a response in only approximately 20%of advanced HCC.This suggests that there may be other immune checkpoints playing important roles in HCC immunotherapy.Recent studies have highlighted Signal regulatory protein alpha(SIRPα)is a phagocytic checkpoint in macrophages and other immune cells,as a promising novel therapeutic target in tumor immunotherapy.This review summarizes current progress on SIRPαin HCC and identifies key challenges for future related research.展开更多
Immune-checkpoint inhibitor-mediated colitis(IMC)is an increasingly recognized adverse event in cancer immunotherapy,particularly associated with immune checkpoint inhibitors(ICIs)such as anti-cytotoxic T-lymphocyte a...Immune-checkpoint inhibitor-mediated colitis(IMC)is an increasingly recognized adverse event in cancer immunotherapy,particularly associated with immune checkpoint inhibitors(ICIs)such as anti-cytotoxic T-lymphocyte antigen-4 and anti-programmed cell death protein-1 antibodies.As this revolutionary immunotherapy gains prominence in cancer treatment,understanding,diagnosing,and effectively managing IMC becomes paramount.IMC represents a unique challenge due to its immune-mediated nature and potential for severe complications.However,a precise picture of IMC pathophysiology is currently unavailable.Therefore,we aimed to summarize the existing data while acknowledging the need for further research.This comprehensive review explores the mechanisms underlying ICIs,gastrointestinal adverse effects,and,in particular,IMC’s incidence,prevalence,and features.Our review also emphasizes the importance of recognizing IMC’s distinct clinical and histopathological features to differentiate it from other forms of colitis.Furthermore,this paper highlights the urgentneed for evolving diagnostic methods,therapeutic strategies,and a multidisciplinary approach to effectively manage IMC.展开更多
Dysfunction of anti-tumor immune responses is crucial for cancer progression. Immune checkpoint blockade(ICB), which can potentiate T cell responses, is an effective strategy for the normalization of host anti-tumor i...Dysfunction of anti-tumor immune responses is crucial for cancer progression. Immune checkpoint blockade(ICB), which can potentiate T cell responses, is an effective strategy for the normalization of host anti-tumor immunity. In recent years, immune checkpoints, expressed on both tumor cells and immune cells, have been identified;some of them have exhibited potential druggability and have been approved by the US Food and Drug Administration(FDA) for clinical treatment. However, limited responses and immune-related adverse events(ir AEs) cannot be ignored. This review outlines the development and applications of ICBs, potential strategies for overcoming resistance, and future directions for ICB-based cancer immunotherapy.展开更多
Treatment with immune checkpoint inhibitors(ICIs)is an innovative therapy for managing certain types of malignancy and has the potential to improve overall patient survival significantly.The most widely used ICIs sele...Treatment with immune checkpoint inhibitors(ICIs)is an innovative therapy for managing certain types of malignancy and has the potential to improve overall patient survival significantly.The most widely used ICIs selectively target different receptors comprising programmed cell death-1 receptor,programmed cell death-ligand 1 receptor,and cytotoxic T lymphocyte antigen 4 receptor.The widespread utilization of ICIs over the past several years,however,is frequently accompanied by immune-related adverse events(irAEs)that substantially impact the patient’s quality of life,particularly those affecting the digestive system,including both the upper and lower gastrointestinal tract.Based on a literature search covering databases such as PubMed,Web of Science,Embase,and the Cochrane Library,we present an insight into primary gastrointestinal irAEs,with a special focus on endoscopic manifestations.Additionally,we analyze data regarding the pathogenetic mechanisms,diagnostic approaches,histological characteristics,and proposed therapeutic interventions for managing irAEs involving the gastrointestinal tract.展开更多
BACKGROUND The optimal sequencing of immune checkpoint inhibitor(ICI)and brain radiotherapy in the management of brain metastasis from non-small cell lung cancer(NSCLC)is unclear.AIM To evaluate the survival of concur...BACKGROUND The optimal sequencing of immune checkpoint inhibitor(ICI)and brain radiotherapy in the management of brain metastasis from non-small cell lung cancer(NSCLC)is unclear.AIM To evaluate the survival of concurrent ICI and consolidation ICI in NSCLC patients treated with brain radiotherapy.METHODS We retrospectively analyzed NSCLC patients treated with brain radiotherapy and ICI.Treatment response and survival were estimated.The cox proportional hazards regression model was utilized to investigate the association between overall survival and clinical variables.RESULTS There were 54 patients in concurrent ICI and radiotherapy group,and 62 individuals treated with radiotherapy followed by consolidation ICI.The objective response rates were similar between the two group.The median progression free survival was significantly high in the concurrent ICI group compared with consolidation ICI group(9.56 months vs 8.15 months,P=0.038).In addition,the median overall survival was 22.08 months in the concurrent ICI group,clearly longer than that in the consolidation group(13.24 months,P=0.009).CONCLUSION In NSCLC patients with brain metastases,our analyses suggested that radio therapy concurrent with ICI was associated with significant benefit compared with radiotherapy followed by consolidation ICI.展开更多
This article pertains to the study by Liu et al.Myocarditis caused by immune checkpoint inhibitors in patients with esophageal cancer is a concerning issue.This was found to be linked by increased levels of creatine k...This article pertains to the study by Liu et al.Myocarditis caused by immune checkpoint inhibitors in patients with esophageal cancer is a concerning issue.This was found to be linked by increased levels of creatine kinase(CK)and CK isoenzymes,as well as older age and male gender.All these risk factors behind this phenomenon,which could be incorporated into a unified prediction model,have been briefly discussed.Several recommendations have been made to validate this prediction model for use in different clinical scenarios.展开更多
