Nature Reviews Clinical Oncology最新文献

{"title":"Stereotactic radiosurgery for patients with brain metastases: current principles, expanding indications and opportunities for multidisciplinary care","authors":"Alireza Mansouri, Ahmad Ozair, Debarati Bhanja, Hannah Wilding, Elad Mashiach, Waqas Haque, Nicholas Mikolajewicz, Leonardo de Macedo Filho, Sean S. Mahase, Mitchell Machtay, Philippe Metellus, Frédéric Dhermain, Jason Sheehan, Douglas Kondziolka, L. Dade Lunsford, Ajay Niranjan, Giuseppe Minniti, Jing Li, Steven N. Kalkanis, Patrick Y. Wen, Rupesh Kotecha, Michael W. McDermott, Chetan Bettegowda, Graeme F. Woodworth, Paul D. Brown, Arjun Sahgal, Manmeet S. Ahluwalia","doi":"10.1038/s41571-025-01013-1","DOIUrl":"10.1038/s41571-025-01013-1","url":null,"abstract":"The management of brain metastases is challenging and should ideally be coordinated through a multidisciplinary approach. Stereotactic radiosurgery (SRS) has been the cornerstone of management for most patients with oligometastatic central nervous system involvement (one to four brain metastases), and several technological and therapeutic advances over the past decade have broadened the indications for SRS to include polymetastatic central nervous system involvement (>4 brain metastases), preoperative application and fractionated SRS, as well as combinatorial approaches with targeted therapy and immune-checkpoint inhibitors. For example, improved imaging and frameless head-immobilization technologies have facilitated fractionated SRS for large brain metastases or postsurgical cavities, or lesions in proximity to organs at risk. However, these opportunities come with new challenges and questions, including the implications of tumour histology as well as the role and sequencing of concurrent systemic treatments. In this Review, we discuss these advances and associated challenges in the context of ongoing clinical trials, with insights from a global group of experts, including recommendations for current clinical practice and future investigations. The updates provided herein are meaningful for all practitioners in clinical oncology. Stereotactic radiosurgery (SRS) has been established as a key therapeutic modality for the management of brain metastases. In this Review, an international group of experts discuss the expanding opportunities for SRS, including application for larger brain metastases and cumulative intracranial tumour volumes, fractionated delivery, neoadjuvant use and combinatorial approaches with modern systemic therapy, as well as associated challenges and remaining questions.","PeriodicalId":19079,"journal":{"name":"Nature Reviews Clinical Oncology","volume":"22 5","pages":"327-347"},"PeriodicalIF":82.2,"publicationDate":"2025-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143660924","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":"Emerging importance of HER3 in tumorigenesis and cancer therapy","authors":"Joan T. Garrett, Salomon Tendler, Wasim Feroz, Mary Kate Kilroy, Helena Yu","doi":"10.1038/s41571-025-01008-y","DOIUrl":"10.1038/s41571-025-01008-y","url":null,"abstract":"HER3 is a member of the HER/ErbB family of receptor tyrosine kinases, together with EGFR (HER1), HER2 and HER4. Despite having only weak intrinsic kinase activity, HER3 can contribute to oncogenic signalling via ligand-induced heterodimerization with other HER family members. Evidence indicates that HER3 is altered or aberrantly expressed across a variety of tumour types and can be associated with poor clinical outcomes. Whereas anticancer agents targeting EGFR and HER2 have been approved for decades, no drug targeting HER3 had been approved until very recently. Initial targeting of HER3 with monoclonal antibodies as single agents or in combination with other therapeutics produced disappointing clinical results. Subsequently, efforts have been made to target HER3 with novel agents such as antibody–drug conjugates and bispecific antibodies, with promising efficacy observed in several trials encompassing various tumour types. In December 2024, the HER3 × HER2 bispecific antibody zenocutuzumab was granted FDA Accelerated Approval for the treatment of non-small-cell lung cancers or pancreatic cancers harbouring fusions involving NRG1, the gene encoding the high-affinity HER3 ligand neuregulin 1. In this Review, we provide an essential guide to