Pub Date : 2025-10-02DOI: 10.1038/s41568-025-00869-w
Alfred Zippelius, Sara M. Tolaney, Paolo Tarantino, Joseph P. Balthasar, Greg M. Thurber
After decades of investment, antibody–drug conjugates (ADCs) are finally demonstrating their potential, marked by a growing number of clinical approvals, applications in earlier lines of treatment and integration into drug combinations, including immunotherapies. This progress has spurred investment in developing new ADCs and expanding the use of approved ADCs in clinical practice. The design of ADCs is complex, involving multiple molecular components that interact with both tumour and host tissue microenvironments. In this Review, we explore the molecular and immunological factors influencing ADC efficacy and toxicity. We describe how the molecular components of ADCs determine their systemic, tissue and cellular distribution, which ultimately dictates therapeutic efficacy. These interactions also determine the toxicity profile and set limitations on maximum dosing. Finally, we discuss the impact of ADC treatment on immune cells, emphasizing the distinct but interconnected roles of immunogenic cell death, activation of immune cells such as dendritic cells and antibody–Fc interactions. These mechanisms are crucial for increasing efficacy beyond the direct cytotoxic effects of the payload. By providing insights into the intricate interactions of ADCs, this Review aims to inform the rational design of combination therapies and guide the development of the next generation of clinically effective ADCs. Antibody–drug conjugates are rapidly expanding both in the clinical treatment of cancer and in preclinical development. In this Review, Zippelius et al. highlight the molecular interactions and immune system effects of these sophisticated drugs that drive their efficacy and toxicity.
{"title":"Unveiling the molecular and immunological drivers of antibody–drug conjugates in cancer treatment","authors":"Alfred Zippelius, Sara M. Tolaney, Paolo Tarantino, Joseph P. Balthasar, Greg M. Thurber","doi":"10.1038/s41568-025-00869-w","DOIUrl":"10.1038/s41568-025-00869-w","url":null,"abstract":"After decades of investment, antibody–drug conjugates (ADCs) are finally demonstrating their potential, marked by a growing number of clinical approvals, applications in earlier lines of treatment and integration into drug combinations, including immunotherapies. This progress has spurred investment in developing new ADCs and expanding the use of approved ADCs in clinical practice. The design of ADCs is complex, involving multiple molecular components that interact with both tumour and host tissue microenvironments. In this Review, we explore the molecular and immunological factors influencing ADC efficacy and toxicity. We describe how the molecular components of ADCs determine their systemic, tissue and cellular distribution, which ultimately dictates therapeutic efficacy. These interactions also determine the toxicity profile and set limitations on maximum dosing. Finally, we discuss the impact of ADC treatment on immune cells, emphasizing the distinct but interconnected roles of immunogenic cell death, activation of immune cells such as dendritic cells and antibody–Fc interactions. These mechanisms are crucial for increasing efficacy beyond the direct cytotoxic effects of the payload. By providing insights into the intricate interactions of ADCs, this Review aims to inform the rational design of combination therapies and guide the development of the next generation of clinically effective ADCs. Antibody–drug conjugates are rapidly expanding both in the clinical treatment of cancer and in preclinical development. In this Review, Zippelius et al. highlight the molecular interactions and immune system effects of these sophisticated drugs that drive their efficacy and toxicity.","PeriodicalId":19055,"journal":{"name":"Nature Reviews Cancer","volume":"25 12","pages":"925-944"},"PeriodicalIF":66.8,"publicationDate":"2025-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145209077","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-09-26DOI: 10.1038/s41568-025-00881-0
Daniela Senft
In a recent study published in Nature Genetics, Kübler, Nardone et al. analysed the mechanisms underlying tamoxifen-associated uterine cancer and identified PI3K pathway activation as a key non-genetic driver.
