Pub Date : 2025-07-14DOI: 10.1038/s41571-025-01052-8
Jianzhou Chen, Eric Deutsch, Guido Kroemer, Lorenzo Galluzzi, Laurence Zitvogel
Radiotherapy has an established role in the clinical treatment of patients with a variety of cancers owing to the ability to preferentially kill malignant cells mostly while sparing their non-malignant counterparts. Results from phase I–II trials also suggest that radiotherapy can have therapeutically relevant immunostimulatory effects, especially when combined with immune-checkpoint inhibitors. Over the past two decades, evidence has emerged showing that intestinal microbial communities have a major influence on the immunological tonus of patients with cancer and can influence sensitivity to various immunotherapies, including immune-checkpoint inhibitors and chimeric antigen receptor T cells. Here, we critically discuss the effects of such microbial ecosystems on radiotherapy-induced toxicities and tumour-targeting immune responses, with a focus on the clinical potential of these relationships for predictive and therapeutic clinical applications. Radiotherapy has an established role in the treatment of many patients with cancer, with evidence suggesting that this modality can also have immunostimulatory effects in certain scenarios. More recently, evidence has emerged supporting a role of the microbiome in influencing the incidence and severity of toxicities in patients receiving radiotherapy as well as in mediating possible synergy with other therapeutic interventions, including immunotherapy. In this Review, the authors explore the clinical potential of these emerging relationships.
{"title":"The microbiota in radiotherapy-induced cancer immunosurveillance","authors":"Jianzhou Chen, Eric Deutsch, Guido Kroemer, Lorenzo Galluzzi, Laurence Zitvogel","doi":"10.1038/s41571-025-01052-8","DOIUrl":"10.1038/s41571-025-01052-8","url":null,"abstract":"Radiotherapy has an established role in the clinical treatment of patients with a variety of cancers owing to the ability to preferentially kill malignant cells mostly while sparing their non-malignant counterparts. Results from phase I–II trials also suggest that radiotherapy can have therapeutically relevant immunostimulatory effects, especially when combined with immune-checkpoint inhibitors. Over the past two decades, evidence has emerged showing that intestinal microbial communities have a major influence on the immunological tonus of patients with cancer and can influence sensitivity to various immunotherapies, including immune-checkpoint inhibitors and chimeric antigen receptor T cells. Here, we critically discuss the effects of such microbial ecosystems on radiotherapy-induced toxicities and tumour-targeting immune responses, with a focus on the clinical potential of these relationships for predictive and therapeutic clinical applications. Radiotherapy has an established role in the treatment of many patients with cancer, with evidence suggesting that this modality can also have immunostimulatory effects in certain scenarios. More recently, evidence has emerged supporting a role of the microbiome in influencing the incidence and severity of toxicities in patients receiving radiotherapy as well as in mediating possible synergy with other therapeutic interventions, including immunotherapy. In this Review, the authors explore the clinical potential of these emerging relationships.","PeriodicalId":19079,"journal":{"name":"Nature Reviews Clinical Oncology","volume":"22 9","pages":"667-679"},"PeriodicalIF":82.2,"publicationDate":"2025-07-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144629608","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 : 2025-07-10DOI: 10.1038/s41571-025-01054-6
Paul Johannet, Benoit Rousseau, Carol Aghajanian, Michael B. Foote, Luis A. Diaz Jr.
DNA mismatch repair (MMR) is one of many evolutionarily conserved processes that act as guardians of genomic integrity. MMR proteins recognize errors that occur during DNA replication and initiate countermeasures to rectify those mistakes. MMR deficiency (MMRd) therefore leads to a dramatic accumulation of mutations. The MMRd genomic signature is characterized by a high frequency of single-base substitutions as well as insertions and/or deletions that preferentially occur in short nucleotide repeat sequences known as microsatellites. This accumulation leads to a phenomenon termed microsatellite instability, which accordingly serves as a marker of underlying MMRd. MMRd is associated with hereditary cancer syndromes such as Lynch syndrome and constitutional MMRd as well as with sporadic tumour development across a variety of tissues. High baseline immune cell infiltration is a characteristic feature of MMRd/microsatellite instability-high tumours, as is the upregulation of immune checkpoints. Importantly, the molecular profile of MMRd tumours confers remarkable sensitivity to immune-checkpoint inhibitors (ICIs). Many patients with MMRd disease derive durable clinical benefit when treated with these agents regardless of the primary tumour site. Nevertheless, a substantial subset of these patients will fail to respond to ICI, and increasing research is focused on identifying the factors that confer resistance. In this Review, we begin by discussing the biological function of the MMR machinery as well as the genomic sequelae of MMRd before then examining the clinical implications of MMRd with a specific focus on cancer predisposition, diagnostic approaches, therapeutic strategies and potential mechanisms of resistance to ICIs. This comprehensive Review describes the biological function of the mismatch repair (MMR) machinery, the genomic sequelae of defects in this machinery and the roles of hereditary or sporadic MMR deficiency in cancer predisposition and/or tumour development. The authors also discuss the clinical implications of MMR deficiency with a specific focus on diagnostic approaches, therapeutic strategies and mechanisms of resistance to immune-checkpoint inhibitors.