BACKGROUND The CRAFITY score is mainly utilized for hepatocellular carcinoma(HCC)patients receiving atezolizumab and bevacizumab,with little investigation in its predictive capacity for alternative regimens,such as le...BACKGROUND The CRAFITY score is mainly utilized for hepatocellular carcinoma(HCC)patients receiving atezolizumab and bevacizumab,with little investigation in its predictive capacity for alternative regimens,such as lenvatinib and programmed cell death protein 1(PD-1)inhibitors,which are widely utilized in Chinese clinical practice.AIM To look at the predictive significance of the CRAFITY score in HCC patients taking lenvatinib and PD-1 inhibitors.METHODS The retrospective investigation consisted of 192 patients with incurable HCC who received lenvatinib and PD-1 inhibitors between January 2018 and January 2022.Patients were stratified according to CRAFITY score(based on baseline alphafetoprotein and C-reactive protein levels)into CRAFITY-low,CRAFITY-intermediate,and CRAFITY-high groups.Overall survival(OS)and progressionfree survival(PFS)were assessed using Kaplan-Meier analysis,and independent prognostic factors were identified through Cox regression analysis.Nomograms were created to forecast survival for a year.RESULTS The median PFS and OS were the longest for patients in the CRAFITY-low group,followed by those in the CRAFITY-intermediate and CRAFITY-high groups(median PFS:8.4 months,6.0 months,and 3.1 months,P<0.0001;median OS:33.4 months,19.2 months,and 6.6 months,P<0.0001).Both the objective response rate(5%,19.6%,and 22%,P=0.0669)and the disease control rate(50%,76.5%,and 80%,P=0.0023)were considerably lower in the CRAFITY-high group.The findings from the multivariate analysis showed that a nomogram which included the tumor number,prior transarterial chemoembolization history,and CRAFITY score predicted 12-month survival with an area under the curve of 0.788(95%confidence interval:0.718-0.859),which was in good agreement with actual data.CONCLUSION The CRAFITY score is a valuable predictor of survival and treatment outcomes in patients receiving lenvatinib and PD-1 inhibitors.展开更多
BACKGROUND Colorectal cancer(CRC)is a prevalent malignant tumor characterized by a high mortality rate,with significant challenges persisting in the identification and management of its metastatic stage.The role of ch...BACKGROUND Colorectal cancer(CRC)is a prevalent malignant tumor characterized by a high mortality rate,with significant challenges persisting in the identification and management of its metastatic stage.The role of checkpoint kinase 1(CHEK1),a cell cycle checkpoint kinase,in CRC has not been fully clarified.We hypothesize that the upregulation of CHEK1 may enhance the proliferation of CRC cells,indicating its potential as a novel therapeutic target for CRC therapy.AIM To investigate the expression and function of CHEK1 in CRC,this study utilizes single-cell RNA sequencing and tissue microarray data.METHODS Single-cell RNA sequencing technology was employed to analyze CRC cells from the GSE144735 dataset,and immunohistochemistry was conducted to confirm the expression of CHEK1 in CRC and adjacent tissues.We also integrated mRNA expression data from multiple public databases to assess global CHEK1 expre-ssion in CRC.Molecular docking experiments were performed to explore the in-teraction between CHEK1 and the potential drug nitidine chloride(NC),as well as to investigate the influence of CHEK1 on CRC cell proliferation.RESULTS We found comparatively elevated CHEK1 expression in the malignant epithelial cells of CRC,with marked upregulation of its mRNA levels in CRC tissues.Immunohistochemical analysis further confirmed the high expression of CHEK1 in CRC tissues,and the receiver operating characteristic curve demonstrated high accuracy(area under the curve=0.964)for CHEK1 as a biomarker.Analysis of global datasets indicated a statistically significant overexpression of CHEK1 in CRC(standard mean difference=1.81,P<0.01),with summary receiver operating characteristic analysis yielding sensitivity and specificity values of 0.83 and 0.88,respectively.Molecular docking studies indicated that NC specifically targeted CHEK1,while clustered regularly interspaced short palindromic repeats knockout experiments demonstrated that CHEK1 promoted CRC cell proliferation.CONCLUSION Upregulation of CHEK1 promotes CRC cell proliferation.However,the dataset's diversity is limited,requiring further investigation into its specific mechanisms.展开更多
BACKGROUND Esophageal cancer is a serious global health concern with poor prognosis in advanced stages.Immune checkpoint inhibitors(ICIs)have shown promise in enhancing survival,but they are associated with immune-rel...BACKGROUND Esophageal cancer is a serious global health concern with poor prognosis in advanced stages.Immune checkpoint inhibitors(ICIs)have shown promise in enhancing survival,but they are associated with immune-related adverse events,including potentially life-threatening myocarditis.Moreover,ICI-induced myocarditis can be asymptomatic,necessitating early diagnosis.Specific risk factors and biomarkers for esophageal cancer remain poorly characterized.AIM To investigate the determinants of ICI-associated asymptomatic myocarditis in patients with esophageal cancer and explore potential early biomarkers.METHODS A retrospective analysis was conducted on 202 cancer patients who received treatment at Shanxi Province Cancer Hospital from July 2019 to July 2024.RESULTS Older age,male gender,and elevated creatine kinase isoenzymes(CK-MB)and CK levels were found to be significant risk factors for asymptomatic myocarditis.The myocarditis occurrence group had higher CK-MB(3.05 ng/mL vs 5.02 ng/mL;P<0.001)and CK levels(187.29 U/L vs 212.25 U/L;P=0.005),and the predictive value of age,gender,CK,and CK-MB was low[are under the receiver operating characteristic curve(AUC)=0.579-0.608].However,their combination in a predictive model showed improved diagnostic capability,with an AUC of 0.808.CONCLUSION Age,gender,and cardiac biomarker levels considerably contribute to the risk of ICI-related myocarditis in patients with esophageal cancer.The integration of these factors into a predictive model enhances early diagnosis,facilitating personalized risk management.展开更多
Gastric cancer(GC)is one of the most common malignant tumors globally.The screening rate of GC is low,and the early symptoms are not obvious,which affects early diagnosis,and most patients have a poor prognosis.Variou...Gastric cancer(GC)is one of the most common malignant tumors globally.The screening rate of GC is low,and the early symptoms are not obvious,which affects early diagnosis,and most patients have a poor prognosis.Various treatments are available for GC,mainly surgery,chemotherapy,radiotherapy,targeted therapy and immunotherapy.Immunotherapy has made significant progress in recent years,especially for unresectable and metastatic GC.Immune checkpoints are proteins which can regulate the congenital and adaptive immu-nity,and are mainly expressed on immune cells.Immune checkpoints are crucial molecules that regulate the immune system,maintaining immune balance through positive or negative modulation.Tumors exploit negative immune checkpoint molecules to suppress immune responses,thereby evading immune surveillance.Immune checkpoint inhibitors(ICIs)can undo this inhibition,reactivating immune cells to destroy tumor cells.The prospects for the treatment of GC with ICIs are promising,but it also faces many difficulties and challenges.This minireview summarizes the progress of immune ICIs in GC,discusses current individualized strategies,and explores future development directions.展开更多