HER3 signalling and oncogenesis, HER3 expression in cancer and its prognostic implications, oncogenic HER3 somatic mutations as well as rare NRG1 fusions that might depend on HER3 signalling, and the roles of HER3 in resistance to cancer therapies. We also highlight efforts to target HER3 with diverse therapeutic strategies and the potential interplay between HER3 and the antitumour immune response. HER3 is emerging as a promising therapeutic target that is often overexpressed or genetically altered across diverse solid tumour types. This Review describes the landscape of HER3 alterations in cancer and their prognostic implications, the roles of HER3 in oncogenesis and resistance to targeted therapies, and the ongoing clinical development of agents targeting HER3.","PeriodicalId":19079,"journal":{"name":"Nature Reviews Clinical Oncology","volume":"22 5","pages":"348-370"},"PeriodicalIF":82.2,"publicationDate":"2025-03-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143627509","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":"Utilizing ctDNA to discover mechanisms of resistance to targeted therapies in patients with metastatic NSCLC: towards more informative trials","authors":"Sophie M. Ernst, Mihaela Aldea, Jan H. von der Thüsen, Adrianus J. de Langen, Egbert F. Smit, Marthe S. Paats, Joachim G. J. V. Aerts, Laura Mezquita, Sanjay Popat, Benjamin Besse, Jordi Remon, Christian Rolfo, Hendrikus J. Dubbink, Anne-Marie C. Dingemans","doi":"10.1038/s41571-025-01011-3","DOIUrl":"10.1038/s41571-025-01011-3","url":null,"abstract":"Advances in targeted therapies for patients with non-small-cell lung cancer have substantially improved the outcomes of those with actionable alterations in certain oncogenic driver genes. However, acquired resistance to these targeted therapies remains a major challenge. Understanding the mechanisms underlying acquired resistance will be crucial for the development of strategies that might either overcome this effect or delay the onset. Circulating tumour DNA, owing to the need for only minimally invasive sampling and a potential role as both a prognostic and predictive biomarker, is increasingly being used in both research and clinical practice. Several studies have explored the landscape of acquired resistance to targeted therapies using this approach. However, the methodologies of the published studies vary widely, and several major challenges remain in addressing the practical difficulties associated with these methods. These challenges currently limit the depth of research insight provided by the available data. In this Perspective, we review clinical reports describing the use of circulating tumour DNA to detect mechanisms of acquired resistance to targeted therapies, predominantly in patients with advanced-stage non-small-cell lung cancer, and highlight key unresolved questions with the aim of moving towards more-informative research studies. Acquired resistance is a common occurrence among patients with oncogene-driven non-small-cell lung cancer receiving targeted therapies. Monitoring of circulating tumour DNA in liquid biopsy samples provides an appealing, minimally invasive method of monitoring for acquired resistance in this setting. However, research into detecting mechanisms of acquired resistance in liquid biopsy samples has thus far been limited by various challenges. In this Perspective, the authors describe the available data on detecting mechanisms of acquired resistance to targeted therapies in patients with non-small-cell lung cancer, as well as the various challenges to progress, such as a lack of a consensus definition of acquired resistance, and other inconsistencies in the approach to detecting and investigating these alterations.","PeriodicalId":19079,"journal":{"name":"Nature Reviews Clinical Oncology","volume":"22 5","pages":"371-378"},"PeriodicalIF":82.2,"publicationDate":"2025-03-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143627420","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":"Reduced-volume radiotherapy for locally advanced NPC improves QOL without compromising efficacy","authors":"David Killock","doi":"10.1038/s41571-025-01014-0","DOIUrl":"10.1038/s41571-025-01014-0","url":null,"abstract":"","PeriodicalId":19079,"journal":{"name":"Nature Reviews Clinical Oncology","volume":"22 