Hepatocellular carcinoma(HCC)is a highly aggressive malignancy,largely driven by an immunosuppres-sive tumor microenvironment(TME)that facilitates tumor growth,immune escape,and resistance to therapy.Although immunoth...Hepatocellular carcinoma(HCC)is a highly aggressive malignancy,largely driven by an immunosuppres-sive tumor microenvironment(TME)that facilitates tumor growth,immune escape,and resistance to therapy.Although immunotherapy—particularly immune checkpoint inhibitors(ICIs)—has transformed the therapeutic landscape by restoring T cell-mediated anti-tumor responses,their clinical benefit as monotherapy remains suboptimal.This limitation is primarily attributed to immunosuppressive components within the TME,including tumor-associated macrophages,regulatory T cells(Tregs),and myeloid-derived suppressor cells(MDSCs).To address these challenges,combination strategies have been explored,such as dual checkpoint blockade targeting programmed cell death protein 1(PD-1),programmed death-ligand 1(PD-L1),and cytotoxic T-lymphocyte-associated antigen 4(CTLA-4),as well as synergistic use of ICIs with anti-angiogenic agents or TME-targeted interventions.These approaches have shown encouraging potential in enhancing immune efficacy.This review outlines the complex crosstalk between the TME and immunotherapeutic responses in HCC,emphasizing how combination regimens may overcome immune resistance.Furthermore,we discuss the remaining hurdles,including therapeutic resistance and immune-related adverse events,and propose future directions involving TME-associated biomarkers and individualized treatment strategies to improve patient outcomes.展开更多
Plants serve as rich repositories of diverse chemical compounds collectively referred to as specialized metabolites.These compounds are of importance for adaptive processes,including interactions with various microbes...Plants serve as rich repositories of diverse chemical compounds collectively referred to as specialized metabolites.These compounds are of importance for adaptive processes,including interactions with various microbes both beneficial and harmful.Considering microbes as bioreactors,the chemical diversity undergoes dynamic changes when root-derived specialized metabolites(RSMs)and microbes encounter each other in the rhizosphere.Recent advancements in sequencing techniques and molecular biology tools have not only accelerated the elucidation of biosynthetic pathways of RSMs but also unveiled the significance of RSMs in plant-microbe interactions.In this review,we provide a comprehensive description of the effects of RSMs on microbe assembly in the rhizosphere and the influence of corresponding microbial changes on plant health,incorporating the most up-to-date information available.Additionally,we highlight open questions that remain for a deeper understanding of and harnessing the potential of RSM-microbe interactions to enhance plant adaptation to the environment.Finally,we propose a pipeline for investigating the intricate associations between root exometabolites and the rhizomicrobiome.展开更多
Background and aims:Despite growing evidence linking pretransplant exposure to immune checkpoint inhibitors(ICIs)to increased allograft rejection risk after liver transplantation(LT),a lack of comparative studies to d...Background and aims:Despite growing evidence linking pretransplant exposure to immune checkpoint inhibitors(ICIs)to increased allograft rejection risk after liver transplantation(LT),a lack of comparative studies to definitively establish the correlation between ICI exposure and adverse short-term outcomes after LT exists.This study aimed to analyze the impact of preoperative ICI exposure on short-term post-LT prognosis and allograft rejection risk.Methods:This retrospective cohort study included 121 recipients who underwent LT for hepatocellular carcinoma(HCC)between June 2019 and March 2023.The recipients were categorized into ICI(n=35)and non-ICI(n=86)exposure groups based on pretransplant ICI exposure.Demographics,clinical characteristics,and short-term outcomes were compared between the cohorts.Kaplan-Meier analysis evaluated the impact of ICI exposure on graft survival.Univariate and multivariate logistic regression models assessed the impact of patient characteristics on allograft rejection.Results:Recipients with or without ICI exposure exhibited comparable demographic baseline charac-teristics.The incidences of early allograft dysfunction and biliary and vascular complications were similar between both groups.Post-transplant infection incidence was 37.1%and 20.9%in the ICI and non-ICI groups,respectively(P=0.064).Allograft rejection rates were significantly higher in the ICI group than in the non-ICI group(22.9%vs.5.8%,P=0.015).The ICI group exhibited a higher 90-day post-transplant mortality rate than that of the non-ICI group(14.3%vs.2.3%,P=0.034).Logistic regression analyses demonstrated that allograft rejection independently correlated with 90-day post-transplant mortality,with ICI exposure being an independent risk factor for allograft rejection.In recipients with ICI exposure,a shorter interval between ICIs and LT(washout period)was significantly associated with a higher allograft rejection risk,with the optimal washout period identified as 21 days for predicting 90-day rejection-free survival(P=0.0001).Moreover,in recipients with allograft rejection,the peripheral CD4^(+)/CD8^(+)T cell ratio was much lower in the ICI group than in the non-ICI group.Conclusions:Pretransplant ICI exposure was an independent risk factor for allograft rejection and was significantly associated with 90-day post-transplant mortality after LT for HCC.A-21-day washout period was significantly associated with allograft rejection.Future multicenter studies with larger cohorts and prospective designs are essential to validate these findings,confirm causality,and establish standardized clinical guidelines for ICI use before transplantation.展开更多