{"title":"Tamoxifen takes the wheel","authors":"Daniela Senft","doi":"10.1038/s41568-025-00881-0","DOIUrl":"10.1038/s41568-025-00881-0","url":null,"abstract":"In a recent study published in Nature Genetics, Kübler, Nardone et al. analysed the mechanisms underlying tamoxifen-associated uterine cancer and identified PI3K pathway activation as a key non-genetic driver.","PeriodicalId":19055,"journal":{"name":"Nature Reviews Cancer","volume":"25 11","pages":"827-827"},"PeriodicalIF":66.8,"publicationDate":"2025-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145177007","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-09-25DOI: 10.1038/s41568-025-00882-z
Douglas G. Ward, Richard T. Bryan, Aadel A. Chaudhuri, James Hadfield, Jennifer Perez-Boza, Renske D. M. Steenbergen, Diana M. Vega, Jennifer Whiting, Alexander W. Wyatt, Lars Dyrskjøt
Urine-based tumour DNA detection enables non-invasive profiling of urological malignancies and may also inform on distant cancers via trans-renal cell-free DNA. However, limited large-scale validation and standardization of urinary cell-free DNA biomarkers constrain their clinical use, highlighting the need for a reporting framework. We therefore propose the ‘minimal urine methods in experiments’ (MUMIE) framework. Urine-based tumour DNA detection enables non-invasive profiling of urological malignancies and may inform on distant cancers via trans-renal cell-free DNA (cfDNA). Here the authors propose the ‘minimal urine methods in experiments’ (MUMIE) framework to enhance validation and standardization of urinary cfDNA biomarkers.
{"title":"Unlocking the potential of urine-based liquid biopsy through improved reporting and standardization","authors":"Douglas G. Ward, Richard T. Bryan, Aadel A. Chaudhuri, James Hadfield, Jennifer Perez-Boza, Renske D. M. Steenbergen, Diana M. Vega, Jennifer Whiting, Alexander W. Wyatt, Lars Dyrskjøt","doi":"10.1038/s41568-025-00882-z","DOIUrl":"10.1038/s41568-025-00882-z","url":null,"abstract":"Urine-based tumour DNA detection enables non-invasive profiling of urological malignancies and may also inform on distant cancers via trans-renal cell-free DNA. However, limited large-scale validation and standardization of urinary cell-free DNA biomarkers constrain their clinical use, highlighting the need for a reporting framework. We therefore propose the ‘minimal urine methods in experiments’ (MUMIE) framework. Urine-based tumour DNA detection enables non-invasive profiling of urological malignancies and may inform on distant cancers via trans-renal cell-free DNA (cfDNA). Here the authors propose the ‘minimal urine methods in experiments’ (MUMIE) framework to enhance validation and standardization of urinary cfDNA biomarkers.","PeriodicalId":19055,"journal":{"name":"Nature Reviews Cancer","volume":"26 2","pages":"79-80"},"PeriodicalIF":66.8,"publicationDate":"2025-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145140227","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-09-25DOI: 10.1038/s41568-025-00873-0
Anqi Dong, Cédric Blanpain
Epithelial-to-mesenchymal transition (EMT) is a cellular process during which cells lose their epithelial characteristics and acquire mesenchymal features with enhanced migration capacities. EMT has key roles in different aspects of tumorigenesis, including tumour initiation, progression, metastasis and resistance to therapy. Here, we have reviewed the recent advances in our understanding of EMT in cancer. Instead of being a binary switch as initially proposed, EMT has been shown to be composed of multiple tumour states residing in specific niches with distinct functional properties that are controlled by different gene regulatory networks. We discuss how the types of oncogenic mutations, signalling pathways, transcription factors, epigenetic regulators and microenvironmental cues regulate the different EMT states. We also highlight the mechanisms by which EMT controls resistance to anticancer therapy and how new approaches to pharmacologically target EMT in clinical settings have recently been developed. In this Review, Dong and Blanpain outline our current understanding of the epithelial-to-mesenchymal transition in cancer, which we now know is not a simple binary switch but the existence of a series of different tumour states. The authors also discuss the implications of this knowledge for pharmacologically targeting epithelial-to-mesenchymal transition to overcome therapy resistance.