5","pages":"307-307"},"PeriodicalIF":82.2,"publicationDate":"2025-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143589669","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":"Hodgkin lymphoma: great progress with room for improvement","authors":"Paul J. Bröckelmann","doi":"10.1038/s41571-025-01012-2","DOIUrl":"10.1038/s41571-025-01012-2","url":null,"abstract":"First-line treatment of advanced-stage classic Hodgkin lymphoma (HL) has successfully entered the era of targeted agents based on results from the phase III German Hodgkin Study Group HD21 and US intergroup S1826 trials. Although these trials bring about important advances, many uncertainties remain and the outcomes of all patients with HL can be further improved.","PeriodicalId":19079,"journal":{"name":"Nature Reviews Clinical Oncology","volume":"22 6","pages":"379-381"},"PeriodicalIF":82.2,"publicationDate":"2025-03-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143583100","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":"MORPHEUS-Liver provides a way forward in expanding the immunotherapy options for hepatocellular carcinoma","authors":"Bruno Sangro, Josepmaria Argemí","doi":"10.1038/s41571-025-01009-x","DOIUrl":"10.1038/s41571-025-01009-x","url":null,"abstract":"Advanced-stage hepatocellular carcinoma is currently treated with various anti-PD-(L)1 antibody-containing regimens. Now, a triplet combining the anti-TIGIT antibody tiragolumab with one of these regimens has demonstrated promising efficacy in a phase Ib/II trial, although these data will need to be confirmed. This study highlights the value of umbrella trials while also raising questions regarding the most effective immune-targeting strategies in patients with this disease.","PeriodicalId":19079,"journal":{"name":"Nature Reviews Clinical Oncology","volume":"22 6","pages":"383-384"},"PeriodicalIF":82.2,"publicationDate":"2025-03-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143583099","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":"SOX superior to CAPOX in resectable G/GEJ cancer","authors":"Peter Sidaway","doi":"10.1038/s41571-025-01010-4","DOIUrl":"10.1038/s41571-025-01010-4","url":null,"abstract":"","PeriodicalId":19079,"journal":{"name":"Nature Reviews Clinical Oncology","volume":"22 5","pages":"308-308"},"PeriodicalIF":82.2,"publicationDate":"2025-03-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143560614","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":"Enhancing immunotherapy with tumour-responsive nanomaterials","authors":"Stephen W. Linderman, Louis DeRidder, Lucía Sanjurjo, Michael B. Foote, María José Alonso, Ameya R. Kirtane, Robert Langer, Giovanni Traverso","doi":"10.1038/s41571-025-01000-6","DOIUrl":"10.1038/s41571-025-01000-6","url":null,"abstract":"The targeted delivery of immunotherapies to tumours using tumour-responsive nanomaterials is a promising area of cancer research with the potential to address the limitations of systemic administration such as on-target off-tumour toxicities and a lack of activity owing to the immunosuppressive tumour microenvironment (TME). Attempts to address these challenges include the design and functionalization of nanomaterials capable of releasing their cargoes in response to specific TME characteristics, thus facilitating the targeted delivery of immune-checkpoint inhibitors, cytokines, mRNAs, vaccines and, potentially, chimaeric antigen receptors as well as of agents that modulate the extracellular matrix and induce immunogenic cell death. In this Review, we describe these various research efforts in the context of the dynamic properties of the TME, such as pH, reductive conditions, reactive oxygen species, hypoxia, specific enzymes, high levels of ATP and locoregional aspects, which can be leveraged to enhance the specificity and efficacy of nanomaterial-based immunotherapies. Highlighting preclinical successes and ongoing clinical trials, we evaluate the current landscape and potential of these innovative approaches. We also consider future research directions as well as the most important barriers to successful clinical translation, emphasizing the transformative potential of tumour-responsive nanomaterials in overcoming the barriers that limit the activity of traditional immunotherapies, thus improving patient outcomes. Immunotherapies, predominantly immune-checkpoint inhibitors and chimaeric antigen receptor