Immune checkpoint inhibitor(ICI)has limited efficacy in the treatment of immune“cold”tumors.Due to insufficient T cell infiltration and heterogeneous programmed death ligand 1(PD-L1)expression,the ORR is only 5%–8%...Immune checkpoint inhibitor(ICI)has limited efficacy in the treatment of immune“cold”tumors.Due to insufficient T cell infiltration and heterogeneous programmed death ligand 1(PD-L1)expression,the ORR is only 5%–8%compared with 30%–40%of“hot”tumors.This article reviews the synergistic mechanism,clinical efficacy and optimization strategy of oncolytic virus(OVs)combined with ICIs in the treatment of refractory malignant tumors.Systematic analysis of mechanistic interactions across tumor types and clinical trial data demonstrates that OVs transform the immunosuppressive microenvironment by inducing immunogenic cell death and activating innate immunity.Concurrently,ICIs enhance adaptive immunity by reversing T-cell exhaustion and expanding T-cell diversity.Clinical trials in melanoma,head and neck cancer and breast cancer showed superior efficacy.The Objective Response Rate(ORR)of combination therapy was 39%–62%,while the ORR of ICI monotherapy was 18%.Treatment heterogeneity is mainly attributed to virus-related factors,including targeting specificity and replication efficiency,tumor characteristics,such as antigen presenting ability and mutation load,and host immune status,including preexisting antiviral antibodies and microbiome composition.This combined approach represents a paradigm shift in cancer immunotherapy,which effectively transforms immune“cold”tumors into“hot”tumors through the continuous activation of innate and adaptive immune responses.In the future,it is expected to improve the therapeutic effect of treatment-resistant malignant tumors through the integration of immune regulatory molecules,accurate biomarkers to guide the treatment scheme and triple combination strategy by a new generation of engineering viruses.展开更多
Background:Liver cancer stem cells(LCSCs)are recognized as pivotal drivers of hepatocellular carcinoma(HCC)progression;however,the molecular mechanisms maintaining their stem-like phenotype remain largely unresolved.T...Background:Liver cancer stem cells(LCSCs)are recognized as pivotal drivers of hepatocellular carcinoma(HCC)progression;however,the molecular mechanisms maintaining their stem-like phenotype remain largely unresolved.This work investigates the role of prefoldin subunit 6-like protein(PFDN6L)in shaping LCSC traits and promoting or restraining HCC progression.Methods:PFDN6L,a cytoskeleton-associated chaperone,was studied using multiple in vitro assays—cell growth evaluation,cell cycle profiling,and spheroid culture—alongside analyses of stemness-associated markers(SOX2,CD133,CD44).Tumorigenic capacity was assessed in xenograft mouse models,and signaling pathway interrogation was performed to define underlying mechanisms.Results:In patient samples,higher PFDN6L expression correlated with improved survival outcomes.Forced expression of PFDN6L induced G2/M arrest,diminished sphere formation,and reduced pluripotency marker expression,whereas knockdown accelerated in vivo tumor formation.Mechanistic experiments demonstrated that PFDN6L suppressesmalignancy by simultaneously dampening AKT and ERK1/2 activation,thereby impairing oncogenic signaling cascades.Conclusion:PFDN6L acts as a negative regulator of LCSC-driven tumorigenesis.Its dual blockade of AKT and ERK pathways forms the mechanistic basis of its tumor-suppressive action,supporting its potential as a prognostic biomarker and therapeutic target in HCC.展开更多
基金supported in part by grants from the National Natural Science Foundation ofChina(Nos.82260462,82460606,32360046)Yunnan Fundamental Research Kunming Medical University Joint Projects(Nos.202201AY0700001-144,202301AY070001-115)+2 种基金Yunnan Fundamental Research Projects(No.202201AT070269)Yunnan health training project of high level talents(Nos.D-2024007,H-2024023)Graduate Innovation Fund of Kunming Medical University(No.2025S100).
