Radiopharmaceuticals are reshaping the landscape of cancer therapy,offering a unique theranostic advantage that is becoming increasingly central to precision medicine.By labeling the same molecular scaffold with diffe...Radiopharmaceuticals are reshaping the landscape of cancer therapy,offering a unique theranostic advantage that is becoming increasingly central to precision medicine.By labeling the same molecular scaffold with different radionuclides,these agents enable seamless integration of diagnostic imaging and targeted therapy.Clinical breakthroughs with somatostatin receptor subtype 2(SSTR2)-and prostate-specificmembrane antigen(PSMA)-targeted radiopharmaceuticals have significantly enhanced both tumor visualization and therapeutic efficacy,establishing new benchmarks in oncology.Ongoing research is exploring novel molecular targets such as cholecystokinin-2 receptor(CCK2R),fibroblast activation protein(FAP),and C-X-C chemokine receptor type 4(CXCR4).In parallel,there is growing interest in utilizing alternative radionuclides,including alpha-particle emitters and Auger electron emitters,beyond the commonly used beta-emitters,to improve therapeutic outcomes.Simultaneously,advances in ligand and linker design are being leveraged to optimize in vivo pharmacokinetics and tissue distribution.Among the emerging targets,CCK2R has attracted notable attention due to its overexpression in multiple malignancies.Research efforts have focused on improving ligand stability,receptor-binding affinity,and tumor retention,while also exploring strategies to enhance CCK2R expression on cancer cells.This review offers a comprehensive overview of the current landscape in cancer radiotheranostics,exploring the role of CCK2R in cancer biology and summarizing the latest advancements in the development of CCK2R-targeted radiopharmaceuticals.Using these advancements as a case study,we systematically examine key aspects of next-generation radiopharmaceutical design,from target selection and ligand engineering to pharmacokinetic optimization and clinical translation,providing a multidimensional framework for future innovation in cancer radiotheranostics.展开更多
Fibroblast growth factor receptor(FGFR)signaling is a pivotal regulator of tumor progression,driving cell proliferation,survival,metastasis,and therapeutic resistance across diverse cancer types.RNA alternative splici...Fibroblast growth factor receptor(FGFR)signaling is a pivotal regulator of tumor progression,driving cell proliferation,survival,metastasis,and therapeutic resistance across diverse cancer types.RNA alternative splicing profoundly shapes FGFR isoform diversity,endowing tumors with heterogeneity and adaptability to targeted interventions.While significant progress has been made in identifying splicing regulators that govern FGFR pre-mRNA processing,the extracellular cues influencing this process and the reciprocal impact of FGFR signaling pathway on global splicing networks remain underexplored.This review provides a comprehensive overview of the bidirectional interplay linking FGFR signaling and RNA splicing in cancer.Mechanistically,we first detail how FGFR mutations,epigenetic modifications,and crosstalks with oncogenic pathways reprogram splicing to generate tumor-specific FGFR splice variants.We then systematically classify distinct FGFR isoforms and delineate how they contribute to main cancer hallmarks,underscoring the central role of the FGFR–splicing axis in driving tumor plasticity,heterogeneity and adaptive progression.Conversely,we also examine how FGFR signaling modulates RNA splicing programs beyond FGFR itself,reshaping global splicing events that contribute to tumorigenesis,an emerging and still largely unexplored area of cancer biology.From therapeutic perspective,we highlight emerging strategies targeting the axis.Notably,FGFR splicing isoform-directed radiopharmaceuticals hold great promise for patient stratification and biomarker-directed theranostics,providing a precise approach to identify aggressive tumors and guide tailored interventions.As well,complementary approaches,including CRISPR/Cas9-based splicing modulation and long non-coding RNAs-targeted therapies,further expand the toolbox for isoform-specific intervention.Moreover,integrating splicing modulators with FGFR TKIs may overcome drug resistance.Understanding the intricate interplay between FGFR signaling and RNA splicing will not only advance biomarker-guided therapeutic development but also provide a novel framework to counteract tumor adaptability,ultimately improving outcomes in FGFR-driven malignancies.展开更多
Radiopharmaceuticals involve the local delivery of radionuclides to targeted lesions for the diagnosis and treatment of multiple diseases.Radiopharmaceutical therapy,which directly causes systematic and irreparable da...Radiopharmaceuticals involve the local delivery of radionuclides to targeted lesions for the diagnosis and treatment of multiple diseases.Radiopharmaceutical therapy,which directly causes systematic and irreparable damage to targeted cells,has attracted increasing attention in the treatment of refractory diseases that are not sensitive to current therapies.As the Food and Drug Administration(FDA)approvals of[177Lu]Lu-DOTA-TATE,[177Lu]Lu-PSMA-617 and their complementary diagnostic agents,namely,[68Ga]Ga-DOTA-TATE and[68Ga]Ga-PSMA-11,targeted radiopharmaceutical-based theranostics(radiotheranostics)are being increasingly implemented in clinical practice in oncology,which lead to a new era of radiopharmaceuticals.The new generation of radiopharmaceuticals utilizes a targeting vector to achieve the accurate delivery of radionuclides to lesions and avoid off-target deposition,making it possible to improve the efficiency and biosafety of tumour diagnosis and therapy.Numerous studies have focused on developing novel radiopharmaceuticals targeting a broader range of disease targets,demonstrating