This editorial provides insights into the pivotal role of checkpoint kinase 1(CHEK1)as both a biomarker and therapeutic target in colorectal cancer(CRC),based on findings from a recent study by Pang et al.Using single...This editorial provides insights into the pivotal role of checkpoint kinase 1(CHEK1)as both a biomarker and therapeutic target in colorectal cancer(CRC),based on findings from a recent study by Pang et al.Using single-cell RNA sequencing and immunohistochemistry,the study demonstrates significant CHEK1 overexpression in CRC tissues and identifies nitidine chloride as a potent CHEK1 inhibitor that disrupts DNA damage repair pathways.These findings underscore the therapeutic potential of CHEK1 inhibition and highlight the need for further research to address gaps in CRC treatment.展开更多
Hepatocellular carcinoma(HCC),a primary malignancy of the liver and leading cause of cancer-related mortality worldwide,poses substantial therapeutic challenges,particularly in advanced and unresectable stages.Immune ...Hepatocellular carcinoma(HCC),a primary malignancy of the liver and leading cause of cancer-related mortality worldwide,poses substantial therapeutic challenges,particularly in advanced and unresectable stages.Immune checkpoint inhibitors(ICIs)have emerged as critical therapeutic agents,targeting immune checkpoint pathways to restore antitumor immune responses.Combinations such as atezolizumab(anti-programmed cell death ligand 1 with bevacizumab antivascular endothelial growth factor),as well as antibodies directed against cytotoxic T-lymphocyte associated protein 4 and programmed cell death protein 1(e.g.,ipilimumab and nivolumab),have demonstrated improved clinical outcome in selected patients.However,the overall efficacy of ICIs remains hindered by variable response rate and primary or acquired resistance.Recent evidence suggests that the gut microbiome plays a pivotal role in modulating host immune responses and may significantly influence the therapeutic efficacy of ICIs.Dysbiosis within the gut-liver axis has been implicated not only in pathogenesis and progression of HCC but also diminishing immunotherapy effectiveness.Emerging studies highlight the potential of microbiome-targeted interventions including dietary modulation,prebiotics,probiotics,and fecal microbiota transplantation to enhance ICIs responsiveness.This review explores the evolving interplay between the gut microbiota and immunotherapy in HCC,with a focus on microbiome-based strategies aimed at optimizing clinical outcomes.展开更多
Background:Hepatocellular carcinoma(HCC)remains a significant global health challenge.While firstline treatments with immune checkpoint inhibitors(ICIs)have improved patient outcomes,the selection of effective second-...Background:Hepatocellular carcinoma(HCC)remains a significant global health challenge.While firstline treatments with immune checkpoint inhibitors(ICIs)have improved patient outcomes,the selection of effective second-line therapies remains unclear.This study evaluated the efficacy and safety of regorafenib as a second-line option in advanced HCC patients post-progression on ICI-based therapies.Methods:Advanced HCC patients from eight hospitals in China who received regorafenib after progression on first-line ICI therapies,alone or combined with ICIs were enrolled.Clinical data were collected,and propensity score matching(PSM)was used to ensure comparability between treatment groups.The primary endpoint was overall survival(OS).The secondary endpoints were progression-free survival(PFS),objective response rate(ORR),disease control rate(DCR),and treatment-related adverse events.The study was registered at www.chictr.org.cn(ChiCTR2400091318).Results:A total of 149 patients were included:113 in the combination therapy group(Rego-ICI group)and 36 in the regorafenib monotherapy group(Rego group).After PSM,the Rego-ICI group showed significantly improved OS[19.0 vs.11.0 months,hazard ratio(HR)=0.426,95%confidence interval(CI):0.235–0.772,P=0.005]and PFS(4.0 vs.3.0 months,HR=0.539,95%CI:0.337–0.863,P=0.010)compared to the Rego group.Differences in ORR and DCR were not statistically significant(ORR:19.4%vs.9.7%,P=0.226;DCR:64.2%vs.48.4%,P=0.139),but the Rego-ICI group showed better disease control.Regorafenib plus ICI improved both OS and PFS with no new safety signals.Conclusions:The combination of ICIs and regorafenib significantly enhances OS in advanced HCC patients post-progression on first-line ICI treatments.These findings support the potential of regorafenib plus ICIs as an effective second-line therapy.展开更多
BACKGROUND Immune checkpoint inhibitors(ICIs)have revolutionized cancer therapy but are associated with immune-related adverse events,including ICIs hepatitis.Mycophenolate mofetil(MMF)is often used as a second-line i...BACKGROUND Immune checkpoint inhibitors(ICIs)have revolutionized cancer therapy but are associated with immune-related adverse events,including ICIs hepatitis.Mycophenolate mofetil(MMF)is often used as a second-line immunosuppressive agent for steroid-refractory cases.However,there is no standardized approach to MMF tapering,leading to uncertainties regarding relapse risk,optimal tapering strategies,and long-term outcomes.AIM To evaluate current evidence on MMF tapering in ICI hepatitis,focusing on strategies,clinical outcomes,and the risk of hepatitis recurrence.Additionally,we explore the feasibility of reintroducing ICI therapy after immunosuppression withdrawal.METHODS A comprehensive literature search was conducted in PubMed,EMBASE,and clinical trial registries to identify studies reporting MMF use and tapering strategies in ICI hepatitis.We extracted data from manuscripts including patient characteristics,MMF dosing regimens,tapering duration,relapse rates,and oncologic outcomes.Risk factors for recurrence and successful tapering were analyzed.RESULTS There was significant heterogeneity in the duration of MMF taper,which ranged from 4 weeks to greater than 6 months.The tapering schedules presented were individualized based on the severity of liver injury,patient response to treatment,and risk factors for relapse.We summarize current tapering approaches,including rapid vs slow withdrawal,predictors of successful tapering,and alternative immunosuppressive strategies.The impact of MMF duration on liver recovery,relapse risk,and cancer prognosis will be discussed.Evidence on ICI rechallenge post-taper will also be reviewed.CONCLUSION While MMF is effective in managing ICI hepatitis,tapering remains a clinical challenge with potential risks of hepatitis flare and disease progression.Standardized tapering protocols are needed to optimize immunosuppression while preserving anticancer efficacy.Future studies should focus on biomarker-driven tapering strategies and prospective trials to establish best practices.展开更多
