Nature Reviews Clinical Oncology最新文献

{"title":"Surprising role of CMV in shaping outcomes of immunotherapy for melanoma — chronic infection yields favourable survival","authors":"Anthony R. Cillo, John M. Kirkwood","doi":"10.1038/s41571-025-01065-3","DOIUrl":"https://doi.org/10.1038/s41571-025-01065-3","url":null,"abstract":"Recent clinical data indicate that infection with the common β-herpesvirus cytomegalovirus (CMV) confers beneficial effects on the T cell compartment that are associated with superior outcomes following immunotherapy in patients with melanoma. These findings warrant further studies of novel therapeutic strategies and biomarkers that might better predict clinical response to and toxicities of immunotherapy, based on systemic immune status.","PeriodicalId":19079,"journal":{"name":"Nature Reviews Clinical Oncology","volume":"9 8 1","pages":""},"PeriodicalIF":78.8,"publicationDate":"2025-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144786627","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}

{"title":"Rethinking cancer of unknown primary: from diagnostic challenge to targeted treatment","authors":"Maria Pouyiourou, Tilmann Bochtler, Chantal Pauli, Holger Moch, Alexander Brobeil, Klaus Pantel, Albrecht Stenzinger, Alwin Krämer","doi":"10.1038/s41571-025-01060-8","DOIUrl":"10.1038/s41571-025-01060-8","url":null,"abstract":"Cancer of unknown primary (CUP) is a metastatic malignancy for which a primary site of origin cannot be identified despite a thorough and standardized diagnostic work-up, and accounts for 1–3% of all malignancies. An unfavourable subgroup of CUP has a poor prognosis, with a median overall survival of <1 year when treated with current standard-of-care platinum-based chemotherapy. Virtually no progress in elucidating the disease biology and improving outcomes for patients with unfavourable CUP has been made over the past several decades, including a failure of initial randomized clinical trials to demonstrate the superiority of tissue-of-origin (ToO) identification by gene-expression profiling and subsequent primary-site-directed treatment over standard chemotherapy. However, large-cohort randomized trials have now shown that molecularly guided therapy improves outcomes for patients with CUP harbouring an actionable target, both in a tissue-agnostic as well as a primary tumour site-specific context. Moreover, data from non-randomized phase II trials suggest that immunotherapy using immune-checkpoint inhibitors can be beneficial even in patients with CUP that has relapsed after, or is refractory to, standard chemotherapy. In addition, a plethora of refined and novel strategies, including DNA and RNA sequencing, DNA-methylation profiling, circulating tumour DNA analysis, and artificial intelligence-based pathology, have been leveraged to facilitate ToO identification. In light of these developments, we review current ToO methodologies and compare the evidence supporting the use of a primary tumour site-guided approach versus a histology-agnostic approach to the management of CUP. We also discuss whether CUP can be viewed as a model disease for the development of histology-agnostic precision oncology treatment strategies. Cancer of unknown primary (CUP) constitutes a diagnostic quandary and has a dismal prognosis, with standard empirical chemotherapy providing limited benefit. This Review outlines diagnostic innovations that are improving tissue-of-origin prediction as well as novel treatment strategies that have shown promise for improving outcomes in patients with CUP.","PeriodicalId":19079,"journal":{"name":"Nature Reviews Clinical Oncology","volume":"22 10","pages":"781-799"},"PeriodicalIF":82.2,"publicationDate":"2025-08-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144777930","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}

{"title":"Understanding and overcoming multidrug resistance in cancer","authors":"Minghua Ge, Xuan-Yu Chen, Ping Huang, Joshua S. Fleishman, Dong-Hua Yang, Zhuo-Xun Wu, Zun-Fu Ke, Zhe-Sheng Chen","doi":"10.1038/s41571-025-01059-1","DOIUrl":"10.1038/s41571-025-01059-1","url":null,"abstract":"Cancer evolution can engender tumours with the ability to resist multiple treatments with distinct chemical structures and mechanisms of action, and this multidrug resistance (MDR) phenotype has long been a substantial challenge in cancer therapy. Despite the established benefits of systemic treatments including chemotherapies, molecularly targeted therapies and immunotherapies across various cancers, MDR inevitably occurs at some point during the course of the disease and its treatment in most patients. Since the discovery of MDR in the 1960s, our understanding of the underlying mechanisms has deepened. However, few strategies are currently available to combat MDR in the clinical setting, and approaches to systematically translate knowledge of new MDR mechanisms and treatments from the laboratory into the clinic are lacking. In this Review, we focus on preclinical and clinical advances in understanding MDR, with an emphasis on resistance to chemotherapy and targeted therapy. We also summarize progress made in translating these findings from bench to bedside through the development of potential strategies to overcome MDR and thus improve patient outcomes. Despite advances in cancer therapy, the persistent challenge of treatment resistance and particularly multidrug resistance remains a substantial barrier to further improvements in patient outcomes. In this Review, the authors discuss preclinical and clinical advances in understanding multidrug resistance, with an emphasis on resistance to chemotherapies and targeted therapies, as well as the progress made in translating these findings into novel strategies to overcome this challenge and thus improve patient outcomes.","PeriodicalId":19079,"journal":{"name":"Nature Reviews Clinical Oncology","volume":"22 10","pages":"760-780"},"PeriodicalIF":82.2,"publicationDate":"2025-07-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144736786","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}

{"title":"Clarifying the role of SONIA: supporting academic evidence on CDK4/6 inhibitor timing","authors":"Avi Petroff, Ian F. Tannock, Daniel A. Goldstein","doi":"10.1038/s41571-025-01063-5","DOIUrl":"10.1038/s41571-025-01063-5","url":null,"abstract":"","PeriodicalId":19079,"journal":{"name":"Nature Reviews Clinical Oncology","volume":"22 9","pages":"701-701"},"PeriodicalIF":82.2,"publicationDate":"2025-07-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144715279","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}