remarkable in vivo performance.These include high tumor uptake,prolonged retention time,and favorable pharmacokinetic properties that align with clinical standards.While radiotheranostics have been widely applied in tumor diagnosis and therapy,their applications are now expanding to neurodegenerative diseases,cardiovascular diseases,and inflammation.Furthermore,radiotheranostic-empowered precision medicine is revolutionizing the cancer treatment paradigm.Diagnostic radiopharmaceuticals play a pivotal role in patient stratification and treatment planning,leading to improved therapeutic outcomes in targeted radionuclide therapy.This review offers a comprehensive overview of the evolution of radiopharmaceuticals,including both FDA-approved and clinically investigated agents,and explores the mechanisms of cell death induced by radiopharmaceuticals.It emphasizes the significance and future prospects of theranostic-based radiopharmaceuticals in advancing precision medicine.展开更多
The activation proteins released by fibroblasts in the tumor microenvironment regulate tumor growth,migration,and treatment response,thereby influencing tumor progression and therapeutic outcomes.Owing to the prolifer...The activation proteins released by fibroblasts in the tumor microenvironment regulate tumor growth,migration,and treatment response,thereby influencing tumor progression and therapeutic outcomes.Owing to the proliferation and metastasis of tumors,fibroblast activation protein(FAP)is typically highly expressed in the tumor stroma,whereas it is nearly absent in adult normal tissues and benign lesions,making it an attractive target for precision medicine.Radiolabeled agents targeting FAP have the potential for targeted cancer diagnosis and therapy.This comprehensive review aims to describe the evolution of FAPI-based radiopharmaceuticals and their structural optimization.Within its scope,this review summarizes the advances in the use of radiolabeled small molecule inhibitors for tumor imaging and therapy as well as the modification strategies for FAPIs,combined with insights from structure-activity relationships and clinical studies,providing a valuable perspective for radiopharmaceutical clinical development and application.展开更多
Peptides that are composed of dextrorotary(D)-amino acids have gained increasing attention as a potential therapeutic class.However,our understanding of the in vivo fate of D-peptides is limited.This highlights the ne...Peptides that are composed of dextrorotary(D)-amino acids have gained increasing attention as a potential therapeutic class.However,our understanding of the in vivo fate of D-peptides is limited.This highlights the need for whole-body,quantitative tracking of D-peptides to better understand how they interact with the living body.Here,we used mouse models to track the movement of a programmed death-ligand 1(PD-L1)-targeting D-dodecapeptide antagonist(DPA)using positron emission tomography(PET).More specifically,we profiled the metabolic routes of[^(64)Cu]DPA and investigated the tumor engagement of[^(64)Cu/^(68)Ga]DPA in mouse models.Our results revealed that intact[^(64)Cu/^(68)Ga]DPA was primarily eliminated by the kidneys and had a notable accumulation in tumors.Moreover,a single dose of[^(64)Cu]DPA effectively delayed tumor growth and improved the survival of mice.Collectively,these results not only deepen our knowledge of the in vivo fate of D-peptides,but also underscore the utility of D-peptides as radiopharmaceuticals.展开更多
基金National University of Singapore,Grant/Award Numbers:NUHSRO/2021/097/Startup/13,NUHSRO/2020/133/Startup/08,NUHSRO/2023/008/NUS Med/TCE/LOANational Medical Research Council,Grant/Award Numbers:MOH-001483-00,MOH-001334-00,MOH-001388-00,MOH-001254-01,CG21APR1005+1 种基金Singapore Ministry of Education,Grant/Award Number:(FY2022)-Tier1-NUHSRO/2022/093/T1/Seed-Sep/06NUS School of Medicine Nanomedicine Translational Research Programme,Grant/Award Number:NUHSRO/2021/034/TRP/09/Nanomedicine。
文摘Radiopharmaceuticals are reshaping the landscape of cancer therapy,offering a unique theranostic advantage that is becoming increasingly central to precision medicine.By labeling the same molecular scaffold with different radionuclides,these agents enable seamless integration of diagnostic imaging and targeted therapy.Clinical breakthroughs with somatostatin receptor subtype 2(SSTR2)-and prostate-specificmembrane antigen(PSMA)-targeted radiopharmaceuticals have significantly enhanced both tumor visualization and therapeutic efficacy,establishing new benchmarks in oncology.Ongoing research is exploring novel molecular targets such as cholecystokinin-2 receptor(CCK2R),fibroblast activation protein(FAP),and C-X-C chemokine receptor type 4(CXCR4).In parallel,there is growing interest in utilizing alternative radionuclides,including alpha-particle emitters and Auger electron emitters,beyond the commonly used beta-emitters,to improve therapeutic outcomes.Simultaneously,advances in ligand and linker design are being leveraged to optimize in vivo pharmacokinetics and tissue distribution.Among the emerging targets,CCK2R has attracted notable attention due to its overexpression in multiple malignancies.Research efforts have focused on improving ligand stability,receptor-binding affinity,and tumor retention,while also exploring strategies to enhance CCK2R expression on cancer cells.This review offers a comprehensive overview of the current landscape in cancer radiotheranostics,exploring the role of CCK2R in cancer biology and summarizing the latest advancements in the development of CCK2R-targeted radiopharmaceuticals.Using these advancements as a case study,we systematically examine key aspects of next-generation radiopharmaceutical design,from target selection and ligand engineering to pharmacokinetic optimization and clinical translation,providing a multidimensional framework for future innovation in cancer radiotheranostics.