BACKGROUND Currently,there is a lack of effective adjuvant therapies for patients at high-risk of recurrent hepatitis B virus-associated hepatocellular carcinoma(HBV-HCC)after radical resection.Given the efficacy of a...BACKGROUND Currently,there is a lack of effective adjuvant therapies for patients at high-risk of recurrent hepatitis B virus-associated hepatocellular carcinoma(HBV-HCC)after radical resection.Given the efficacy of anti-programmed death 1/anti-programmed death ligand 1 plus anti-vascular endothelial growth factor receptor agents in advanced HCC,we conducted this study to investigate the efficacy of this combination regimen in the postoperative adjuvant treatment of patients with HBV-HCC.AIM To evaluate the value of postoperative combined therapy(PCT)with anti-programmed death 1/anti-programmed death ligand 1 and anti-vascular endothelial growth factor receptor agents in patients with HBV-HCC.METHODS Patients with HBV-HCC who underwent radical resection surgery at Anhui Provincial Hospital Affiliated to Anhui Medical University between July 2020 and April 2023 were included.Recurrence-free survival(RFS)and overall survival were assessed using propensity score matching and inverse probability of treatment weighting.Cox regression analysis was used to identify factors affecting recurrence,and subgroup analysis was conducted to investigate the impact of medications on different populations.Treatment-related adverse events and liver function measurements were evaluated.RESULTS A total of 150 patients were recruited,of whom 30 underwent PCT and 120 did not.After adjusting for confounders,patients who underwent PCT had better RFS at 6 and 12 months than those who did not(P>0.05).Similar results were observed in the Kaplan-Meier curves after propensity score matching or inverse probability of treatment weighting,although the difference was not statistically significant(P>0.05).A maximum diameter of>5 cm,vascular invasion,satellite nodules,and high gamma-glutamyl transferase levels were independent risk factors for recurrence(P<0.05).No significant interaction effects were observed in subgroup analyses.The most prevalent adverse event was hypertension(66.7%).PCT was associated with an increased risk of hepatic impairment which may predict RFS rates(P=0.041).CONCLUSION The recurrence rate was not significantly reduced in patients who underwent PCT.Hepatic impairment during treatment may indicate recurrence,and close monitoring of liver function and HBV infection is recommended.展开更多
Psoriasiform rash is a notable immune-related cutaneous adverse event(ircAE)accounting for approximately 5%of all ircAEs1,2.Patients with cancer and pre-existing psoriasis face elevated risk of disease recurrence or e...Psoriasiform rash is a notable immune-related cutaneous adverse event(ircAE)accounting for approximately 5%of all ircAEs1,2.Patients with cancer and pre-existing psoriasis face elevated risk of disease recurrence or exacerbation after receiving immune checkpoint inhibitors(ICIs).A European multicenter study has reported a reactivation rate of 28.7%in this population3.ICIs also trigger de novo psoriatic lesions,which mirror conventional lesion subtypes(plaque,guttate,erythrodermic,or pustular).展开更多
Esophageal squamous cell carcinoma(ESCC)remains a daunting global health concern.It is marked by aggressive progression and poor survival.While immunotherapy has emerged as a promising treatment modality,both primary ...Esophageal squamous cell carcinoma(ESCC)remains a daunting global health concern.It is marked by aggressive progression and poor survival.While immunotherapy has emerged as a promising treatment modality,both primary and acquired resistance continue to limit its clinical impact,leaving many patients without durable benefits(e.g.,CheckMate-648,ESCORT-1st).This review explains resistance mechanisms and suggests new strategies to improve outcomes.These mechanisms include immunosuppressive cells(Treg cells,myeloid-derived suppressor cells),inhibitory cytokines,molecular alterations involving programmed death 1/programmed death-ligand 1 signaling,and impaired antigen presentation.We also highlight key clinical trials—for example,CheckMate-648 and ESCORT-1st—that reveal both the potential and pitfalls of current immune checkpoint blockade strategies,underscoring the need for robust predictive biomarkers.Moreover,we examine cutting-edge tactics to overcome resistance,including combination regimens,tumor microenvironment remodeling,and tailored treatment approaches rooted in the patient’s unique genomic and immunologic landscape.展开更多
BACKGROUND Colorectal cancer(CRC)is among the most prevalent and deadly cancers globally,particularly in China.Treatment challenges remain in advanced and metastatic cases,especially in third-and fourth-line settings....BACKGROUND Colorectal cancer(CRC)is among the most prevalent and deadly cancers globally,particularly in China.Treatment challenges remain in advanced and metastatic cases,especially in third-and fourth-line settings.The combination of targeted therapies with immune checkpoint inhibitors(ICIs)has shown potential in addressing the limitations of single-agent treatments.AIM To evaluate the efficacy and safety of targeted therapy(TT)alone and in combination with ICIs for metastatic CRC(mCRC).METHODS A multicenter retrospective observational study was conducted to evaluate the efficacy and safety of TT alone and in combination with ICIs for mCRC.A total of 99 patients treated with regorafenib or fruquintinib,with or without ICIs,were enrolled.Propensity score matching(PSM)and inverse probability weighting(IPW)were employed to balance baseline characteristics.The primary endpoint was progression-free survival(PFS),while overall survival(OS)and safety were secondary.RESULTS Patients who received combined therapy showed significantly longer median PFS rates compared to those who underwent TT in all analyses(original:6.0 vs 3.4 months,P<0.01;PSM:6.15 vs 4.25 months,P<0.05;IPW:5.6 vs 3.3 months,P<0.01).Although the median OS showed a trend toward improvement in the combination group,the difference was insignificant.Cox regression analysis revealed that combining TT with ICIs significantly reduced the risk of disease progression(hazard ratio=0.38,P<0.001).Adverse events(AEs)were generally manageable with both regimens,while serious AEs(grade 3-4)were primarily hypertension,fatigue,and reduced platelet counts.All AEs were controlled effectively by symptomatic treatment or discontinuation of the drug,and no treatment-related deaths were observed.CONCLUSION The combination of TT with ICIs offers a significant advantage in terms of PFS for patients with advanced mCRC,accompanied by a favorable safety profile.These findings underscore the benefits of combination therapy in this setting,warranting further investigation in larger prospective clinical trials.展开更多
基金Deutsche Forschungsgemeinschaft(DFG,German Research Foundation),project numbers 324633948 and 409784463(DFG grants Hi 678/9-3 and Hi 678/10-2,FOR2953)to HHBundesministerium für Bildung und Forschung-BMBF,project number 16LW0463K to HT.
