Pub Date : 2025-09-22DOI: 10.1038/s41571-025-01076-0
Hejia Henry Wang, Mark Yarchoan
Final results from the phase I AMPLIFY-201 trial show that ELI-002 2P, a therapeutic cancer vaccine targeting mutant KRAS, elicits polyfunctional T cell responses in patients with minimal residual disease-positive pancreatic or colorectal cancer. Importantly, the magnitude of this response correlated with improved clinical outcomes. Herein, we discuss how these results could set the stage for ongoing randomized trials.
{"title":"Neoantigen vaccines at the crossroads: lessons from AMPLIFY-201","authors":"Hejia Henry Wang, Mark Yarchoan","doi":"10.1038/s41571-025-01076-0","DOIUrl":"10.1038/s41571-025-01076-0","url":null,"abstract":"Final results from the phase I AMPLIFY-201 trial show that ELI-002 2P, a therapeutic cancer vaccine targeting mutant KRAS, elicits polyfunctional T cell responses in patients with minimal residual disease-positive pancreatic or colorectal cancer. Importantly, the magnitude of this response correlated with improved clinical outcomes. Herein, we discuss how these results could set the stage for ongoing randomized trials.","PeriodicalId":19079,"journal":{"name":"Nature Reviews Clinical Oncology","volume":"23 1","pages":"3-4"},"PeriodicalIF":82.2,"publicationDate":"2025-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145116798","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 : 2025-09-19DOI: 10.1038/s41571-025-01072-4
Karl Petri, Elvira D’Ippolito, Annette Künkele, Ulrike Köhl, Dirk H. Busch, Hermann Einsele, Michael Hudecek
T cells can be reprogrammed with transgenic antigen recognition receptors, including chimeric antigen receptors and T cell receptors, to selectively recognize and kill cancer cells. Such adoptive T cell therapies are effective in patients with certain haematological cancers but challenges persist, including primary and secondary resistance, a lack of efficacy in patients with solid tumours, a narrow range of targetable antigens, and time-consuming and complex manufacturing processes. CRISPR-based genome editing is a potent strategy to enhance cellular immunotherapies. Conventional CRISPR–Cas9 systems are useful for gene editing, transgene knock-in or gene knockout but can result in undesired editing outcomes, including translocations and chromosomal truncations. Base editing and prime editing technologies constitute a new generation of CRISPR platforms and enable highly precise and programmable installation of defined nucleotide variants in primary T cells. Owing to their high precision and versatility, base editing and prime editing systems, hereafter collectively referred to as CRISPR 2.0, are advancing to become the new standard for precision-engineering of cellular immunotherapies. CRISPR 2.0 can be used to augment immune cell function, broaden the spectrum of targetable antigens and facilitate streamlined production of T cell therapies. Notably, CRISPR 2.0 is reaching clinical maturity, with multiple clinical trials of CRISPR 2.0-modified cellular therapies currently ongoing. In this Review, we discuss emerging CRISPR 2.0 technologies and their progress towards clinical translation, highlighting challenges and opportunities, and describe strategies for the use of CRISPR 2.0 to advance cellular immunotherapy for haematological malignancies and solid tumours in the future. Several persistent challenges limit the efficacy and applicability of adoptive T cell therapies for cancer, including suboptimal function and/or persistence in vivo, a narrow range of targetable antigens and complex manufacturing processes. This Review discusses the potential of ‘CRISPR 2.0’ precision gene-editing platforms, such as base editing and prime editing to address all of these challenges, and describes the progress made towards clinical translation of these technologies.