{"title":"Identification, functional insights and therapeutic targeting of EMT tumour states","authors":"Anqi Dong, Cédric Blanpain","doi":"10.1038/s41568-025-00873-0","DOIUrl":"10.1038/s41568-025-00873-0","url":null,"abstract":"Epithelial-to-mesenchymal transition (EMT) is a cellular process during which cells lose their epithelial characteristics and acquire mesenchymal features with enhanced migration capacities. EMT has key roles in different aspects of tumorigenesis, including tumour initiation, progression, metastasis and resistance to therapy. Here, we have reviewed the recent advances in our understanding of EMT in cancer. Instead of being a binary switch as initially proposed, EMT has been shown to be composed of multiple tumour states residing in specific niches with distinct functional properties that are controlled by different gene regulatory networks. We discuss how the types of oncogenic mutations, signalling pathways, transcription factors, epigenetic regulators and microenvironmental cues regulate the different EMT states. We also highlight the mechanisms by which EMT controls resistance to anticancer therapy and how new approaches to pharmacologically target EMT in clinical settings have recently been developed. In this Review, Dong and Blanpain outline our current understanding of the epithelial-to-mesenchymal transition in cancer, which we now know is not a simple binary switch but the existence of a series of different tumour states. The authors also discuss the implications of this knowledge for pharmacologically targeting epithelial-to-mesenchymal transition to overcome therapy resistance.","PeriodicalId":19055,"journal":{"name":"Nature Reviews Cancer","volume":"26 1","pages":"8-26"},"PeriodicalIF":66.8,"publicationDate":"2025-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145140226","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-09-24DOI: 10.1038/s41568-025-00870-3
In the current landscape of a rapidly ageing global population, the mechanisms of ageing that contribute to cancer development, progression and treatment are of particular importance. This Focus highlights current research at this intersection between ageing and cancer, and explores how insights gained from this work may lead to better cancer prevention strategies and diagnostics, enhanced therapeutic efficacy and improvements to both patient quality of life and outcomes. This Focus issue highlights current research at the intersection of ageing and cancer, and explores how insights gained from this may lead to better cancer prevention strategies and diagnostics, enhanced therapeutic efficacy and improvements to both patient quality of life and outcomes.
{"title":"Focusing on the complex and dynamic interplay between ageing and cancer","authors":"","doi":"10.1038/s41568-025-00870-3","DOIUrl":"10.1038/s41568-025-00870-3","url":null,"abstract":"In the current landscape of a rapidly ageing global population, the mechanisms of ageing that contribute to cancer development, progression and treatment are of particular importance. This Focus highlights current research at this intersection between ageing and cancer, and explores how insights gained from this work may lead to better cancer prevention strategies and diagnostics, enhanced therapeutic efficacy and improvements to both patient quality of life and outcomes. This Focus issue highlights current research at the intersection of ageing and cancer, and explores how insights gained from this may lead to better cancer prevention strategies and diagnostics, enhanced therapeutic efficacy and improvements to both patient quality of life and outcomes.","PeriodicalId":19055,"journal":{"name":"Nature Reviews Cancer","volume":"25 10","pages":"749-750"},"PeriodicalIF":66.8,"publicationDate":"2025-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41568-025-00870-3.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145123525","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-09-24DOI: 10.1038/s41568-025-00877-w
F. Anthony Greco
The outcomes for patients with cancer of unknown primary have improved through the use of molecularly guided therapies, for those both with and without a presumptive tissue-of-origin diagnosis. Genomic testing followed by molecularly guided therapies significantly improves survival compared to empiric chemotherapy, highlighting its practice-changing potential.