文摘Microglia are the resident macrophages of the central nervous system.They act as the first line of defense against pathogens and play essential roles in neuroinflammation and tissue repair after brain insult or in neurodegenerative and demyelinating diseases(Borst et al.,2021).Together with infiltrating monocyte-derived macrophages,microglia also play a critical role for brain tumor development,since immunosuppressive interactions between tumor cells and tumor-associated microglia and macrophages(TAM)are linked to malignant progression.This mechanism is of particular relevance in glioblastoma(GB),the deadliest form of brain cancer with a median overall survival of less than 15 months(Khan et al.,2023).Therefore,targeting microglia and macrophage activation is a promising strategy for therapeutic interference in brain disease.
基金Supported by 2021 Key Topic of Qinghai Provincial Health System–Guiding Plan Topic,No.2021-WJZDX-43.
文摘Currently,the use of immune checkpoint inhibitors(ICIs)has shown notable clinical efficacy in treating various malignant tumors,significantly improving patient prognosis.However,while ICIs enhance the body’s anti-tumor effects,they can also trigger immune-related adverse events(irAEs),with ICI-associated colitis being one of the more prevalent forms.This condition can disrupt treatment,necessitate drug discontinuation,and adversely affect therapeutic outcomes.In severe cases,irAEs may even become life-threatening.A recent case report by Hong et al highlights the importance of vigilance for ICI-associated colitis in patients experiencing symptoms such as diarrhea and abdominal pain,which can arise both during and even after completion of ICI treatment.Early identification,multidisciplinary management,and continuous monitoring of patients are essential steps to further improve outcomes.
基金Supported by the National Key Sci-Tech Special Project of China,No.2018ZX10302207the Beijing Natural Science Foundation,No.7222191+3 种基金the Beijing Natural Science Foundation,No.7244426the Fundamental Research Funds for the Central Universities,Peking University,No.PKU2024XGK005the Peking University Medicine Seed Fund for Interdisciplinary Research,No.BMU2021MX007 and No.BMU2022MX001Fundamental Research Funds for the Central Universities,Peking University People’s Hospital Scientific Research Development Funds,No.RDY2020-06 and No.RDJ2022-14.
文摘Hepatocellular carcinoma(HCC)is a primary malignant tumor of the liver and one of the most common malignant tumors,as well as the third leading cause of cancer-related death.In recent years,immune checkpoint inhibitors have emerged as a key strategy in cancer treatment.However,anti-programmed cell death 1/programmed death ligand 1 therapies,one of the main immunotherapeutic approaches,only elicit a response in only approximately 20%of advanced HCC.This suggests that there may be other immune checkpoints playing important roles in HCC immunotherapy.Recent studies have highlighted Signal regulatory protein alpha(SIRPα)is a phagocytic checkpoint in macrophages and other immune cells,as a promising novel therapeutic target in tumor immunotherapy.This review summarizes current progress on SIRPαin HCC and identifies key challenges for future related research.
基金Supported by the European Union-NextGenerationEU,through the National Recovery and Resilience Plan of the Republic of Bulgaria,No.BG-RRP-2.004-0008.
文摘Immune-checkpoint inhibitor-mediated colitis(IMC)is an increasingly recognized adverse event in cancer immunotherapy,particularly associated with immune checkpoint inhibitors(ICIs)such as anti-cytotoxic T-lymphocyte antigen-4 and anti-programmed cell death protein-1 antibodies.As this revolutionary immunotherapy gains prominence in cancer treatment,understanding,diagnosing,and effectively managing IMC becomes paramount.IMC represents a unique challenge due to its immune-mediated nature and potential for severe complications.However,a precise picture of IMC pathophysiology is currently unavailable.Therefore,we aimed to summarize the existing data while acknowledging the need for further research.This comprehensive review explores the mechanisms underlying ICIs,gastrointestinal adverse effects,and,in particular,IMC’s incidence,prevalence,and features.Our review also emphasizes the importance of recognizing IMC’s distinct clinical and histopathological features to differentiate it from other forms of colitis.Furthermore,this paper highlights the urgentneed for evolving diagnostic methods,therapeutic strategies,and a multidisciplinary approach to effectively manage IMC.
基金supported by the National Key Research and Development Program of China(No.2022YFE0102100)the National Natural Science Foundation of China(Nos.U22A20307 and 81930041)。
文摘Dysfunction of anti-tumor immune responses is crucial for cancer progression. Immune checkpoint blockade(ICB), which can potentiate T cell responses, is an effective strategy for the normalization of host anti-tumor immunity. In recent years, immune checkpoints, expressed on both tumor cells and immune cells, have been identified;some of them have exhibited potential druggability and have been approved by the US Food and Drug Administration(FDA) for clinical treatment. However, limited responses and immune-related adverse events(ir AEs) cannot be ignored. This review outlines the development and applications of ICBs, potential strategies for overcoming resistance, and future directions for ICB-based cancer immunotherapy.
文摘Treatment with immune checkpoint inhibitors(ICIs)is an innovative therapy for managing certain types of malignancy and has the potential to improve overall patient survival significantly.The most widely used ICIs selectively target different receptors comprising programmed cell death-1 receptor,programmed cell death-ligand 1 receptor,and cytotoxic T lymphocyte antigen 4 receptor.The widespread utilization of ICIs over the past several years,however,is frequently accompanied by immune-related adverse events(irAEs)that substantially impact the patient’s quality of life,particularly those affecting the digestive system,including both the upper and lower gastrointestinal tract.Based on a literature search covering databases such as PubMed,Web of Science,Embase,and the Cochrane Library,we present an insight into primary gastrointestinal irAEs,with a special focus on endoscopic manifestations.Additionally,we analyze data regarding the pathogenetic mechanisms,diagnostic approaches,histological characteristics,and proposed therapeutic interventions for managing irAEs involving the gastrointestinal tract.
文摘BACKGROUND The optimal sequencing of immune checkpoint inhibitor(ICI)and brain radiotherapy in the management of brain metastasis from non-small cell lung cancer(NSCLC)is unclear.AIM To evaluate the survival of concurrent ICI and consolidation ICI in NSCLC patients treated with brain radiotherapy.METHODS We retrospectively analyzed NSCLC patients treated with brain radiotherapy and ICI.Treatment response and survival were estimated.The cox proportional hazards regression model was utilized to investigate the association between overall survival and clinical variables.RESULTS There were 54 patients in concurrent ICI and radiotherapy group,and 62 individuals treated with radiotherapy followed by consolidation ICI.The objective response rates were similar between the two group.The median progression free survival was significantly high in the concurrent ICI group compared with consolidation ICI group(9.56 months vs 8.15 months,P=0.038).In addition,the median overall survival was 22.08 months in the concurrent ICI group,clearly longer than that in the consolidation group(13.24 months,P=0.009).CONCLUSION In NSCLC patients with brain metastases,our analyses suggested that radio therapy concurrent with ICI was associated with significant benefit compared with radiotherapy followed by consolidation ICI.