{"title":"Therapeutic targeting of mismatch repair-deficient cancers","authors":"Paul Johannet, Benoit Rousseau, Carol Aghajanian, Michael B. Foote, Luis A. Diaz Jr.","doi":"10.1038/s41571-025-01054-6","DOIUrl":"10.1038/s41571-025-01054-6","url":null,"abstract":"DNA mismatch repair (MMR) is one of many evolutionarily conserved processes that act as guardians of genomic integrity. MMR proteins recognize errors that occur during DNA replication and initiate countermeasures to rectify those mistakes. MMR deficiency (MMRd) therefore leads to a dramatic accumulation of mutations. The MMRd genomic signature is characterized by a high frequency of single-base substitutions as well as insertions and/or deletions that preferentially occur in short nucleotide repeat sequences known as microsatellites. This accumulation leads to a phenomenon termed microsatellite instability, which accordingly serves as a marker of underlying MMRd. MMRd is associated with hereditary cancer syndromes such as Lynch syndrome and constitutional MMRd as well as with sporadic tumour development across a variety of tissues. High baseline immune cell infiltration is a characteristic feature of MMRd/microsatellite instability-high tumours, as is the upregulation of immune checkpoints. Importantly, the molecular profile of MMRd tumours confers remarkable sensitivity to immune-checkpoint inhibitors (ICIs). Many patients with MMRd disease derive durable clinical benefit when treated with these agents regardless of the primary tumour site. Nevertheless, a substantial subset of these patients will fail to respond to ICI, and increasing research is focused on identifying the factors that confer resistance. In this Review, we begin by discussing the biological function of the MMR machinery as well as the genomic sequelae of MMRd before then examining the clinical implications of MMRd with a specific focus on cancer predisposition, diagnostic approaches, therapeutic strategies and potential mechanisms of resistance to ICIs. This comprehensive Review describes the biological function of the mismatch repair (MMR) machinery, the genomic sequelae of defects in this machinery and the roles of hereditary or sporadic MMR deficiency in cancer predisposition and/or tumour development. The authors also discuss the clinical implications of MMR deficiency with a specific focus on diagnostic approaches, therapeutic strategies and mechanisms of resistance to immune-checkpoint inhibitors.","PeriodicalId":19079,"journal":{"name":"Nature Reviews Clinical Oncology","volume":"22 10","pages":"734-759"},"PeriodicalIF":82.2,"publicationDate":"2025-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41571-025-01054-6.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144594119","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 : 2025-07-07DOI: 10.1038/s41571-025-01041-x
Meletios A. Dimopoulos, Evangelos Terpos, Mario Boccadoro, Philippe Moreau, María-Victoria Mateos, Sonja Zweegman, Gordon Cook, Monika Engelhardt, Michel Delforge, Roman Hajek, Fredrik Schjesvold, Francesca Gay, Salomon Manier, Katja C. Weisel, Martin Kaiser, Niels W. C. J. van de Donk, Elena Zamagni, Paula Rodriguez-Otero, Aurore Perrot, Christoph Driessen, Jelena Bila, Edward Laane, Dominik Dytfeld, Cyrille Touzeau, Meral Beksac, Marc S. Raab, Michele Cavo, Mohamad Mohty, Andrew Spencer, Heinz Ludwig, Hermann Einsele, Jesus San-Miguel, Pieter Sonneveld
Since the publication in 2021 of the European Hematology Association (EHA) Clinical Practice Guidelines for the treatment of patients with smouldering multiple myeloma (SMM) and multiple myeloma (MM), developed in collaboration with the European Society for Medical Oncology, a novel international staging system (R2-ISS) has been developed, several prognostic factors are entering clinical practice (such as minimal residual disease, circulating plasma cells and monoclonal protein assessed by mass spectrometry) and, at the time of writing, 14 novel regimens have been approved by the EMA and/or the FDA for the treatment of patients with MM. A multidisciplinary group of experts from the EHA and European Myeloma Network, based in various institutions mostly located in Europe, have updated the previous guidelines and produced algorithms for everyday clinical practice that incorporate levels of evidence and grades of recommendation based on the aforementioned new data. In these Evidence-Based Guidelines, we provide key treatment recommendations for both patients with newly diagnosed MM and those with relapsed and/or refractory MM, including guidance for the use of established drugs as well as contemporary immunotherapies. Novel approaches for the management of patients with SMM focus on those who might require early intervention. Finally, we provide recommendations for myeloma-related complications and adverse events, such as bone disease, renal impairment and infections, as well as for those associated with T cell-mobilizing therapies, such as cytokine-release syndrome and immune effector cell-associated neurotoxicity syndrome. In these Evidence-Based Guidelines, a multidisciplinary panel of experts from the European Hematology Association and the European Myeloma Network provide key treatment recommendations for patients with smouldering multiple myeloma, and newly diagnosed or relapsed and/or refractory multiple myeloma, addressing the use of established drugs and novel immunotherapies as well as the management of disease-specific and treatment-related complications and adverse events.