基金funded by Startup Foundation for Recruited High-level Talents of Mianyang Central Hospital(2025RCYJ-010,China)Science and Technology Department of Sichuan Province 2023NSFSC0130 and 2023NSFSC1992(China)State Key Laboratory of Respiratory Disease(SKLRD-OP-202501,China).
文摘Fibroblast growth factor receptor(FGFR)signaling is a pivotal regulator of tumor progression,driving cell proliferation,survival,metastasis,and therapeutic resistance across diverse cancer types.RNA alternative splicing profoundly shapes FGFR isoform diversity,endowing tumors with heterogeneity and adaptability to targeted interventions.While significant progress has been made in identifying splicing regulators that govern FGFR pre-mRNA processing,the extracellular cues influencing this process and the reciprocal impact of FGFR signaling pathway on global splicing networks remain underexplored.This review provides a comprehensive overview of the bidirectional interplay linking FGFR signaling and RNA splicing in cancer.Mechanistically,we first detail how FGFR mutations,epigenetic modifications,and crosstalks with oncogenic pathways reprogram splicing to generate tumor-specific FGFR splice variants.We then systematically classify distinct FGFR isoforms and delineate how they contribute to main cancer hallmarks,underscoring the central role of the FGFR–splicing axis in driving tumor plasticity,heterogeneity and adaptive progression.Conversely,we also examine how FGFR signaling modulates RNA splicing programs beyond FGFR itself,reshaping global splicing events that contribute to tumorigenesis,an emerging and still largely unexplored area of cancer biology.From therapeutic perspective,we highlight emerging strategies targeting the axis.Notably,FGFR splicing isoform-directed radiopharmaceuticals hold great promise for patient stratification and biomarker-directed theranostics,providing a precise approach to identify aggressive tumors and guide tailored interventions.As well,complementary approaches,including CRISPR/Cas9-based splicing modulation and long non-coding RNAs-targeted therapies,further expand the toolbox for isoform-specific intervention.Moreover,integrating splicing modulators with FGFR TKIs may overcome drug resistance.Understanding the intricate interplay between FGFR signaling and RNA splicing will not only advance biomarker-guided therapeutic development but also provide a novel framework to counteract tumor adaptability,ultimately improving outcomes in FGFR-driven malignancies.
基金supported by the National Natural Science Foundation of China(No.82372002)the Nonprofit Central Research Institute Fund of the Chinese Academy of Medical Sciences(No.2022-RC350-04)+5 种基金the CAMS Innovation Fund for Medical Sciences(Nos.2023-I2M-2-006,2023-I2M-QJ-010,02149942,2021-I2M-1-026,2022-I2M-2-002-2,and 2021-I2M-3-001)the National Key Research and Development Programme of China(No.2022YFE0111700)the Beijing Nova Programme to K.H..This work was also supported by the Beijing Natural Science Foundation(Nos.L234044 and L248087)the Fundamental Research Funds for the Central Universities(Nos.3332023044 and 3332023151)the CIRP Open Fund of Radiation Protection Laboratories(No.ZHYLYB2021005)the China National Nuclear Corporation Young Talent Programme.