文摘This article pertains to the study by Liu et al.Myocarditis caused by immune checkpoint inhibitors in patients with esophageal cancer is a concerning issue.This was found to be linked by increased levels of creatine kinase(CK)and CK isoenzymes,as well as older age and male gender.All these risk factors behind this phenomenon,which could be incorporated into a unified prediction model,have been briefly discussed.Several recommendations have been made to validate this prediction model for use in different clinical scenarios.
基金Supported by the Capital’s Funds for Health Improvement and Research,No.SF202222175.
文摘BACKGROUND The CRAFITY score is mainly utilized for hepatocellular carcinoma(HCC)patients receiving atezolizumab and bevacizumab,with little investigation in its predictive capacity for alternative regimens,such as lenvatinib and programmed cell death protein 1(PD-1)inhibitors,which are widely utilized in Chinese clinical practice.AIM To look at the predictive significance of the CRAFITY score in HCC patients taking lenvatinib and PD-1 inhibitors.METHODS The retrospective investigation consisted of 192 patients with incurable HCC who received lenvatinib and PD-1 inhibitors between January 2018 and January 2022.Patients were stratified according to CRAFITY score(based on baseline alphafetoprotein and C-reactive protein levels)into CRAFITY-low,CRAFITY-intermediate,and CRAFITY-high groups.Overall survival(OS)and progressionfree survival(PFS)were assessed using Kaplan-Meier analysis,and independent prognostic factors were identified through Cox regression analysis.Nomograms were created to forecast survival for a year.RESULTS The median PFS and OS were the longest for patients in the CRAFITY-low group,followed by those in the CRAFITY-intermediate and CRAFITY-high groups(median PFS:8.4 months,6.0 months,and 3.1 months,P<0.0001;median OS:33.4 months,19.2 months,and 6.6 months,P<0.0001).Both the objective response rate(5%,19.6%,and 22%,P=0.0669)and the disease control rate(50%,76.5%,and 80%,P=0.0023)were considerably lower in the CRAFITY-high group.The findings from the multivariate analysis showed that a nomogram which included the tumor number,prior transarterial chemoembolization history,and CRAFITY score predicted 12-month survival with an area under the curve of 0.788(95%confidence interval:0.718-0.859),which was in good agreement with actual data.CONCLUSION The CRAFITY score is a valuable predictor of survival and treatment outcomes in patients receiving lenvatinib and PD-1 inhibitors.
基金Supported by Innovation Project of Guangxi Graduate Education,No.YCBZ2023096Guangxi Zhuang Autonomous Region Health Commission Scientific Research Project,No.Z20210442+1 种基金China Undergraduate Innovation and Entrepreneurship Training Program,No.S202410598185Future Academic Star of Guangxi Medical University,No.WLXSZX24101.
文摘BACKGROUND Colorectal cancer(CRC)is a prevalent malignant tumor characterized by a high mortality rate,with significant challenges persisting in the identification and management of its metastatic stage.The role of checkpoint kinase 1(CHEK1),a cell cycle checkpoint kinase,in CRC has not been fully clarified.We hypothesize that the upregulation of CHEK1 may enhance the proliferation of CRC cells,indicating its potential as a novel therapeutic target for CRC therapy.AIM To investigate the expression and function of CHEK1 in CRC,this study utilizes single-cell RNA sequencing and tissue microarray data.METHODS Single-cell RNA sequencing technology was employed to analyze CRC cells from the GSE144735 dataset,and immunohistochemistry was conducted to confirm the expression of CHEK1 in CRC and adjacent tissues.We also integrated mRNA expression data from multiple public databases to assess global CHEK1 expre-ssion in CRC.Molecular docking experiments were performed to explore the in-teraction between CHEK1 and the potential drug nitidine chloride(NC),as well as to investigate the influence of CHEK1 on CRC cell proliferation.RESULTS We found comparatively elevated CHEK1 expression in the malignant epithelial cells of CRC,with marked upregulation of its mRNA levels in CRC tissues.Immunohistochemical analysis further confirmed the high expression of CHEK1 in CRC tissues,and the receiver operating characteristic curve demonstrated high accuracy(area under the curve=0.964)for CHEK1 as a biomarker.Analysis of global datasets indicated a statistically significant overexpression of CHEK1 in CRC(standard mean difference=1.81,P<0.01),with summary receiver operating characteristic analysis yielding sensitivity and specificity values of 0.83 and 0.88,respectively.Molecular docking studies indicated that NC specifically targeted CHEK1,while clustered regularly interspaced short palindromic repeats knockout experiments demonstrated that CHEK1 promoted CRC cell proliferation.CONCLUSION Upregulation of CHEK1 promotes CRC cell proliferation.However,the dataset's diversity is limited,requiring further investigation into its specific mechanisms.
文摘BACKGROUND Esophageal cancer is a serious global health concern with poor prognosis in advanced stages.Immune checkpoint inhibitors(ICIs)have shown promise in enhancing survival,but they are associated with immune-related adverse events,including potentially life-threatening myocarditis.Moreover,ICI-induced myocarditis can be asymptomatic,necessitating early diagnosis.Specific risk factors and biomarkers for esophageal cancer remain poorly characterized.AIM To investigate the determinants of ICI-associated asymptomatic myocarditis in patients with esophageal cancer and explore potential early biomarkers.METHODS A retrospective analysis was conducted on 202 cancer patients who received treatment at Shanxi Province Cancer Hospital from July 2019 to July 2024.RESULTS Older age,male gender,and elevated creatine kinase isoenzymes(CK-MB)and CK levels were found to be significant risk factors for asymptomatic myocarditis.The myocarditis occurrence group had higher CK-MB(3.05 ng/mL vs 5.02 ng/mL;P<0.001)and CK levels(187.29 U/L vs 212.25 U/L;P=0.005),and the predictive value of age,gender,CK,and CK-MB was low[are under the receiver operating characteristic curve(AUC)=0.579-0.608].However,their combination in a predictive model showed improved diagnostic capability,with an AUC of 0.808.CONCLUSION Age,gender,and cardiac biomarker levels considerably contribute to the risk of ICI-related myocarditis in patients with esophageal cancer.The integration of these factors into a predictive model enhances early diagnosis,facilitating personalized risk management.
