Pub Date : 2025-06-17DOI: 10.1038/s41571-025-01035-9
Shen Zhao, Hongyun Zhao, Weiwei Yang, Li Zhang
Immunotherapies, specifically immune-checkpoint inhibitors (ICIs) targeting PD-(L)1 or CTLA4, have revolutionized the treatment of lung cancer; however, many patients do not have a response to ICIs and most of those with an initial tumour response eventually have disease progression owing to acquired resistance. Over the past few years, numerous therapeutic strategies have been explored to address the problems of intrinsic and acquired resistance to ICIs. In 2024, regulatory approvals of the bispecific PD-1 × VEGF antibody ivonescimab for the treatment of non-small-cell lung cancer in China and the bispecific DLL3 × CD3 T cell engager tarlatamab for patients with small cell lung cancer in the USA provided clinical proof-of-concept for overcoming the challenge of ICI resistance using novel immunotherapeutic agents, thereby increasing enthusiasm for the exploration of next-generation immunotherapies for lung cancer. A large variety of immunotherapies with diverse targets and mechanisms of action are currently being tested in clinical trials involving patients with lung cancer. In this Review, we provide an overview of these emerging immunotherapies in clinical development for non-small-cell lung cancer and/or small cell lung cancer, including novel immune-checkpoint modulators, immune cell engagers, adoptive cell therapies and therapeutic cancer vaccines. We describe the designs of these agents and the mechanisms by which they might overcome resistance to the current generation of ICIs. We also discuss hurdles impeding the clinical translation of each immunotherapeutic modality and potential strategies to address these challenges, using representative examples of agents that have entered the later phases of clinical testing. Immune-checkpoint inhibitors (ICIs) have improved lung cancer outcomes, although resistance to these agents presents a substantial challenge. This Review describes the progress made in developing the next generation of immunotherapies for non-small-cell and small cell lung cancers, including novel immune-checkpoint modulators, immune cell engagers, adoptive cell therapies and therapeutic vaccines, as well as the mechanisms by which these agents might overcome resistance to the current generation of ICIs.
{"title":"The next generation of immunotherapies for lung cancers","authors":"Shen Zhao, Hongyun Zhao, Weiwei Yang, Li Zhang","doi":"10.1038/s41571-025-01035-9","DOIUrl":"10.1038/s41571-025-01035-9","url":null,"abstract":"Immunotherapies, specifically immune-checkpoint inhibitors (ICIs) targeting PD-(L)1 or CTLA4, have revolutionized the treatment of lung cancer; however, many patients do not have a response to ICIs and most of those with an initial tumour response eventually have disease progression owing to acquired resistance. Over the past few years, numerous therapeutic strategies have been explored to address the problems of intrinsic and acquired resistance to ICIs. In 2024, regulatory approvals of the bispecific PD-1 × VEGF antibody ivonescimab for the treatment of non-small-cell lung cancer in China and the bispecific DLL3 × CD3 T cell engager tarlatamab for patients with small cell lung cancer in the USA provided clinical proof-of-concept for overcoming the challenge of ICI resistance using novel immunotherapeutic agents, thereby increasing enthusiasm for the exploration of next-generation immunotherapies for lung cancer. A large variety of immunotherapies with diverse targets and mechanisms of action are currently being tested in clinical trials involving patients with lung cancer. In this Review, we provide an overview of these emerging immunotherapies in clinical development for non-small-cell lung cancer and/or small cell lung cancer, including novel immune-checkpoint modulators, immune cell engagers, adoptive cell therapies and therapeutic cancer vaccines. We describe the designs of these agents and the mechanisms by which they might overcome resistance to the current generation of ICIs. We also discuss hurdles impeding the clinical translation of each immunotherapeutic modality and potential strategies to address these challenges, using representative examples of agents that have entered the later phases of clinical testing. Immune-checkpoint inhibitors (ICIs) have improved lung cancer outcomes, although resistance to these agents presents a substantial challenge. This Review describes the progress made in developing the next generation of immunotherapies for non-small-cell and small cell lung cancers, including novel immune-checkpoint modulators, immune cell engagers, adoptive cell therapies and therapeutic vaccines, as well as the mechanisms by which these agents might overcome resistance to the current generation of ICIs.","PeriodicalId":19079,"journal":{"name":"Nature Reviews Clinical Oncology","volume":"22 8","pages":"592-616"},"PeriodicalIF":82.2,"publicationDate":"2025-06-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144305168","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 : 2025-06-13DOI: 10.1038/s41571-025-01033-x