{"title":"Next-generation T cell immunotherapies engineered with CRISPR base and prime editing: challenges and opportunities","authors":"Karl Petri, Elvira D’Ippolito, Annette Künkele, Ulrike Köhl, Dirk H. Busch, Hermann Einsele, Michael Hudecek","doi":"10.1038/s41571-025-01072-4","DOIUrl":"10.1038/s41571-025-01072-4","url":null,"abstract":"T cells can be reprogrammed with transgenic antigen recognition receptors, including chimeric antigen receptors and T cell receptors, to selectively recognize and kill cancer cells. Such adoptive T cell therapies are effective in patients with certain haematological cancers but challenges persist, including primary and secondary resistance, a lack of efficacy in patients with solid tumours, a narrow range of targetable antigens, and time-consuming and complex manufacturing processes. CRISPR-based genome editing is a potent strategy to enhance cellular immunotherapies. Conventional CRISPR–Cas9 systems are useful for gene editing, transgene knock-in or gene knockout but can result in undesired editing outcomes, including translocations and chromosomal truncations. Base editing and prime editing technologies constitute a new generation of CRISPR platforms and enable highly precise and programmable installation of defined nucleotide variants in primary T cells. Owing to their high precision and versatility, base editing and prime editing systems, hereafter collectively referred to as CRISPR 2.0, are advancing to become the new standard for precision-engineering of cellular immunotherapies. CRISPR 2.0 can be used to augment immune cell function, broaden the spectrum of targetable antigens and facilitate streamlined production of T cell therapies. Notably, CRISPR 2.0 is reaching clinical maturity, with multiple clinical trials of CRISPR 2.0-modified cellular therapies currently ongoing. In this Review, we discuss emerging CRISPR 2.0 technologies and their progress towards clinical translation, highlighting challenges and opportunities, and describe strategies for the use of CRISPR 2.0 to advance cellular immunotherapy for haematological malignancies and solid tumours in the future. Several persistent challenges limit the efficacy and applicability of adoptive T cell therapies for cancer, including suboptimal function and/or persistence in vivo, a narrow range of targetable antigens and complex manufacturing processes. This Review discusses the potential of ‘CRISPR 2.0’ precision gene-editing platforms, such as base editing and prime editing to address all of these challenges, and describes the progress made towards clinical translation of these technologies.","PeriodicalId":19079,"journal":{"name":"Nature Reviews Clinical Oncology","volume":"22 12","pages":"902-923"},"PeriodicalIF":82.2,"publicationDate":"2025-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145089761","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 : 2025-09-09DOI: 10.1038/s41571-025-01069-z
Irina Primac, Kevin Tabury, Alpaslan Tasdogan, Sarah Baatout, Ken Herrmann
Targeted radionuclide therapy (TRT) is a cutting-edge treatment approach in oncology that combines the molecular precision of targeted agents with the effect of radiotherapy to selectively deliver cytotoxic radiation to cancer cells. Research efforts from the past few decades have led to a diverse molecular landscape of TRT and have provided lessons for further rational development of targeted radiopharmaceuticals and expansion of the clinical applications of this treatment modality. In this Review, we discuss TRT in the context of therapeutic approaches currently available in oncology, describe the broad range of established and emerging targets for TRT including innovative approaches to exploit vulnerabilities presented by the tumour microenvironment, and address the challenges for clinical translation and molecular optimization. By bridging technological innovation and preclinical discoveries with real-world clinical implementation, ongoing research on TRT is seeking to provide effective and safe treatment options for patients across a variety of cancer types and treatment settings. Overall, we emphasize the transformative potential of TRT and highlight how a comprehensive understanding of what constitutes an optimal target can redefine clinical practice, fostering the evolution of TRT as a highly individualized and adaptable therapeutic option that improves outcomes across a broad range of cancer types. Targeted radionuclide therapy (TRT) is a therapeutic modality that combines the strengths of radiotherapy and systemic molecularly targeted therapy. Over the past few years, new TRT agents have been developed against an expanding array of molecular targets, particularly in cancers with limited treatment options. The authors of this Review discuss these advances, focusing on what constitutes an optimal target and discussing lessons learned from past experience in order to broaden the scope of TRT.