{"title":"EHA–EMN Evidence-Based Guidelines for diagnosis, treatment and follow-up of patients with multiple myeloma","authors":"Meletios A. Dimopoulos, Evangelos Terpos, Mario Boccadoro, Philippe Moreau, María-Victoria Mateos, Sonja Zweegman, Gordon Cook, Monika Engelhardt, Michel Delforge, Roman Hajek, Fredrik Schjesvold, Francesca Gay, Salomon Manier, Katja C. Weisel, Martin Kaiser, Niels W. C. J. van de Donk, Elena Zamagni, Paula Rodriguez-Otero, Aurore Perrot, Christoph Driessen, Jelena Bila, Edward Laane, Dominik Dytfeld, Cyrille Touzeau, Meral Beksac, Marc S. Raab, Michele Cavo, Mohamad Mohty, Andrew Spencer, Heinz Ludwig, Hermann Einsele, Jesus San-Miguel, Pieter Sonneveld","doi":"10.1038/s41571-025-01041-x","DOIUrl":"10.1038/s41571-025-01041-x","url":null,"abstract":"Since the publication in 2021 of the European Hematology Association (EHA) Clinical Practice Guidelines for the treatment of patients with smouldering multiple myeloma (SMM) and multiple myeloma (MM), developed in collaboration with the European Society for Medical Oncology, a novel international staging system (R2-ISS) has been developed, several prognostic factors are entering clinical practice (such as minimal residual disease, circulating plasma cells and monoclonal protein assessed by mass spectrometry) and, at the time of writing, 14 novel regimens have been approved by the EMA and/or the FDA for the treatment of patients with MM. A multidisciplinary group of experts from the EHA and European Myeloma Network, based in various institutions mostly located in Europe, have updated the previous guidelines and produced algorithms for everyday clinical practice that incorporate levels of evidence and grades of recommendation based on the aforementioned new data. In these Evidence-Based Guidelines, we provide key treatment recommendations for both patients with newly diagnosed MM and those with relapsed and/or refractory MM, including guidance for the use of established drugs as well as contemporary immunotherapies. Novel approaches for the management of patients with SMM focus on those who might require early intervention. Finally, we provide recommendations for myeloma-related complications and adverse events, such as bone disease, renal impairment and infections, as well as for those associated with T cell-mobilizing therapies, such as cytokine-release syndrome and immune effector cell-associated neurotoxicity syndrome. In these Evidence-Based Guidelines, a multidisciplinary panel of experts from the European Hematology Association and the European Myeloma Network provide key treatment recommendations for patients with smouldering multiple myeloma, and newly diagnosed or relapsed and/or refractory multiple myeloma, addressing the use of established drugs and novel immunotherapies as well as the management of disease-specific and treatment-related complications and adverse events.","PeriodicalId":19079,"journal":{"name":"Nature Reviews Clinical Oncology","volume":"22 9","pages":"680-700"},"PeriodicalIF":82.2,"publicationDate":"2025-07-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41571-025-01041-x.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144568754","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 : 2025-06-30DOI: 10.1038/s41571-025-01055-5
Josep M. Llovet
Immune-checkpoint inhibitors have revolutionized the management of hepatocellular carcinoma. Currently, anti-PD-(L)-1 antibodies combined with either bevacizumab or anti-CTLA4 antibodies are the standard of care for advanced-stage tumours. Now, two phase III studies (CheckMate 9DW and APOLLO) have reported positive survival results in the first-line setting, although with distinct implications for clinical practice.