文摘Gastric cancer(GC)is one of the most common malignant tumors globally.The screening rate of GC is low,and the early symptoms are not obvious,which affects early diagnosis,and most patients have a poor prognosis.Various treatments are available for GC,mainly surgery,chemotherapy,radiotherapy,targeted therapy and immunotherapy.Immunotherapy has made significant progress in recent years,especially for unresectable and metastatic GC.Immune checkpoints are proteins which can regulate the congenital and adaptive immu-nity,and are mainly expressed on immune cells.Immune checkpoints are crucial molecules that regulate the immune system,maintaining immune balance through positive or negative modulation.Tumors exploit negative immune checkpoint molecules to suppress immune responses,thereby evading immune surveillance.Immune checkpoint inhibitors(ICIs)can undo this inhibition,reactivating immune cells to destroy tumor cells.The prospects for the treatment of GC with ICIs are promising,but it also faces many difficulties and challenges.This minireview summarizes the progress of immune ICIs in GC,discusses current individualized strategies,and explores future development directions.
文摘This editorial provides insights into the pivotal role of checkpoint kinase 1(CHEK1)as both a biomarker and therapeutic target in colorectal cancer(CRC),based on findings from a recent study by Pang et al.Using single-cell RNA sequencing and immunohistochemistry,the study demonstrates significant CHEK1 overexpression in CRC tissues and identifies nitidine chloride as a potent CHEK1 inhibitor that disrupts DNA damage repair pathways.These findings underscore the therapeutic potential of CHEK1 inhibition and highlight the need for further research to address gaps in CRC treatment.
文摘Hepatocellular carcinoma(HCC),a primary malignancy of the liver and leading cause of cancer-related mortality worldwide,poses substantial therapeutic challenges,particularly in advanced and unresectable stages.Immune checkpoint inhibitors(ICIs)have emerged as critical therapeutic agents,targeting immune checkpoint pathways to restore antitumor immune responses.Combinations such as atezolizumab(anti-programmed cell death ligand 1 with bevacizumab antivascular endothelial growth factor),as well as antibodies directed against cytotoxic T-lymphocyte associated protein 4 and programmed cell death protein 1(e.g.,ipilimumab and nivolumab),have demonstrated improved clinical outcome in selected patients.However,the overall efficacy of ICIs remains hindered by variable response rate and primary or acquired resistance.Recent evidence suggests that the gut microbiome plays a pivotal role in modulating host immune responses and may significantly influence the therapeutic efficacy of ICIs.Dysbiosis within the gut-liver axis has been implicated not only in pathogenesis and progression of HCC but also diminishing immunotherapy effectiveness.Emerging studies highlight the potential of microbiome-targeted interventions including dietary modulation,prebiotics,probiotics,and fecal microbiota transplantation to enhance ICIs responsiveness.This review explores the evolving interplay between the gut microbiota and immunotherapy in HCC,with a focus on microbiome-based strategies aimed at optimizing clinical outcomes.
基金supported by a grant from the Zhongda Hospital Affiliated to Southeast University,Jiangsu Province High-Level Hospital Construction Funds(No.YKK24270)。
文摘Background:Hepatocellular carcinoma(HCC)remains a significant global health challenge.While firstline treatments with immune checkpoint inhibitors(ICIs)have improved patient outcomes,the selection of effective second-line therapies remains unclear.This study evaluated the efficacy and safety of regorafenib as a second-line option in advanced HCC patients post-progression on ICI-based therapies.Methods:Advanced HCC patients from eight hospitals in China who received regorafenib after progression on first-line ICI therapies,alone or combined with ICIs were enrolled.Clinical data were collected,and propensity score matching(PSM)was used to ensure comparability between treatment groups.The primary endpoint was overall survival(OS).The secondary endpoints were progression-free survival(PFS),objective response rate(ORR),disease control rate(DCR),and treatment-related adverse events.The study was registered at www.chictr.org.cn(ChiCTR2400091318).Results:A total of 149 patients were included:113 in the combination therapy group(Rego-ICI group)and 36 in the regorafenib monotherapy group(Rego group).After PSM,the Rego-ICI group showed significantly improved OS[19.0 vs.11.0 months,hazard ratio(HR)=0.426,95%confidence interval(CI):0.235–0.772,P=0.005]and PFS(4.0 vs.3.0 months,HR=0.539,95%CI:0.337–0.863,P=0.010)compared to the Rego group.Differences in ORR and DCR were not statistically significant(ORR:19.4%vs.9.7%,P=0.226;DCR:64.2%vs.48.4%,P=0.139),but the Rego-ICI group showed better disease control.Regorafenib plus ICI improved both OS and PFS with no new safety signals.Conclusions:The combination of ICIs and regorafenib significantly enhances OS in advanced HCC patients post-progression on first-line ICI treatments.These findings support the potential of regorafenib plus ICIs as an effective second-line therapy.
文摘BACKGROUND Immune checkpoint inhibitors(ICIs)have revolutionized cancer therapy but are associated with immune-related adverse events,including ICIs hepatitis.Mycophenolate mofetil(MMF)is often used as a second-line immunosuppressive agent for steroid-refractory cases.However,there is no standardized approach to MMF tapering,leading to uncertainties regarding relapse risk,optimal tapering strategies,and long-term outcomes.AIM To evaluate current evidence on MMF tapering in ICI hepatitis,focusing on strategies,clinical outcomes,and the risk of hepatitis recurrence.Additionally,we explore the feasibility of reintroducing ICI therapy after immunosuppression withdrawal.METHODS A comprehensive literature search was conducted in PubMed,EMBASE,and clinical trial registries to identify studies reporting MMF use and tapering strategies in ICI hepatitis.We extracted data from manuscripts including patient characteristics,MMF dosing regimens,tapering duration,relapse rates,and oncologic outcomes.Risk factors for recurrence and successful tapering were analyzed.RESULTS There was significant heterogeneity in the duration of MMF taper,which ranged from 4 weeks to greater than 6 months.The tapering schedules presented were individualized based on the severity of liver injury,patient response to treatment,and risk factors for relapse.We summarize current tapering approaches,including rapid vs slow withdrawal,predictors of successful tapering,and alternative immunosuppressive strategies.The impact of MMF duration on liver recovery,relapse risk,and cancer prognosis will be discussed.Evidence on ICI rechallenge post-taper will also be reviewed.CONCLUSION While MMF is effective in managing ICI hepatitis,tapering remains a clinical challenge with potential risks of hepatitis flare and disease progression.Standardized tapering protocols are needed to optimize immunosuppression while preserving anticancer efficacy.Future studies should focus on biomarker-driven tapering strategies and prospective trials to establish best practices.