{"title":"The molecular blueprint of targeted radionuclide therapy","authors":"Irina Primac, Kevin Tabury, Alpaslan Tasdogan, Sarah Baatout, Ken Herrmann","doi":"10.1038/s41571-025-01069-z","DOIUrl":"10.1038/s41571-025-01069-z","url":null,"abstract":"Targeted radionuclide therapy (TRT) is a cutting-edge treatment approach in oncology that combines the molecular precision of targeted agents with the effect of radiotherapy to selectively deliver cytotoxic radiation to cancer cells. Research efforts from the past few decades have led to a diverse molecular landscape of TRT and have provided lessons for further rational development of targeted radiopharmaceuticals and expansion of the clinical applications of this treatment modality. In this Review, we discuss TRT in the context of therapeutic approaches currently available in oncology, describe the broad range of established and emerging targets for TRT including innovative approaches to exploit vulnerabilities presented by the tumour microenvironment, and address the challenges for clinical translation and molecular optimization. By bridging technological innovation and preclinical discoveries with real-world clinical implementation, ongoing research on TRT is seeking to provide effective and safe treatment options for patients across a variety of cancer types and treatment settings. Overall, we emphasize the transformative potential of TRT and highlight how a comprehensive understanding of what constitutes an optimal target can redefine clinical practice, fostering the evolution of TRT as a highly individualized and adaptable therapeutic option that improves outcomes across a broad range of cancer types. Targeted radionuclide therapy (TRT) is a therapeutic modality that combines the strengths of radiotherapy and systemic molecularly targeted therapy. Over the past few years, new TRT agents have been developed against an expanding array of molecular targets, particularly in cancers with limited treatment options. The authors of this Review discuss these advances, focusing on what constitutes an optimal target and discussing lessons learned from past experience in order to broaden the scope of TRT.","PeriodicalId":19079,"journal":{"name":"Nature Reviews Clinical Oncology","volume":"22 11","pages":"869-894"},"PeriodicalIF":82.2,"publicationDate":"2025-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41571-025-01069-z.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145017651","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 : 2025-09-03DOI: 10.1038/s41571-025-01073-3
Saroj Niraula, Ian F. Tannock
Some of the most consequential conflicts in oncology and medicine overall are not financial; these remain poorly defined and weakly regulated. Here we offer a policy-relevant definition and examine how reputation, ambition, ideology and institutional loyalty can shape research, guidelines, policy and hiring decisions. We argue for structural safeguards to preserve trust in medicine.
{"title":"Non-financial conflicts of interest","authors":"Saroj Niraula, Ian F. Tannock","doi":"10.1038/s41571-025-01073-3","DOIUrl":"10.1038/s41571-025-01073-3","url":null,"abstract":"Some of the most consequential conflicts in oncology and medicine overall are not financial; these remain poorly defined and weakly regulated. Here we offer a policy-relevant definition and examine how reputation, ambition, ideology and institutional loyalty can shape research, guidelines, policy and hiring decisions. We argue for structural safeguards to preserve trust in medicine.","PeriodicalId":19079,"journal":{"name":"Nature Reviews Clinical Oncology","volume":"22 12","pages":"895-897"},"PeriodicalIF":82.2,"publicationDate":"2025-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144930597","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 : 2025-09-03DOI: 10.1038/s41571-025-01067-1
Philippe Lambin, Henry C. Woodruff, Shruti Atul Mali, Xian Zhong, Sheng Kuang, Elizaveta Lavrova, Hamza Khan, Karim Lekadir, Alex Zwanenburg, Joseph Deasy, Maciej Bobowicz, Luis Marti-Bonmati, Andrew Maidment, Michel Dumontier, Paul E. Kinahan, J. Martijn Nobel, Sina Amirrajab, Zohaib Salahuddin
Radiomics is a tool for medical imaging analysis that could have a relevant role in precision oncology by offering precise quantitative support for clinical decision-making. The Radiomics Quality Score (RQS) is a tool developed to assess the rigour of radiomics studies that has now been widely adopted by researchers. Although RQS version 1.0 established a benchmark, an updated framework is required to account for evolving knowledge and ensure optimal evaluation of the quality of radiomics studies through the inclusion of fairness, explainability, rigorous quality control and harmonization. In this Review, we introduce the updated RQS 2.0, which maintains the scientific rigour of its predecessor and addresses these contemporary needs, and therefore could potentially accelerate clinical translation. Moreover, we introduce the radiomics readiness levels, inspired by the technology readiness level framework, which are integrated in RQS 2.0 and reflect nine distinct levels of incremental improvement in radiomics research with the ultimate aim of clinical implementation. We also detail anticipated future directions in radiomics, outlining a strategic vision to advance precision oncology, which is the ultimate aim of RQS 2.0. The Radiomics Quality Score (RQS) was developed to assess the rigour of studies using radiomics, a tool for medical imaging analysis. The RQS has been widely used in the field and now needs an update (RQS 2.0) to address contemporary needs. The authors of this Review introduce RQS 2.0, which integrates radiomics readiness levels to provide a structured framework towards clinical implementation.