Background:Pre-transplant exposure to immune checkpoint inhibitors(ICIs)significantly increases the risk of allograft rejection after liver transplantation(LT);however,whether ICI-related rejection leads to increased ...Background:Pre-transplant exposure to immune checkpoint inhibitors(ICIs)significantly increases the risk of allograft rejection after liver transplantation(LT);however,whether ICI-related rejection leads to increased graft loss remains controversial.Therefore,this study aimed to investigate the association between ICI-related allograft rejection and perioperative graft loss.Methods:This was a retrospective analysis of adult liver transplant recipients with early biopsy-proven T-cell-mediated rejection(TCMR)at Liver Transplantation Center of Sun Yat-sen Memorial Hospital from June 2019 to September 2024.The pathological features,clinical characteristics,and perioperative graft survival were analyzed.Results:Twenty-eight patients who underwent early TCMR between June 2019 and September 2024 were included.Based on pre-LT ICI exposure,recipients were categorized into ICI-related TCMR(irTCMR,n=12)and conventional TCMR(cTCMR,n=16)groups.Recipients with irTCMR had a higher median Banff rejection activity index(RAI)(6 vs.5,P=0.012)and more aggressive tissue damage and inflammation.Recipients with irTCMR showed higher proportion of treatment resistance,achieving a complete resolution rate of only 8/12 compared to 16/16 for cTCMR.Graft loss occurred in 5/12 of irTCMR recipients within 90 days after LT,with no graft loss in cTCMRs recipients.Cox analysis demonstrated that irTCMR with an ICI washout period of<30 days was an independent risk factor for perioperative graft loss(hazard ratio[HR],6.540;95%confidence interval[CI],1.067-40.067,P=0.042).Conclusion:IrTCMR is associated with severe pathological features,increased resistance to treatment,and higher graft loss in adult liver transplant recipients.展开更多
基金supported by Guangdong Basic and Applied Basic Research Foundation(2024A1515012993)the Project of Hunan Provincial Health Commission(No.D202303078877).
文摘Hepatocellular carcinoma(HCC)is a highly aggressive malignancy,largely driven by an immunosuppres-sive tumor microenvironment(TME)that facilitates tumor growth,immune escape,and resistance to therapy.Although immunotherapy—particularly immune checkpoint inhibitors(ICIs)—has transformed the therapeutic landscape by restoring T cell-mediated anti-tumor responses,their clinical benefit as monotherapy remains suboptimal.This limitation is primarily attributed to immunosuppressive components within the TME,including tumor-associated macrophages,regulatory T cells(Tregs),and myeloid-derived suppressor cells(MDSCs).To address these challenges,combination strategies have been explored,such as dual checkpoint blockade targeting programmed cell death protein 1(PD-1),programmed death-ligand 1(PD-L1),and cytotoxic T-lymphocyte-associated antigen 4(CTLA-4),as well as synergistic use of ICIs with anti-angiogenic agents or TME-targeted interventions.These approaches have shown encouraging potential in enhancing immune efficacy.This review outlines the complex crosstalk between the TME and immunotherapeutic responses in HCC,emphasizing how combination regimens may overcome immune resistance.Furthermore,we discuss the remaining hurdles,including therapeutic resistance and immune-related adverse events,and propose future directions involving TME-associated biomarkers and individualized treatment strategies to improve patient outcomes.
基金National Key Research and Development Program of China(2018YFA0900603 to G.W.and 2022YFF1001800 to Y.B.)the National Natural Science Foundation of China(grant No.32000232)to X.W.the State Key Laboratory of Plant Genomics of China(SKLPG2016A-13)to G.W.
文摘Plants serve as rich repositories of diverse chemical compounds collectively referred to as specialized metabolites.These compounds are of importance for adaptive processes,including interactions with various microbes both beneficial and harmful.Considering microbes as bioreactors,the chemical diversity undergoes dynamic changes when root-derived specialized metabolites(RSMs)and microbes encounter each other in the rhizosphere.Recent advancements in sequencing techniques and molecular biology tools have not only accelerated the elucidation of biosynthetic pathways of RSMs but also unveiled the significance of RSMs in plant-microbe interactions.In this review,we provide a comprehensive description of the effects of RSMs on microbe assembly in the rhizosphere and the influence of corresponding microbial changes on plant health,incorporating the most up-to-date information available.Additionally,we highlight open questions that remain for a deeper understanding of and harnessing the potential of RSM-microbe interactions to enhance plant adaptation to the environment.Finally,we propose a pipeline for investigating the intricate associations between root exometabolites and the rhizomicrobiome.