{"title":"Role of novel immunotherapy combinations in the management of advanced-stage hepatocellular carcinoma","authors":"Josep M. Llovet","doi":"10.1038/s41571-025-01055-5","DOIUrl":"10.1038/s41571-025-01055-5","url":null,"abstract":"Immune-checkpoint inhibitors have revolutionized the management of hepatocellular carcinoma. Currently, anti-PD-(L)-1 antibodies combined with either bevacizumab or anti-CTLA4 antibodies are the standard of care for advanced-stage tumours. Now, two phase III studies (CheckMate 9DW and APOLLO) have reported positive survival results in the first-line setting, although with distinct implications for clinical practice.","PeriodicalId":19079,"journal":{"name":"Nature Reviews Clinical Oncology","volume":"22 9","pages":"625-626"},"PeriodicalIF":82.2,"publicationDate":"2025-06-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144515543","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 : 2025-06-27DOI: 10.1038/s41571-025-01049-3
Joao B. Xavier
The composition of the intestinal microbiota influences the outcomes of patients receiving cancer treatment, although the best way to use this knowledge to improve cancer care remains unclear. In this Review, I synthesize the current understanding of host–microbiota dynamics in patients with cancer, and propose the integration of microbiota management guided by ecological principles in cancer care. Ecological management of the microbiota emphasizes the preservation of microbial populations — and the benefits they provide to the host — from the disruption caused by treatments such as chemotherapy and prophylactic antibiotics. The microbiota can be routinely and longitudinally monitored in patients using proven non-invasive methods, such as 16S ribosomal RNA amplicon sequencing. Longitudinal microbiome data can be processed with innovative computational tools based on principles of mathematical ecology to predict the risk of microbiota-related complications, guide treatment choices that minimize disturbance to the microbiota and restore microbial populations damaged by cancer treatment. Routine microbiome monitoring could also generate extensive datasets for human-based research, which could inform new microbiota-targeted interventions that improve responses to cancer treatments, including immune-checkpoint inhibitors. Applying ecological approaches to manage microbiota could enhance cancer care and improve patient outcomes. This Review synthesizes the current understanding of host–microbiota dynamics in patients with cancer and proposes to integrate microbiota management approaches guided by ecological principles in cancer care. Mathematical ecology could help to predict the risk of microbiota-related complications and guide treatment choices that minimize disturbance to microbial ecosystems, ultimately informing microbiota-targeted interventions that could improve responses to cancer treatments.
{"title":"Ecological management of the microbiota in patients with cancer","authors":"Joao B. Xavier","doi":"10.1038/s41571-025-01049-3","DOIUrl":"10.1038/s41571-025-01049-3","url":null,"abstract":"The composition of the intestinal microbiota influences the outcomes of patients receiving cancer treatment, although the best way to use this knowledge to improve cancer care remains unclear. In this Review, I synthesize the current understanding of host–microbiota dynamics in patients with cancer, and propose the integration of microbiota management guided by ecological principles in cancer care. Ecological management of the microbiota emphasizes the preservation of microbial populations — and the benefits they provide to the host — from the disruption caused by treatments such as chemotherapy and prophylactic antibiotics. The microbiota can be routinely and longitudinally monitored in patients using proven non-invasive methods, such as 16S ribosomal RNA amplicon sequencing. Longitudinal microbiome data can be processed with innovative computational tools based on principles of mathematical ecology to predict the risk of microbiota-related complications, guide treatment choices that minimize disturbance to the microbiota and restore microbial populations damaged by cancer treatment. Routine microbiome monitoring could also generate extensive datasets for human-based research, which could inform new microbiota-targeted interventions that improve responses to cancer treatments, including immune-checkpoint inhibitors. Applying ecological approaches to manage microbiota could enhance cancer care and improve patient outcomes. This Review synthesizes the current understanding of host–microbiota dynamics in patients with cancer and proposes to integrate microbiota management approaches guided by ecological principles in cancer care. Mathematical ecology could help to predict the risk of microbiota-related complications and guide treatment choices that minimize disturbance to microbial ecosystems, ultimately informing microbiota-targeted interventions that could improve responses to cancer treatments.","PeriodicalId":19079,"journal":{"name":"Nature Reviews Clinical Oncology","volume":"22 9","pages":"627-639"},"PeriodicalIF":82.2,"publicationDate":"2025-06-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144500610","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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