T cells, have transformed oncology. Nonetheless, these systemically administered agents have several limitations, including the risk of off-target toxicities and a lack of activity owing to an inability to overcome an immunosuppressive tumour microenvironment (TME). In this Review, the authors describe the potential to overcome these challenges using functionalized nanomaterials that are designed to release a wide range of immunotherapeutic cargoes in response to specific TME characteristics, including hypoxia, differences in pH, the presence of specific enzymes, reactive oxygen species and/or high levels of extracellular ATP.","PeriodicalId":19079,"journal":{"name":"Nature Reviews Clinical Oncology","volume":"22 4","pages":"262-282"},"PeriodicalIF":81.1,"publicationDate":"2025-03-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143561283","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":"Will I feel better? Raising the bar for quality of life in oncology","authors":"Ariadna Tibau, Alejandra Romano, Aaron S. Kesselheim","doi":"10.1038/s41571-025-01002-4","DOIUrl":"10.1038/s41571-025-01002-4","url":null,"abstract":"Patients with advanced-stage cancer seek treatments that prolong survival and improve quality of life. We analysed new anticancer drug indications approved by the FDA and EMA between 2020 and 2023 using the European Society for Medical Oncology-Magnitude of Clinical Benefit Scale quality-of-life checklist. Our findings highlight critical gaps in the availability and reliability of quality-of-life outcomes from the pivotal trials that support these approvals.","PeriodicalId":19079,"journal":{"name":"Nature Reviews Clinical Oncology","volume":"22 4","pages":"235-236"},"PeriodicalIF":81.1,"publicationDate":"2025-02-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143517865","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":"Emerging clinical applications of single-cell RNA sequencing in oncology","authors":"Emily Boxer, Nisan Feigin, Roi Tschernichovsky, Noam Galili Darnell, Alissa R. Greenwald, Rouven Hoefflin, Daniel Kovarsky, Dor Simkin, Shira Turgeman, Lingling Zhang, Itay Tirosh","doi":"10.1038/s41571-025-01003-3","DOIUrl":"10.1038/s41571-025-01003-3","url":null,"abstract":"Single-cell RNA sequencing (scRNA-seq) has revolutionized our understanding of complex tissues both in health and in disease. Over the past decade, scRNA-seq has been applied to tumour samples obtained from patients with cancer in hundreds of studies, thereby advancing the view that each tumour is a complex ecosystem and uncovering the diverse states of both cancer cells and the tumour microenvironment. Such studies have primarily investigated and provided insights into the basic biology of cancer, although considerable research interest exists in leveraging these findings towards clinical applications. In this Review, we summarize the available data from scRNA-seq studies investigating samples from patients with cancer with a particular focus on findings that are of potential clinical relevance. We highlight four main research objectives of scRNA-seq studies and describe some of the most relevant findings towards such goals. We also describe the limitations of scRNA-seq, as well as future approaches in this field that are anticipated to further advance clinical applicability. Single-cell RNA sequencing has transformed our understanding of the biology of cancer cells and that of nonmalignant cells present in the tumour microenvironment. However, how this new knowledge can be translated into improved outcomes for patients often remains uncertain. In this Review, the authors describe the results of single-cell RNA analyses of samples from patients with cancer with an emphasis on how the findings of these studies have, or are anticipated to lead to, improved patient outcomes, with a focus on four key aspects: refinement of tumour subtyping, characterization of treatment-induced changes, identification of gene expression programmes predictive of treatment response and resistance, and the discovery of novel therapeutic targets.","PeriodicalId":19079,"journal":{"name":"Nature Reviews Clinical Oncology","volume":"22 5","pages":"315-326"},"PeriodicalIF":82.2,"publicationDate":"2025-02-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143518494","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}