{"title":"Radiomics Quality Score 2.0: towards radiomics readiness levels and clinical translation for personalized medicine","authors":"Philippe Lambin, Henry C. Woodruff, Shruti Atul Mali, Xian Zhong, Sheng Kuang, Elizaveta Lavrova, Hamza Khan, Karim Lekadir, Alex Zwanenburg, Joseph Deasy, Maciej Bobowicz, Luis Marti-Bonmati, Andrew Maidment, Michel Dumontier, Paul E. Kinahan, J. Martijn Nobel, Sina Amirrajab, Zohaib Salahuddin","doi":"10.1038/s41571-025-01067-1","DOIUrl":"10.1038/s41571-025-01067-1","url":null,"abstract":"Radiomics is a tool for medical imaging analysis that could have a relevant role in precision oncology by offering precise quantitative support for clinical decision-making. The Radiomics Quality Score (RQS) is a tool developed to assess the rigour of radiomics studies that has now been widely adopted by researchers. Although RQS version 1.0 established a benchmark, an updated framework is required to account for evolving knowledge and ensure optimal evaluation of the quality of radiomics studies through the inclusion of fairness, explainability, rigorous quality control and harmonization. In this Review, we introduce the updated RQS 2.0, which maintains the scientific rigour of its predecessor and addresses these contemporary needs, and therefore could potentially accelerate clinical translation. Moreover, we introduce the radiomics readiness levels, inspired by the technology readiness level framework, which are integrated in RQS 2.0 and reflect nine distinct levels of incremental improvement in radiomics research with the ultimate aim of clinical implementation. We also detail anticipated future directions in radiomics, outlining a strategic vision to advance precision oncology, which is the ultimate aim of RQS 2.0. The Radiomics Quality Score (RQS) was developed to assess the rigour of studies using radiomics, a tool for medical imaging analysis. The RQS has been widely used in the field and now needs an update (RQS 2.0) to address contemporary needs. The authors of this Review introduce RQS 2.0, which integrates radiomics readiness levels to provide a structured framework towards clinical implementation.","PeriodicalId":19079,"journal":{"name":"Nature Reviews Clinical Oncology","volume":"22 11","pages":"831-846"},"PeriodicalIF":82.2,"publicationDate":"2025-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144930598","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 : 2025-09-01DOI: 10.1038/s41571-025-01068-0
Antonino Glaviano, Ellen Weisberg, Hiu Y. Lam, Donavan J. J. Tan, Andrew J. Innes, Yubin Ge, Catherine E. Lai, Wendy Stock, Christina Glytsou, Linda Smit, Tatsushi Yoshida, Tian Y. Zhang, Vanessa E. Kennedy, B. Douglas Smith, Thomas Mercher, Stéphane de Botton, Patrizia Diana, Marina Konopleva, Michael J. Mauro, James D. Griffin, Courtney D. DiNardo, Alan P. Kumar
Acute myeloid leukaemia (AML) remains a challenging haematological malignancy, with most patients developing resistance to standard-of-care (SOC) treatments. This resistance is often attributed to the overexpression of anti-apoptotic BCL-2 family proteins, which regulate the intrinsic apoptotic pathway by inhibiting pro-apoptotic effector proteins such as BAX and BAK. AML cells exploit this imbalance to evade apoptosis and sustain survival, necessitating the development of novel therapeutic strategies. BH3 mimetics are small-molecule inhibitors targeting the pro-survival BCL-2 family proteins and have emerged as promising agents in patients with AML who are unable to receive high-intensity induction chemotherapy. Co-treatment with the BCL-2-specific inhibitor venetoclax and various SOC therapies has been proven effective, with several combinations now approved by the US Food and Drug Administration for adults with AML who are ≥75 years of age and/or are ineligible for intensive induction chemotherapy, on the basis of improved response rates and survival outcomes compared with the previous SOC. In this Review, we highlight the transformative potential of BH3 mimetics in AML therapy, including ongoing studies investigating novel combination regimens and efforts to further refine treatment strategies, with the ultimate goal of improving outcomes for patients with AML. Patients with acute myeloid leukaemia are often unable to tolerate intensive chemotherapy, and the outcomes of these patients have improved considerably following the availability of regimens containing the BH3 mimetic venetoclax. Nonetheless, not all of these patients will respond to venetoclax, and virtually all will ultimately develop resistance, indicating a need for novel treatment strategies targeting this pathway. In this Review, the authors describe the development of BCL-2 inhibitors, discuss mechanisms of resistance and summarize ongoing research efforts aimed at optimizing the therapeutic benefit of these agents.