文摘Immune checkpoint inhibitor(ICI)has limited efficacy in the treatment of immune“cold”tumors.Due to insufficient T cell infiltration and heterogeneous programmed death ligand 1(PD-L1)expression,the ORR is only 5%–8%compared with 30%–40%of“hot”tumors.This article reviews the synergistic mechanism,clinical efficacy and optimization strategy of oncolytic virus(OVs)combined with ICIs in the treatment of refractory malignant tumors.Systematic analysis of mechanistic interactions across tumor types and clinical trial data demonstrates that OVs transform the immunosuppressive microenvironment by inducing immunogenic cell death and activating innate immunity.Concurrently,ICIs enhance adaptive immunity by reversing T-cell exhaustion and expanding T-cell diversity.Clinical trials in melanoma,head and neck cancer and breast cancer showed superior efficacy.The Objective Response Rate(ORR)of combination therapy was 39%–62%,while the ORR of ICI monotherapy was 18%.Treatment heterogeneity is mainly attributed to virus-related factors,including targeting specificity and replication efficiency,tumor characteristics,such as antigen presenting ability and mutation load,and host immune status,including preexisting antiviral antibodies and microbiome composition.This combined approach represents a paradigm shift in cancer immunotherapy,which effectively transforms immune“cold”tumors into“hot”tumors through the continuous activation of innate and adaptive immune responses.In the future,it is expected to improve the therapeutic effect of treatment-resistant malignant tumors through the integration of immune regulatory molecules,accurate biomarkers to guide the treatment scheme and triple combination strategy by a new generation of engineering viruses.
基金supported by the National Natural Science Foundation of China(Grant Numbers 82350117,82160476,32360046,82260462)First-Class Discipline Team of Kunming Medical University 2024XKTDYS07,Yunnan Provincial Department of Science and Technology Key Research and Development Plan for Social Development Special Projects(202403AC100022)+4 种基金The Fundamental Research Project of Yunnan Provincial Department of Science and Technology(202301AT070129)the Joint Special Funds for the Department of Science and Technology of Yunnan Province KunmingMedical University(Grant Number 202401AY070001-360)the Yunnan Provincial Department of Education Science Research Fund Project(Grant Number 2023Y0655,2024Y234)Yunnan Province Science and Technology Talents and Platform Plan Project(202305AF150067)Beijing Sci-Tech Innovation Medical Development Foundation KC2023-JX-0288-PM94.
文摘Background:Liver cancer stem cells(LCSCs)are recognized as pivotal drivers of hepatocellular carcinoma(HCC)progression;however,the molecular mechanisms maintaining their stem-like phenotype remain largely unresolved.This work investigates the role of prefoldin subunit 6-like protein(PFDN6L)in shaping LCSC traits and promoting or restraining HCC progression.Methods:PFDN6L,a cytoskeleton-associated chaperone,was studied using multiple in vitro assays—cell growth evaluation,cell cycle profiling,and spheroid culture—alongside analyses of stemness-associated markers(SOX2,CD133,CD44).Tumorigenic capacity was assessed in xenograft mouse models,and signaling pathway interrogation was performed to define underlying mechanisms.Results:In patient samples,higher PFDN6L expression correlated with improved survival outcomes.Forced expression of PFDN6L induced G2/M arrest,diminished sphere formation,and reduced pluripotency marker expression,whereas knockdown accelerated in vivo tumor formation.Mechanistic experiments demonstrated that PFDN6L suppressesmalignancy by simultaneously dampening AKT and ERK1/2 activation,thereby impairing oncogenic signaling cascades.Conclusion:PFDN6L acts as a negative regulator of LCSC-driven tumorigenesis.Its dual blockade of AKT and ERK pathways forms the mechanistic basis of its tumor-suppressive action,supporting its potential as a prognostic biomarker and therapeutic target in HCC.