文摘Radiopharmaceuticals involve the local delivery of radionuclides to targeted lesions for the diagnosis and treatment of multiple diseases.Radiopharmaceutical therapy,which directly causes systematic and irreparable damage to targeted cells,has attracted increasing attention in the treatment of refractory diseases that are not sensitive to current therapies.As the Food and Drug Administration(FDA)approvals of[177Lu]Lu-DOTA-TATE,[177Lu]Lu-PSMA-617 and their complementary diagnostic agents,namely,[68Ga]Ga-DOTA-TATE and[68Ga]Ga-PSMA-11,targeted radiopharmaceutical-based theranostics(radiotheranostics)are being increasingly implemented in clinical practice in oncology,which lead to a new era of radiopharmaceuticals.The new generation of radiopharmaceuticals utilizes a targeting vector to achieve the accurate delivery of radionuclides to lesions and avoid off-target deposition,making it possible to improve the efficiency and biosafety of tumour diagnosis and therapy.Numerous studies have focused on developing novel radiopharmaceuticals targeting a broader range of disease targets,demonstrating remarkable in vivo performance.These include high tumor uptake,prolonged retention time,and favorable pharmacokinetic properties that align with clinical standards.While radiotheranostics have been widely applied in tumor diagnosis and therapy,their applications are now expanding to neurodegenerative diseases,cardiovascular diseases,and inflammation.Furthermore,radiotheranostic-empowered precision medicine is revolutionizing the cancer treatment paradigm.Diagnostic radiopharmaceuticals play a pivotal role in patient stratification and treatment planning,leading to improved therapeutic outcomes in targeted radionuclide therapy.This review offers a comprehensive overview of the evolution of radiopharmaceuticals,including both FDA-approved and clinically investigated agents,and explores the mechanisms of cell death induced by radiopharmaceuticals.It emphasizes the significance and future prospects of theranostic-based radiopharmaceuticals in advancing precision medicine.
基金supported by the National Natural Science Foundation of China(No.82372002)the Nonprofit Central Research Institute Fund of the Chinese Academy of Medical Sciences(No.2022-RC350-04)+6 种基金the CAMS Innovation Fund for Medical Sciences(Nos.2024-12M-ZH-009,2023-I2M-2-006,2023-I2M-QJ010,2021-I2M-1-026,and 2021-I2M-3-001,China)the Beijing Nova Program and Beijing Nova Program Interdisciplinary Cooperation Project to Ksupported by the Beijing Natural Science Foundation(Nos.L234044,L248087,L246051 and 7252206,China)the Fundamental Research Funds for the Central Universities(Nos.3332023044,3332023151,China)the China Postdoctoral Science Foundation(No.2025M773592)the China National Nuclear Corporation Young Talent Program,the special project of“Technological Innovation”project of CNNC Medical Industry Co.Ltd(ZHYLYB2021005)Medical+X Innovation Team of the Discipline Construction Enhancement Project,the Second Affiliated Hospital of Soochow University(XKTJ-TD202410).
文摘The activation proteins released by fibroblasts in the tumor microenvironment regulate tumor growth,migration,and treatment response,thereby influencing tumor progression and therapeutic outcomes.Owing to the proliferation and metastasis of tumors,fibroblast activation protein(FAP)is typically highly expressed in the tumor stroma,whereas it is nearly absent in adult normal tissues and benign lesions,making it an attractive target for precision medicine.Radiolabeled agents targeting FAP have the potential for targeted cancer diagnosis and therapy.This comprehensive review aims to describe the evolution of FAPI-based radiopharmaceuticals and their structural optimization.Within its scope,this review summarizes the advances in the use of radiolabeled small molecule inhibitors for tumor imaging and therapy as well as the modification strategies for FAPIs,combined with insights from structure-activity relationships and clinical studies,providing a valuable perspective for radiopharmaceutical clinical development and application.
基金financial support from the JSPS KAKENHI grant Nos.19K17156,21H02873,21K07659,and 20H03635,Japansupported by QST President’s Strategic Grant(Exploratory Research,Japan)+3 种基金financial support from the National Natural Science Foundation of China(82003532)General Project of Science and Technology Development Fund of Nanjing Medical University(NMUB2019154,China)the second round of Nanjing Clinical Medical Center"Nanjing Nuclear Medicine Center"the China Postdoctoral Science Foundation(2019M650302)。
文摘Peptides that are composed of dextrorotary(D)-amino acids have gained increasing attention as a potential therapeutic class.However,our understanding of the in vivo fate of D-peptides is limited.This highlights the need for whole-body,quantitative tracking of D-peptides to better understand how they interact with the living body.Here,we used mouse models to track the movement of a programmed death-ligand 1(PD-L1)-targeting D-dodecapeptide antagonist(DPA)using positron emission tomography(PET).More specifically,we profiled the metabolic routes of[^(64)Cu]DPA and investigated the tumor engagement of[^(64)Cu/^(68)Ga]DPA in mouse models.Our results revealed that intact[^(64)Cu/^(68)Ga]DPA was primarily eliminated by the kidneys and had a notable accumulation in tumors.Moreover,a single dose of[^(64)Cu]DPA effectively delayed tumor growth and improved the survival of mice.Collectively,these results not only deepen our knowledge of the in vivo fate of D-peptides,but also underscore the utility of D-peptides as radiopharmaceuticals.