Jonathan C. M. Wan, Peter Sasieni, Nitzan Rosenfeld
Cancer screening is an essential public health intervention for diagnosing cancers at an early stage that can enable earlier treatment — ideally with curative intent — and thus lead to improved outcomes. Over the past decade, liquid biopsy-based tests have emerged as a promising, minimally invasive and broadly applicable screening approach by combining multi-cancer early detection (MCED) with tumour tissue-of-origin identification. Large-scale randomized clinical trials evaluating liquid biopsy-based MCED approaches are now under way, although whether the diagnostic performance of this first generation of MCED tests is sufficient to translate into clinical benefits remains to be determined. In this Review, we discuss the promises and pitfalls of current MCED tests and highlight possible trajectories for the field of early cancer detection. Liquid biopsy-based tests have demonstrated potential as a minimally invasive and broadly applicable approach to simultaneously screen individuals for multiple cancer types. In this Review, Wan, Sasieni and Rosenfeld discuss the promises and limitations of such multi-cancer early detection tests as well as future directions for this field.
{"title":"Promises and pitfalls of multi-cancer early detection using liquid biopsy tests","authors":"Jonathan C. M. Wan, Peter Sasieni, Nitzan Rosenfeld","doi":"10.1038/s41571-025-01033-x","DOIUrl":"10.1038/s41571-025-01033-x","url":null,"abstract":"Cancer screening is an essential public health intervention for diagnosing cancers at an early stage that can enable earlier treatment — ideally with curative intent — and thus lead to improved outcomes. Over the past decade, liquid biopsy-based tests have emerged as a promising, minimally invasive and broadly applicable screening approach by combining multi-cancer early detection (MCED) with tumour tissue-of-origin identification. Large-scale randomized clinical trials evaluating liquid biopsy-based MCED approaches are now under way, although whether the diagnostic performance of this first generation of MCED tests is sufficient to translate into clinical benefits remains to be determined. In this Review, we discuss the promises and pitfalls of current MCED tests and highlight possible trajectories for the field of early cancer detection. Liquid biopsy-based tests have demonstrated potential as a minimally invasive and broadly applicable approach to simultaneously screen individuals for multiple cancer types. In this Review, Wan, Sasieni and Rosenfeld discuss the promises and limitations of such multi-cancer early detection tests as well as future directions for this field.","PeriodicalId":19079,"journal":{"name":"Nature Reviews Clinical Oncology","volume":"22 8","pages":"566-580"},"PeriodicalIF":82.2,"publicationDate":"2025-06-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144288632","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}
Lung cancer remains the leading cause of cancer-related mortality globally, with many patients diagnosed with advanced-stage disease. Treatment in this setting relies on systemic therapies, including chemotherapy, targeted therapy and immunotherapy. Immune-checkpoint inhibitors (ICIs), which promote or restore antitumour immunity by inhibiting immunosuppressive signalling pathways, are currently the most widely used immunotherapies in these patients. However, immune-related adverse events (irAEs) or disease progression often necessitate discontinuation of these agents, leaving many patients with limited subsequent treatment options. In this scenario, ICI rechallenge has emerged as a potential strategy. Despite this potential, evidence for ICI rechallenge after either disease progression or irAEs in patients with non-small-cell lung cancer is limited and evidence for those with small cell lung cancer seems to be non-existent. In this Review, we provide a comprehensive overview of the available data on ICI rechallenge in the context of both disease progression and irAEs, including a summary of current guidance on clinical management and detailed discussions of safety and efficacy. We also highlight important unanswered questions in an attempt to guide future research in this area. Patients with advanced-stage lung cancer might discontinue immune-checkpoint inhibitor (ICI) treatment for various reasons, including toxicities, disease progression or disease remission. Nonetheless, treatment options in this setting are often limited and some patients might derive benefit from re-administration of a previously received ICI. In this Review, the authors summarize the available data on ICI rechallenge, including the reasons for discontinuation and the feasibility of rechallenge in various clinical scenarios, and highlight important unaddressed research questions.