基金supported by the National Natural Science Foundation of China(No. 82472903, 82203747, 82173229, and82173195)Guangzhou Key Laboratory of Precise Diagnosis and Treatment of Biliary Tract Cancer(No. 202201020375)+4 种基金China Postdoctoral Science Foundation(No. 2022TQ0388 and 2023 M734036)Science and Technology Program of Guangzhou(No. 202102010326 and 2023A03J0700)Sun Yat-sen University Clinical Research 5010 Program(No. 2018008)Sun Yat-sen Memorial Hospital Clinical Research 5010 Program(No. SYS-5010-202305)Sun Yat-sen Pilot Scientific Research Fund(SYSQH-Ⅱ-2024-05)
文摘Background and aims:Despite growing evidence linking pretransplant exposure to immune checkpoint inhibitors(ICIs)to increased allograft rejection risk after liver transplantation(LT),a lack of comparative studies to definitively establish the correlation between ICI exposure and adverse short-term outcomes after LT exists.This study aimed to analyze the impact of preoperative ICI exposure on short-term post-LT prognosis and allograft rejection risk.Methods:This retrospective cohort study included 121 recipients who underwent LT for hepatocellular carcinoma(HCC)between June 2019 and March 2023.The recipients were categorized into ICI(n=35)and non-ICI(n=86)exposure groups based on pretransplant ICI exposure.Demographics,clinical characteristics,and short-term outcomes were compared between the cohorts.Kaplan-Meier analysis evaluated the impact of ICI exposure on graft survival.Univariate and multivariate logistic regression models assessed the impact of patient characteristics on allograft rejection.Results:Recipients with or without ICI exposure exhibited comparable demographic baseline charac-teristics.The incidences of early allograft dysfunction and biliary and vascular complications were similar between both groups.Post-transplant infection incidence was 37.1%and 20.9%in the ICI and non-ICI groups,respectively(P=0.064).Allograft rejection rates were significantly higher in the ICI group than in the non-ICI group(22.9%vs.5.8%,P=0.015).The ICI group exhibited a higher 90-day post-transplant mortality rate than that of the non-ICI group(14.3%vs.2.3%,P=0.034).Logistic regression analyses demonstrated that allograft rejection independently correlated with 90-day post-transplant mortality,with ICI exposure being an independent risk factor for allograft rejection.In recipients with ICI exposure,a shorter interval between ICIs and LT(washout period)was significantly associated with a higher allograft rejection risk,with the optimal washout period identified as 21 days for predicting 90-day rejection-free survival(P=0.0001).Moreover,in recipients with allograft rejection,the peripheral CD4^(+)/CD8^(+)T cell ratio was much lower in the ICI group than in the non-ICI group.Conclusions:Pretransplant ICI exposure was an independent risk factor for allograft rejection and was significantly associated with 90-day post-transplant mortality after LT for HCC.A-21-day washout period was significantly associated with allograft rejection.Future multicenter studies with larger cohorts and prospective designs are essential to validate these findings,confirm causality,and establish standardized clinical guidelines for ICI use before transplantation.
基金This study was supported by grants from the National Natural Science Foundation of China(Nos.82203747,82173229,81972255,and 82173195)Guangzhou Key Laboratory of Precise Diagnosis and Treatment of Biliary Tract Cancer(No.202201020375)+6 种基金China Postdoctoral Science Foundation(Nos.2022TQ0388 and 2023M734036)Guangdong Basic and Applied Basic Research Foundation(No.2021A1515010095)Science and Technology Program of Guangzhou(Nos.202102010326 and 2023A03J0700)Sun Yat-sen University Clinical Research 5010 Program(No.2018008)Sun Yat-Sen Memorial Hospital Clinical Research 5010 Program(No.SYS-5010-202305)Sun Yat-sen Pilot Scientific Research Fund(No.SYSQH-II-2025-01)Guangzhou Key Laboratory of Organ Transplantation(No.2025A03J4036).
文摘Background:Pre-transplant exposure to immune checkpoint inhibitors(ICIs)significantly increases the risk of allograft rejection after liver transplantation(LT);however,whether ICI-related rejection leads to increased graft loss remains controversial.Therefore,this study aimed to investigate the association between ICI-related allograft rejection and perioperative graft loss.Methods:This was a retrospective analysis of adult liver transplant recipients with early biopsy-proven T-cell-mediated rejection(TCMR)at Liver Transplantation Center of Sun Yat-sen Memorial Hospital from June 2019 to September 2024.The pathological features,clinical characteristics,and perioperative graft survival were analyzed.Results:Twenty-eight patients who underwent early TCMR between June 2019 and September 2024 were included.Based on pre-LT ICI exposure,recipients were categorized into ICI-related TCMR(irTCMR,n=12)and conventional TCMR(cTCMR,n=16)groups.Recipients with irTCMR had a higher median Banff rejection activity index(RAI)(6 vs.5,P=0.012)and more aggressive tissue damage and inflammation.Recipients with irTCMR showed higher proportion of treatment resistance,achieving a complete resolution rate of only 8/12 compared to 16/16 for cTCMR.Graft loss occurred in 5/12 of irTCMR recipients within 90 days after LT,with no graft loss in cTCMRs recipients.Cox analysis demonstrated that irTCMR with an ICI washout period of<30 days was an independent risk factor for perioperative graft loss(hazard ratio[HR],6.540;95%confidence interval[CI],1.067-40.067,P=0.042).Conclusion:IrTCMR is associated with severe pathological features,increased resistance to treatment,and higher graft loss in adult liver transplant recipients.