{"title":"PROTAC SERD vepdegestrant outperforms fulvestrant for advanced-stage ER+HER2− breast cancer harbouring acquired ESR1 mutations","authors":"Patrick Neven, Sileny N. Han","doi":"10.1038/s41571-025-01062-6","DOIUrl":"10.1038/s41571-025-01062-6","url":null,"abstract":"Next-generation, oral selective oestrogen receptor degraders (SERDs) have been shown to improve outcomes in patients with advanced-stage oestrogen receptor (ER)-positive, HER2-negative breast cancer, particularly those with acquired ESR1 mutations. Now, the proteolysis-targeting chimera (PROTAC) SERD vepdegestrant, which induces ER degradation directly rather than indirectly, has also demonstrated efficacy in this setting, raising questions over the optimal choice and sequencing of treatments.","PeriodicalId":19079,"journal":{"name":"Nature Reviews Clinical Oncology","volume":"22 10","pages":"709-710"},"PeriodicalIF":82.2,"publicationDate":"2025-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144677434","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}

{"title":"EMT and cancer: what clinicians should know","authors":"Erik W. Thompson, Andrew D. Redfern, Simone Brabletz, Geert Berx, Veenoo Agarwal, Karuna Ganesh, Ruby Y. Huang, Dana Ishay-Ronen, Pierre Savagner, Guojun Sheng, Marc P. Stemmler, Thomas Brabletz","doi":"10.1038/s41571-025-01058-2","DOIUrl":"10.1038/s41571-025-01058-2","url":null,"abstract":"Cell plasticity is a crucial trait for cancer progression towards metastasis and treatment resistance. Research efforts from the past 20–30 years have revealed that the dynamic flux of the epithelial–mesenchymal transition (EMT) programme is one of the major underlying processes enabling cancer cell plasticity and greatly facilitates these major causes of cancer mortality. The spectrum of evidence ranges from extensive data from cell line and animal model studies across multiple cancer types through a rapidly expanding body of work demonstrating associations between EMT biomarkers and disease progression and mortality in patients. EMT is also implicated in resistance to most of the major treatment modalities, yet our efforts to harness this knowledge to improve therapeutic outcomes are currently in their early stages. In this Review, we describe clinical evidence supporting a role of EMT and the associated epithelial–mesenchymal plasticity in various stages of cancer in patients and discuss the subsequent clinical opportunities and challenges associated with attempts to implement this knowledge as novel therapies or clinical management approaches. Despite several decades of research that has revealed roles in the development and progression of many solid tumours, clinical translation of research targeting epithelial–mesenchymal transition (EMT) has thus far been limited. In this Review, the authors provide a summary of the role of EMT in cancer development and progression in the context of this lack of clinical translation, summarize the current status of direct or indirect EMT-modulating agents in clinical development, and highlight the major barriers to the development of EMT-related clinical interventions.","PeriodicalId":19079,"journal":{"name":"Nature Reviews Clinical Oncology","volume":"22 10","pages":"711-733"},"PeriodicalIF":82.2,"publicationDate":"2025-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41571-025-01058-2.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144677438","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}

{"title":"Evolving roles of MET as a therapeutic target in NSCLC and beyond","authors":"Jii Bum Lee, Joo Sung Shim, Byoung Chul Cho","doi":"10.1038/s41571-025-01051-9","DOIUrl":"10.1038/s41571-025-01051-9","url":null,"abstract":"Alterations in the proto-oncogene MET are associated with tumour development, invasion and metastasis across various solid cancers. Therapeutically actionable MET alterations include MET exon 14 skipping (METex14) mutations, MET amplification and/or MET overexpression and MET fusions, which vary in incidence by tumour type. In contrast to rare de novo MET alterations, acquired MET amplification and/or MET overexpression is a relatively common phenomenon that is associated with distinct clinical implications and responses to treatment. METex14 is a distinct oncogenic driver mutation in non-small-cell lung cancer (NSCLC). To date, the MET tyrosine-kinase inhibitors (TKIs) capmatinib, tepotinib and savolitinib have been approved for the treatment of advanced-stage METex14-mutant NSCLC. However, the treatment paradigms for MET-altered solid tumours are rapidly evolving to include diverse MET-targeted agents. Emerging data support the role of MET TKIs, anti-MET antibodies and MET-directed antibody–drug conjugates (ADCs) as monotherapy or in combination with other therapies for NSCLC or other tumour types with MET amplification and/or overexpression. Indeed, in May 2025, the MET-directed ADC telisotuzumab vedotin was approved by the FDA for patients with previously treated advanced-stage nonsquamous NSCLC overexpressing MET (≥50% of tumour cells with 3+ staining on immunohistochemistry). Understanding the unique MET-related adverse events will be crucial when incorporating these agents into daily clinical practice. In this Review, we highlight the rationale for targeting MET alterations across various solid tumour types and provide a summary of the clinical efficacy and toxicity profiles of the approved and emerging MET-targeted TKIs, monoclonal or bispecific antibodies and ADCs. MET mutations, amplifications and fusions and MET overexpression are promising therapeutic targets across various cancers. In this Review, the authors summarize the prevalence, molecular diagnosis and prognostic implications of these alterations and discuss the clinical efficacy and toxicity profiles of diverse MET-targeted therapies, including tyrosine-kinase inhibitors, monoclonal or bispecific antibodies and antibody–drug conjugates.","PeriodicalId":19079,"journal":{"name":"Nature Reviews Clinical Oncology","volume":"22 9","pages":"640-666"},"PeriodicalIF":82.2,"publicationDate":"2025-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144652274","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}

{"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}

{"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}

{"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}