{"title":"Rechallenge with immune-checkpoint inhibitors in patients with advanced-stage lung cancer","authors":"Li-Bo Tang, Ying-Long Peng, Ji Chen, Jia-Ting Li, Mei-Mei Zheng, Lv Wu, Chang Lu, Xue-Wu Wei, Dong-Xuan Cai, Zhi Guo, Zi-Rui Ren, Si-Di Lv, Yu Deng, Zhi-Hong Chen, Chong-Rui Xu, Qing Zhou","doi":"10.1038/s41571-025-01029-7","DOIUrl":"10.1038/s41571-025-01029-7","url":null,"abstract":"Lung cancer remains the leading cause of cancer-related mortality globally, with many patients diagnosed with advanced-stage disease. Treatment in this setting relies on systemic therapies, including chemotherapy, targeted therapy and immunotherapy. Immune-checkpoint inhibitors (ICIs), which promote or restore antitumour immunity by inhibiting immunosuppressive signalling pathways, are currently the most widely used immunotherapies in these patients. However, immune-related adverse events (irAEs) or disease progression often necessitate discontinuation of these agents, leaving many patients with limited subsequent treatment options. In this scenario, ICI rechallenge has emerged as a potential strategy. Despite this potential, evidence for ICI rechallenge after either disease progression or irAEs in patients with non-small-cell lung cancer is limited and evidence for those with small cell lung cancer seems to be non-existent. In this Review, we provide a comprehensive overview of the available data on ICI rechallenge in the context of both disease progression and irAEs, including a summary of current guidance on clinical management and detailed discussions of safety and efficacy. We also highlight important unanswered questions in an attempt to guide future research in this area. Patients with advanced-stage lung cancer might discontinue immune-checkpoint inhibitor (ICI) treatment for various reasons, including toxicities, disease progression or disease remission. Nonetheless, treatment options in this setting are often limited and some patients might derive benefit from re-administration of a previously received ICI. In this Review, the authors summarize the available data on ICI rechallenge, including the reasons for discontinuation and the feasibility of rechallenge in various clinical scenarios, and highlight important unaddressed research questions.","PeriodicalId":19079,"journal":{"name":"Nature Reviews Clinical Oncology","volume":"22 8","pages":"546-565"},"PeriodicalIF":82.2,"publicationDate":"2025-06-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144237819","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 : 2025-06-09DOI: 10.1038/s41571-025-01040-y
Neil Carleton, Priscilla F. McAuliffe
Many women ≥75 years of age continue to undergo screening for breast cancer despite a lack of evidence supporting this practice. Evidence from the past 5 years suggests rising rates of breast cancer diagnosis in this age group without a corresponding increase in survival — either because the tumour itself is biologically indolent or because life-limiting comorbidities render a biologically aggressive tumour unlikely to further reduce life expectancy. Here, we review what we know, and what we do not know, about screening and overdiagnosis of breast cancer in women ≥75 years of age and build a case for active monitoring for selected screen-detected breast cancers in this population.
{"title":"Overdiagnosis, competing morbidity and tumour biology in older women with breast cancer: building a case for active monitoring","authors":"Neil Carleton, Priscilla F. McAuliffe","doi":"10.1038/s41571-025-01040-y","DOIUrl":"10.1038/s41571-025-01040-y","url":null,"abstract":"Many women ≥75 years of age continue to undergo screening for breast cancer despite a lack of evidence supporting this practice. Evidence from the past 5 years suggests rising rates of breast cancer diagnosis in this age group without a corresponding increase in survival — either because the tumour itself is biologically indolent or because life-limiting comorbidities render a biologically aggressive tumour unlikely to further reduce life expectancy. Here, we review what we know, and what we do not know, about screening and overdiagnosis of breast cancer in women ≥75 years of age and build a case for active monitoring for selected screen-detected breast cancers in this population.","PeriodicalId":19079,"journal":{"name":"Nature Reviews Clinical Oncology","volume":"22 9","pages":"621-622"},"PeriodicalIF":82.2,"publicationDate":"2025-06-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144237815","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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