{"title":"Implementing practice-changing progress for managing cancer of unknown primary","authors":"F. Anthony Greco","doi":"10.1038/s41568-025-00877-w","DOIUrl":"10.1038/s41568-025-00877-w","url":null,"abstract":"The outcomes for patients with cancer of unknown primary have improved through the use of molecularly guided therapies, for those both with and without a presumptive tissue-of-origin diagnosis. Genomic testing followed by molecularly guided therapies significantly improves survival compared to empiric chemotherapy, highlighting its practice-changing potential.","PeriodicalId":19055,"journal":{"name":"Nature Reviews Cancer","volume":"26 2","pages":"77-78"},"PeriodicalIF":66.8,"publicationDate":"2025-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145134378","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-09-24DOI: 10.1038/s41568-025-00884-x
Alessandro Lopez‐Hernandez, Diego Ortega-Del Vecchyo
In this Journal Club, Lopez-Hernandez and Ortega-Del Vecchyo discuss a study that mapped the genetic basis of hybrid incompatibility in swordtail fish, revealing melanoma-causing gene interactions that reduce survival in natural hybrid populations.
{"title":"Discovering genetic interactions that cause melanoma in a non-model species","authors":"Alessandro Lopez‐Hernandez, Diego Ortega-Del Vecchyo","doi":"10.1038/s41568-025-00884-x","DOIUrl":"10.1038/s41568-025-00884-x","url":null,"abstract":"In this Journal Club, Lopez-Hernandez and Ortega-Del Vecchyo discuss a study that mapped the genetic basis of hybrid incompatibility in swordtail fish, revealing melanoma-causing gene interactions that reduce survival in natural hybrid populations.","PeriodicalId":19055,"journal":{"name":"Nature Reviews Cancer","volume":"26 2","pages":"83-83"},"PeriodicalIF":66.8,"publicationDate":"2025-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145134370","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-09-22DOI: 10.1038/s41568-025-00880-1
Gabrielle Brewer
In a study published in Nature Immunology, Fuentes et al. demonstrate that the pre-T cell receptor (TCR) is expressed in leukaemia-initiating cells in patients with T cell acute lymphoblastic leukaemia, and that targeting it can inhibit tumour progression.
{"title":"Slaying the pre-TCR beast","authors":"Gabrielle Brewer","doi":"10.1038/s41568-025-00880-1","DOIUrl":"10.1038/s41568-025-00880-1","url":null,"abstract":"In a study published in Nature Immunology, Fuentes et al. demonstrate that the pre-T cell receptor (TCR) is expressed in leukaemia-initiating cells in patients with T cell acute lymphoblastic leukaemia, and that targeting it can inhibit tumour progression.","PeriodicalId":19055,"journal":{"name":"Nature Reviews Cancer","volume":"25 11","pages":"827-827"},"PeriodicalIF":66.8,"publicationDate":"2025-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145125423","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-09-22DOI: 10.1038/s41568-025-00872-1
Kilian B. Kennel, Florian R. Greten
Colorectal cancer (CRC) progression depends on the close interaction of tumour cells and the tumour microenvironment (TME). Although the TME contributes to poor therapy responses and immune evasion, immune cells within the TME can be therapeutically leveraged, as exemplified by immune checkpoint blockade (ICB). Unfortunately, only a small subset of patients with CRC benefit from ICB therapy; those with immune-activated, microsatellite unstable CRC respond, whereas the predominant group of patients with CRC, those with microsatellite-stable tumours, do not. Although challenging, modulating the TME of CRC to convert these lowly immunogenic and immunosuppressed tumours into immune-activated tumours holds tremendous therapeutic potential. In this Review we provide an overview of the cellular and molecular components of immunity in the TME of CRCs at various stages of disease as well as the mechanisms of immunosuppression and immune evasion. We further describe how systemic and local therapies for CRC impact the tumour and systemic immune microenvironments, and how immunity could serve as a therapeutic and prognostic biomarker. Lastly, we highlight novel immunotherapeutic strategies and approaches that modulate the TME of CRCs to make them amenable to immunotherapy. In this Review, Kennel and Greten highlight the role of immune cells in colorectal cancer (CRC) development, progression and metastasis as well as the impact of therapies on the immune microenvironment. They emphasize the need for novel strategies to enhance immunogenicity and CRC patient stratification to improve outcomes.