{"title":"Apoptosis-targeting BH3 mimetics: transforming treatment for patients with acute myeloid leukaemia","authors":"Antonino Glaviano, Ellen Weisberg, Hiu Y. Lam, Donavan J. J. Tan, Andrew J. Innes, Yubin Ge, Catherine E. Lai, Wendy Stock, Christina Glytsou, Linda Smit, Tatsushi Yoshida, Tian Y. Zhang, Vanessa E. Kennedy, B. Douglas Smith, Thomas Mercher, Stéphane de Botton, Patrizia Diana, Marina Konopleva, Michael J. Mauro, James D. Griffin, Courtney D. DiNardo, Alan P. Kumar","doi":"10.1038/s41571-025-01068-0","DOIUrl":"10.1038/s41571-025-01068-0","url":null,"abstract":"Acute myeloid leukaemia (AML) remains a challenging haematological malignancy, with most patients developing resistance to standard-of-care (SOC) treatments. This resistance is often attributed to the overexpression of anti-apoptotic BCL-2 family proteins, which regulate the intrinsic apoptotic pathway by inhibiting pro-apoptotic effector proteins such as BAX and BAK. AML cells exploit this imbalance to evade apoptosis and sustain survival, necessitating the development of novel therapeutic strategies. BH3 mimetics are small-molecule inhibitors targeting the pro-survival BCL-2 family proteins and have emerged as promising agents in patients with AML who are unable to receive high-intensity induction chemotherapy. Co-treatment with the BCL-2-specific inhibitor venetoclax and various SOC therapies has been proven effective, with several combinations now approved by the US Food and Drug Administration for adults with AML who are ≥75 years of age and/or are ineligible for intensive induction chemotherapy, on the basis of improved response rates and survival outcomes compared with the previous SOC. In this Review, we highlight the transformative potential of BH3 mimetics in AML therapy, including ongoing studies investigating novel combination regimens and efforts to further refine treatment strategies, with the ultimate goal of improving outcomes for patients with AML. Patients with acute myeloid leukaemia are often unable to tolerate intensive chemotherapy, and the outcomes of these patients have improved considerably following the availability of regimens containing the BH3 mimetic venetoclax. Nonetheless, not all of these patients will respond to venetoclax, and virtually all will ultimately develop resistance, indicating a need for novel treatment strategies targeting this pathway. In this Review, the authors describe the development of BCL-2 inhibitors, discuss mechanisms of resistance and summarize ongoing research efforts aimed at optimizing the therapeutic benefit of these agents.","PeriodicalId":19079,"journal":{"name":"Nature Reviews Clinical Oncology","volume":"22 11","pages":"847-868"},"PeriodicalIF":82.2,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144928550","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 : 2025-08-26DOI: 10.1038/s41571-025-01071-5
Justin Y. Jeon
The landmark CHALLENGE trial has revealed that a 3-year structured, behaviourally supported exercise intervention substantially improves both disease-free and overall survival in patients with resected phase II–III colon cancer, marking a genuine paradigm shift in survivorship care. By demonstrating modification of the course of disease rather than merely symptom alleviation, these results elevate exercise from ancillary support to evidence-based therapy and should compel oncology teams to embed expert-guided exercise into routine care.
{"title":"Exercise as a new therapeutic modality in oncology: CHALLENGE trial refines survivorship care","authors":"Justin Y. Jeon","doi":"10.1038/s41571-025-01071-5","DOIUrl":"10.1038/s41571-025-01071-5","url":null,"abstract":"The landmark CHALLENGE trial has revealed that a 3-year structured, behaviourally supported exercise intervention substantially improves both disease-free and overall survival in patients with resected phase II–III colon cancer, marking a genuine paradigm shift in survivorship care. By demonstrating modification of the course of disease rather than merely symptom alleviation, these results elevate exercise from ancillary support to evidence-based therapy and should compel oncology teams to embed expert-guided exercise into routine care.","PeriodicalId":19079,"journal":{"name":"Nature Reviews Clinical Oncology","volume":"22 12","pages":"900-901"},"PeriodicalIF":82.2,"publicationDate":"2025-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144899073","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 : 2025-08-18DOI: 10.1038/s41571-025-01070-6
David Killock
{"title":"ASTER 70 suggests no clinical benefit from adjuvant chemotherapy in older patients with ER+HER2– breast cancer","authors":"David Killock","doi":"10.1038/s41571-025-01070-6","DOIUrl":"10.1038/s41571-025-01070-6","url":null,"abstract":"","PeriodicalId":19079,"journal":{"name":"Nature Reviews Clinical Oncology","volume":"22 10","pages":"707-707"},"PeriodicalIF":82.2,"publicationDate":"2025-08-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144874284","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 : 2025-08-14DOI: 10.1038/s41571-025-01061-7
