Tumor survival,genomic stability,and therapy resistance are dictated by the DNA damage response(DDR).Although poly(ADP-ribose)polymerase(PARP)inhibitors have established the DDR as a therapeutic target,many tumors eva...Tumor survival,genomic stability,and therapy resistance are dictated by the DNA damage response(DDR).Although poly(ADP-ribose)polymerase(PARP)inhibitors have established the DDR as a therapeutic target,many tumors evade first-generation drugs by rewiring their adaptive repair pathways and imposing microenvironmental constraints.This review synthesizes recent discoveries in key DDR pathways,such as PARP,ataxia telangiectasia and Rad3-related kinase(ATR),ataxia telangiectasia mutated kinase(ATM),checkpoint kinase 1(CHK1),WEE1 G2 checkpoint kinase(WEE1),and DNA-dependent protein kinase(DNA-PK),and describes the next-generation inhibitors designed to increase selectivity and circumvent resistance.We also analyze the role of hypoxia,stromal remodeling,inflammatory cytokines,and immune-cell plasticity in the tumor microenvironment in determining DDR dependency and response.Special attention is paid to cGAS-STING,immunogenic signaling via damage-associated molecular patterns(DAMPs),and mechanisms that convert a cold tumor into a hot one.Lastly,we touch upon the new nanocarrier-based delivery approaches that enhance pharmacokinetics,target resistant tumor niches,and expand the possibilities for combinatorics with immunotherapy and radiotherapy.Collectively,these findings provide a guide to the implementation of next-generation DDR inhibitors and nanomedicines to deliver a more accurate,durable,and context-specific cancer therapy.展开更多
Aim:Cancer as a complex disease poses significant challenges for both diagnosis and treatment.Researchers have been exploring various avenues to find effective therapeutic strategies,with a particular emphasis on cell...Aim:Cancer as a complex disease poses significant challenges for both diagnosis and treatment.Researchers have been exploring various avenues to find effective therapeutic strategies,with a particular emphasis on cellular signaling pathways and immunotherapy.One such pathway that has recently been suggested is the PD-1/PD-L1 pathway,which is an immune checkpoint signaling system that plays an important role in regulating the immune system and maintaining tissue homeostasis.Cancer cells exploit this pathway by producing PD-L1,which attaches to PD-1 on T cells,thus inhibiting immune responses and enabling the cancer cells to escape detection by the immune system.This study aimed to evaluate the role of the PD-1/PD-L1 pathway in cancer pathogenesis and treatment.Method:This study was performed based on the principles of Preferred Reporting Items for Systematic Reviews and Meta-Analysis(PRISMA).All in vitro,in vivo,and clinical studies that were published in English have been considered during a thorough search of the Scopus,Web of Science,and PubMed databases without date restriction until March 2024.Results:According to the studies reviewed,the PD-1/PD-L1 signaling axis suggests promising therapeutic effects on various types of cancers such as non-small cell lung cancer,melanoma,breast cancer,hepatocellular carcinoma,squamous cell carcinoma,and colorectal cancer,among others.Additionally,research suggests that immune checkpoint inhibitors that block PD1/PD-L1,such as pembrolizumab,atezolizumab,nivolumab,durvalumab,cemiplimab,avelumab,etc.,can effectively prevent tumor cells from escaping the immune system.Moreover,there might be a possible interaction between microbiome,obesity,etc.on immune mechanisms and on the immune checkpoint inhibitors(ICIs).Conclusion:Although we have gained considerable knowledge about ICIs,we are still facing challenges in effectively prescribing the appropriate ICIs for individual patients.This is largely due to the complex interactions between different intracellular pathways,which need to be thoroughly studied.To resolve this issue,it is necessary to conduct more reliable clinical trials that can produce a scientific consensus.展开更多
文摘Tumor survival,genomic stability,and therapy resistance are dictated by the DNA damage response(DDR).Although poly(ADP-ribose)polymerase(PARP)inhibitors have established the DDR as a therapeutic target,many tumors evade first-generation drugs by rewiring their adaptive repair pathways and imposing microenvironmental constraints.This review synthesizes recent discoveries in key DDR pathways,such as PARP,ataxia telangiectasia and Rad3-related kinase(ATR),ataxia telangiectasia mutated kinase(ATM),checkpoint kinase 1(CHK1),WEE1 G2 checkpoint kinase(WEE1),and DNA-dependent protein kinase(DNA-PK),and describes the next-generation inhibitors designed to increase selectivity and circumvent resistance.We also analyze the role of hypoxia,stromal remodeling,inflammatory cytokines,and immune-cell plasticity in the tumor microenvironment in determining DDR dependency and response.Special attention is paid to cGAS-STING,immunogenic signaling via damage-associated molecular patterns(DAMPs),and mechanisms that convert a cold tumor into a hot one.Lastly,we touch upon the new nanocarrier-based delivery approaches that enhance pharmacokinetics,target resistant tumor niches,and expand the possibilities for combinatorics with immunotherapy and radiotherapy.Collectively,these findings provide a guide to the implementation of next-generation DDR inhibitors and nanomedicines to deliver a more accurate,durable,and context-specific cancer therapy.
文摘Aim:Cancer as a complex disease poses significant challenges for both diagnosis and treatment.Researchers have been exploring various avenues to find effective therapeutic strategies,with a particular emphasis on cellular signaling pathways and immunotherapy.One such pathway that has recently been suggested is the PD-1/PD-L1 pathway,which is an immune checkpoint signaling system that plays an important role in regulating the immune system and maintaining tissue homeostasis.Cancer cells exploit this pathway by producing PD-L1,which attaches to PD-1 on T cells,thus inhibiting immune responses and enabling the cancer cells to escape detection by the immune system.This study aimed to evaluate the role of the PD-1/PD-L1 pathway in cancer pathogenesis and treatment.Method:This study was performed based on the principles of Preferred Reporting Items for Systematic Reviews and Meta-Analysis(PRISMA).All in vitro,in vivo,and clinical studies that were published in English have been considered during a thorough search of the Scopus,Web of Science,and PubMed databases without date restriction until March 2024.Results:According to the studies reviewed,the PD-1/PD-L1 signaling axis suggests promising therapeutic effects on various types of cancers such as non-small cell lung cancer,melanoma,breast cancer,hepatocellular carcinoma,squamous cell carcinoma,and colorectal cancer,among others.Additionally,research suggests that immune checkpoint inhibitors that block PD1/PD-L1,such as pembrolizumab,atezolizumab,nivolumab,durvalumab,cemiplimab,avelumab,etc.,can effectively prevent tumor cells from escaping the immune system.Moreover,there might be a possible interaction between microbiome,obesity,etc.on immune mechanisms and on the immune checkpoint inhibitors(ICIs).Conclusion:Although we have gained considerable knowledge about ICIs,we are still facing challenges in effectively prescribing the appropriate ICIs for individual patients.This is largely due to the complex interactions between different intracellular pathways,which need to be thoroughly studied.To resolve this issue,it is necessary to conduct more reliable clinical trials that can produce a scientific consensus.