基金Supported by the Key Research and Development Projects of Anhui Province,No.202104j07020048National Key Research and Development Program of China,No.2022YFA1304500.
文摘BACKGROUND Currently,there is a lack of effective adjuvant therapies for patients at high-risk of recurrent hepatitis B virus-associated hepatocellular carcinoma(HBV-HCC)after radical resection.Given the efficacy of anti-programmed death 1/anti-programmed death ligand 1 plus anti-vascular endothelial growth factor receptor agents in advanced HCC,we conducted this study to investigate the efficacy of this combination regimen in the postoperative adjuvant treatment of patients with HBV-HCC.AIM To evaluate the value of postoperative combined therapy(PCT)with anti-programmed death 1/anti-programmed death ligand 1 and anti-vascular endothelial growth factor receptor agents in patients with HBV-HCC.METHODS Patients with HBV-HCC who underwent radical resection surgery at Anhui Provincial Hospital Affiliated to Anhui Medical University between July 2020 and April 2023 were included.Recurrence-free survival(RFS)and overall survival were assessed using propensity score matching and inverse probability of treatment weighting.Cox regression analysis was used to identify factors affecting recurrence,and subgroup analysis was conducted to investigate the impact of medications on different populations.Treatment-related adverse events and liver function measurements were evaluated.RESULTS A total of 150 patients were recruited,of whom 30 underwent PCT and 120 did not.After adjusting for confounders,patients who underwent PCT had better RFS at 6 and 12 months than those who did not(P>0.05).Similar results were observed in the Kaplan-Meier curves after propensity score matching or inverse probability of treatment weighting,although the difference was not statistically significant(P>0.05).A maximum diameter of>5 cm,vascular invasion,satellite nodules,and high gamma-glutamyl transferase levels were independent risk factors for recurrence(P<0.05).No significant interaction effects were observed in subgroup analyses.The most prevalent adverse event was hypertension(66.7%).PCT was associated with an increased risk of hepatic impairment which may predict RFS rates(P=0.041).CONCLUSION The recurrence rate was not significantly reduced in patients who underwent PCT.Hepatic impairment during treatment may indicate recurrence,and close monitoring of liver function and HBV infection is recommended.
基金supported by grants from the National Natural Science Foundation of China(Nos.82373372 and U22A20330)Key Project of Research and Development Plan in Heilongjiang Province(Nos.2022ZX06C01 and JD2023SJ40)+1 种基金National Cancer Center Climbing Fund(No.NCC201908A03)Beijing Xisike Clinical Oncology Research Foundation(No.Y-HR2020MS-0900).
文摘Psoriasiform rash is a notable immune-related cutaneous adverse event(ircAE)accounting for approximately 5%of all ircAEs1,2.Patients with cancer and pre-existing psoriasis face elevated risk of disease recurrence or exacerbation after receiving immune checkpoint inhibitors(ICIs).A European multicenter study has reported a reactivation rate of 28.7%in this population3.ICIs also trigger de novo psoriatic lesions,which mirror conventional lesion subtypes(plaque,guttate,erythrodermic,or pustular).
文摘Esophageal squamous cell carcinoma(ESCC)remains a daunting global health concern.It is marked by aggressive progression and poor survival.While immunotherapy has emerged as a promising treatment modality,both primary and acquired resistance continue to limit its clinical impact,leaving many patients without durable benefits(e.g.,CheckMate-648,ESCORT-1st).This review explains resistance mechanisms and suggests new strategies to improve outcomes.These mechanisms include immunosuppressive cells(Treg cells,myeloid-derived suppressor cells),inhibitory cytokines,molecular alterations involving programmed death 1/programmed death-ligand 1 signaling,and impaired antigen presentation.We also highlight key clinical trials—for example,CheckMate-648 and ESCORT-1st—that reveal both the potential and pitfalls of current immune checkpoint blockade strategies,underscoring the need for robust predictive biomarkers.Moreover,we examine cutting-edge tactics to overcome resistance,including combination regimens,tumor microenvironment remodeling,and tailored treatment approaches rooted in the patient’s unique genomic and immunologic landscape.
基金Supported by Hebei Provincial Medical Science Research Project Program,No.20240164.
文摘BACKGROUND Colorectal cancer(CRC)is among the most prevalent and deadly cancers globally,particularly in China.Treatment challenges remain in advanced and metastatic cases,especially in third-and fourth-line settings.The combination of targeted therapies with immune checkpoint inhibitors(ICIs)has shown potential in addressing the limitations of single-agent treatments.AIM To evaluate the efficacy and safety of targeted therapy(TT)alone and in combination with ICIs for metastatic CRC(mCRC).METHODS A multicenter retrospective observational study was conducted to evaluate the efficacy and safety of TT alone and in combination with ICIs for mCRC.A total of 99 patients treated with regorafenib or fruquintinib,with or without ICIs,were enrolled.Propensity score matching(PSM)and inverse probability weighting(IPW)were employed to balance baseline characteristics.The primary endpoint was progression-free survival(PFS),while overall survival(OS)and safety were secondary.RESULTS Patients who received combined therapy showed significantly longer median PFS rates compared to those who underwent TT in all analyses(original:6.0 vs 3.4 months,P<0.01;PSM:6.15 vs 4.25 months,P<0.05;IPW:5.6 vs 3.3 months,P<0.01).Although the median OS showed a trend toward improvement in the combination group,the difference was insignificant.Cox regression analysis revealed that combining TT with ICIs significantly reduced the risk of disease progression(hazard ratio=0.38,P<0.001).Adverse events(AEs)were generally manageable with both regimens,while serious AEs(grade 3-4)were primarily hypertension,fatigue,and reduced platelet counts.All AEs were controlled effectively by symptomatic treatment or discontinuation of the drug,and no treatment-related deaths were observed.CONCLUSION The combination of TT with ICIs offers a significant advantage in terms of PFS for patients with advanced mCRC,accompanied by a favorable safety profile.These findings underscore the benefits of combination therapy in this setting,warranting further investigation in larger prospective clinical trials.