Martin Reck, Nikolaj Frost, Solange Peters, Bernard A. Fox, Roberto Ferrara, Rajkumar Savai, Fabrice Barlesi
The treatment landscape of non-small-cell lung cancer (NSCLC) has evolved considerably with the integration of immune-checkpoint inhibitors (ICIs) into first-line regimens. However, the majority of patients will ultimately have primary resistance or develop secondary resistance, driven by a complex interplay of intrinsic tumour biology and adaptive changes within the tumour microenvironment (TME), which can be further amplified by host-related factors such as dysbiosis and organ-specific conditions. Despite these heterogeneous origins, most mechanisms of resistance to ICIs lead to an immunosuppressive TME as the final common pathway. Consequently, current strategies designed to overcome resistance aim to restore antitumour immunity via antibody-based therapies (including bispecific antibodies, T cell engagers and antibody–drug conjugates), targeted therapies, adoptive cell therapies, therapeutic vaccines or intratumoural immunotherapies. Although substantial progress has been made in identifying potential biomarkers associated with immune resistance, the clinical relevance of many of these observations remains limited. Biomarker-driven studies using adaptive, hypothesis-generating designs might offer a promising path forward by navigating the complexity of resistance and enabling the timely evaluation of novel therapeutic concepts. In this Review, we summarize the latest advances in addressing resistance to ICIs in patients with advanced-stage NSCLC and provide insights into emerging clinical strategies and future research directions. Immune-checkpoint inhibitors have dramatically improved the outcomes in patients with advanced-stage driver-negative non-small-cell lung cancer (NSCLC), although most patients will ultimately have disease progression on these agents and the most effective treatment approach in this scenario remains uncertain. In this Review, the authors describe the outcomes in patients receiving second-line therapy for advanced-stage NSCLC and provide an overview of emerging therapies and future areas of research in this challenging clinical setting.
{"title":"Treatment of NSCLC after chemoimmunotherapy — are we making headway?","authors":"Martin Reck, Nikolaj Frost, Solange Peters, Bernard A. Fox, Roberto Ferrara, Rajkumar Savai, Fabrice Barlesi","doi":"10.1038/s41571-025-01061-7","DOIUrl":"10.1038/s41571-025-01061-7","url":null,"abstract":"The treatment landscape of non-small-cell lung cancer (NSCLC) has evolved considerably with the integration of immune-checkpoint inhibitors (ICIs) into first-line regimens. However, the majority of patients will ultimately have primary resistance or develop secondary resistance, driven by a complex interplay of intrinsic tumour biology and adaptive changes within the tumour microenvironment (TME), which can be further amplified by host-related factors such as dysbiosis and organ-specific conditions. Despite these heterogeneous origins, most mechanisms of resistance to ICIs lead to an immunosuppressive TME as the final common pathway. Consequently, current strategies designed to overcome resistance aim to restore antitumour immunity via antibody-based therapies (including bispecific antibodies, T cell engagers and antibody–drug conjugates), targeted therapies, adoptive cell therapies, therapeutic vaccines or intratumoural immunotherapies. Although substantial progress has been made in identifying potential biomarkers associated with immune resistance, the clinical relevance of many of these observations remains limited. Biomarker-driven studies using adaptive, hypothesis-generating designs might offer a promising path forward by navigating the complexity of resistance and enabling the timely evaluation of novel therapeutic concepts. In this Review, we summarize the latest advances in addressing resistance to ICIs in patients with advanced-stage NSCLC and provide insights into emerging clinical strategies and future research directions. Immune-checkpoint inhibitors have dramatically improved the outcomes in patients with advanced-stage driver-negative non-small-cell lung cancer (NSCLC), although most patients will ultimately have disease progression on these agents and the most effective treatment approach in this scenario remains uncertain. In this Review, the authors describe the outcomes in patients receiving second-line therapy for advanced-stage NSCLC and provide an overview of emerging therapies and future areas of research in this challenging clinical setting.","PeriodicalId":19079,"journal":{"name":"Nature Reviews Clinical Oncology","volume":"22 11","pages":"806-830"},"PeriodicalIF":82.2,"publicationDate":"2025-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144850816","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}
京公网安备 11010802042870号
京ICP备2023020795号-1
扫码关注我们
求助内容：
应助结果提醒方式：