{"title":"The immune microenvironment of colorectal cancer","authors":"Kilian B. Kennel, Florian R. Greten","doi":"10.1038/s41568-025-00872-1","DOIUrl":"10.1038/s41568-025-00872-1","url":null,"abstract":"Colorectal cancer (CRC) progression depends on the close interaction of tumour cells and the tumour microenvironment (TME). Although the TME contributes to poor therapy responses and immune evasion, immune cells within the TME can be therapeutically leveraged, as exemplified by immune checkpoint blockade (ICB). Unfortunately, only a small subset of patients with CRC benefit from ICB therapy; those with immune-activated, microsatellite unstable CRC respond, whereas the predominant group of patients with CRC, those with microsatellite-stable tumours, do not. Although challenging, modulating the TME of CRC to convert these lowly immunogenic and immunosuppressed tumours into immune-activated tumours holds tremendous therapeutic potential. In this Review we provide an overview of the cellular and molecular components of immunity in the TME of CRCs at various stages of disease as well as the mechanisms of immunosuppression and immune evasion. We further describe how systemic and local therapies for CRC impact the tumour and systemic immune microenvironments, and how immunity could serve as a therapeutic and prognostic biomarker. Lastly, we highlight novel immunotherapeutic strategies and approaches that modulate the TME of CRCs to make them amenable to immunotherapy. In this Review, Kennel and Greten highlight the role of immune cells in colorectal cancer (CRC) development, progression and metastasis as well as the impact of therapies on the immune microenvironment. They emphasize the need for novel strategies to enhance immunogenicity and CRC patient stratification to improve outcomes.","PeriodicalId":19055,"journal":{"name":"Nature Reviews Cancer","volume":"25 12","pages":"945-964"},"PeriodicalIF":66.8,"publicationDate":"2025-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145116797","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-09-10DOI: 10.1038/s41568-025-00874-z
James R. Hebert, E. Angela Murphy, Mary C. Playdon, Liza Makowski, Anna R. Ibele, Ciaran M. Fairman, Lorne J. Hofseth
Glucagon-like peptide-1 (GLP-1) receptor agonists are widely prescribed for weight loss. Here, we discuss the need to monitor long-term use for cancer risk and to couple dietary and physical activity recommendations to prevent skeletal muscle atrophy and maintain metabolic health among people using these drugs. Glucagon-like peptide-1 (GLP-1) receptor agonists are widely prescribed for weight loss. Here, Hebert and colleagues discuss the need for long-term studies assessing the impacts of this on muscle mass and nutritional deficiencies, which may influence cancer susceptibility and metabolic health.
{"title":"Are GLP-1 receptor agonists a ‘magic bullet’ for cancer?","authors":"James R. Hebert, E. Angela Murphy, Mary C. Playdon, Liza Makowski, Anna R. Ibele, Ciaran M. Fairman, Lorne J. Hofseth","doi":"10.1038/s41568-025-00874-z","DOIUrl":"10.1038/s41568-025-00874-z","url":null,"abstract":"Glucagon-like peptide-1 (GLP-1) receptor agonists are widely prescribed for weight loss. Here, we discuss the need to monitor long-term use for cancer risk and to couple dietary and physical activity recommendations to prevent skeletal muscle atrophy and maintain metabolic health among people using these drugs. Glucagon-like peptide-1 (GLP-1) receptor agonists are widely prescribed for weight loss. Here, Hebert and colleagues discuss the need for long-term studies assessing the impacts of this on muscle mass and nutritional deficiencies, which may influence cancer susceptibility and metabolic health.","PeriodicalId":19055,"journal":{"name":"Nature Reviews Cancer","volume":"26 1","pages":"3-4"},"PeriodicalIF":66.8,"publicationDate":"2025-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145026053","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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