Pub Date : 2025-11-12DOI: 10.1038/s41568-025-00888-7
Muhammad H. Shahzad, Roni F. Rayes, Jonathan Cools-Lartigue, Jonathan D. Spicer
Within the tumour immune microenvironment (TIME), neutrophils can undergo NETosis to release neutrophil extracellular traps (NETs), which are protein-decorated DNA webs that promote cancer progression, metastasis and immune evasion. NETs promote cancer progression by fostering an immunosuppressive, pre-metastatic niche in regional lymph nodes prior to overt metastasis. Anticancer therapies such as immune checkpoint inhibitors, chemotherapy and radiation therapy can induce the formation of NETs, which can facilitate subsequent cancer invasion, migration, metastasis and recurrence through several mechanisms that dampen antitumour immune responses and sequester neoplastic cells. Precision blood and tumour testing for the NET burden could inform both patient prognosis as well as eligibility for treatments aimed at targeting NETosis, NETs and/or neutrophils. The importance of staging with other patient and treatment factors will thus inform the design of clinical trials evaluating NET-directed therapies. In this Review, we highlight our recent understandings of NET biology in cancer, and emphasize the translational data available, as well as the need for further clinical trials evaluating NETs and NET-directed therapies. Neutrophil extracellular traps (NETs) influence cancer initiation, progression and metastasis through immunosuppressive mechanisms within the tumour microenvironment. In this Review, Shahzad et al. highlight our recent understanding of NET biology in cancer and emphasize both the translational data available and the need for further clinical trials evaluating NETs and NET-directed therapies.
{"title":"Neutrophil extracellular traps in cancer","authors":"Muhammad H. Shahzad, Roni F. Rayes, Jonathan Cools-Lartigue, Jonathan D. Spicer","doi":"10.1038/s41568-025-00888-7","DOIUrl":"10.1038/s41568-025-00888-7","url":null,"abstract":"Within the tumour immune microenvironment (TIME), neutrophils can undergo NETosis to release neutrophil extracellular traps (NETs), which are protein-decorated DNA webs that promote cancer progression, metastasis and immune evasion. NETs promote cancer progression by fostering an immunosuppressive, pre-metastatic niche in regional lymph nodes prior to overt metastasis. Anticancer therapies such as immune checkpoint inhibitors, chemotherapy and radiation therapy can induce the formation of NETs, which can facilitate subsequent cancer invasion, migration, metastasis and recurrence through several mechanisms that dampen antitumour immune responses and sequester neoplastic cells. Precision blood and tumour testing for the NET burden could inform both patient prognosis as well as eligibility for treatments aimed at targeting NETosis, NETs and/or neutrophils. The importance of staging with other patient and treatment factors will thus inform the design of clinical trials evaluating NET-directed therapies. In this Review, we highlight our recent understandings of NET biology in cancer, and emphasize the translational data available, as well as the need for further clinical trials evaluating NETs and NET-directed therapies. Neutrophil extracellular traps (NETs) influence cancer initiation, progression and metastasis through immunosuppressive mechanisms within the tumour microenvironment. In this Review, Shahzad et al. highlight our recent understanding of NET biology in cancer and emphasize both the translational data available and the need for further clinical trials evaluating NETs and NET-directed therapies.","PeriodicalId":19055,"journal":{"name":"Nature Reviews Cancer","volume":"26 2","pages":"104-117"},"PeriodicalIF":66.8,"publicationDate":"2025-11-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145492526","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 : 2025-11-03DOI: 10.1038/s41568-025-00891-y
Daniela Senft
In a recent study, Mohri et al. reveal how melanocyte stem cells integrate distinct genotoxic signals through niche-derived KITL to drive either hair greying or melanomagenesis.
{"title":"Melanomagenesis antagonizes stem cell ageing","authors":"Daniela Senft","doi":"10.1038/s41568-025-00891-y","DOIUrl":"10.1038/s41568-025-00891-y","url":null,"abstract":"In a recent study, Mohri et al. reveal how melanocyte stem cells integrate distinct genotoxic signals through niche-derived KITL to drive either hair greying or melanomagenesis.","PeriodicalId":19055,"journal":{"name":"Nature Reviews Cancer","volume":"25 12","pages":"884-884"},"PeriodicalIF":66.8,"publicationDate":"2025-11-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145427421","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 : 2025-10-27DOI: 10.1038/s41568-025-00883-y
Tae Gun Kang, Jordan T. Johnson, Caitlin C. Zebley, Ben Youngblood
Current T cell-based immunotherapy strategies, including immune checkpoint blockade (ICB) and chimeric antigen receptor (CAR) T cells, have revolutionized cancer care. However, many patients with cancer who are treated with these approaches fail to respond or do not achieve durable protection against disease relapse, highlighting the need for further optimization of such strategies. The advent of cancer immunotherapy has ushered in an era of research centred on immune oncology with a specific focus on defining T cell-intrinsic mechanisms that delineate therapeutic responders and non-responders. Among the major barriers limiting immunotherapy efficacy, T cell exhaustion — which is characterized by repression of the effector functions and proliferative potential of T cells — has emerged as a common mechanism among various cancers. Here, we review transcriptional and epigenetic mechanisms that control T cell exhaustion. We discuss how T cell subset-specific gene regulatory programmes limit immunotherapy success and theorize on the development of next-generation strategies for increasing the clinical breadth, efficacy and durability of T cell immunotherapy. Transcriptional and epigenetic mechanisms governing T cell exhaustion substantially impact immunotherapy effectiveness. In this Review, Kang et al. outline epigenetic regulatory programmes that influence T cell differentiation fates, proposing strategies to enhance clinical outcomes and immunotherapy durability in cancer through improved understanding of T cell biology.
{"title":"Epigenetic regulation of T cell exhaustion in cancer","authors":"Tae Gun Kang, Jordan T. Johnson, Caitlin C. Zebley, Ben Youngblood","doi":"10.1038/s41568-025-00883-y","DOIUrl":"10.1038/s41568-025-00883-y","url":null,"abstract":"Current T cell-based immunotherapy strategies, including immune checkpoint blockade (ICB) and chimeric antigen receptor (CAR) T cells, have revolutionized cancer care. However, many patients with cancer who are treated with these approaches fail to respond or do not achieve durable protection against disease relapse, highlighting the need for further optimization of such strategies. The advent of cancer immunotherapy has ushered in an era of research centred on immune oncology with a specific focus on defining T cell-intrinsic mechanisms that delineate therapeutic responders and non-responders. Among the major barriers limiting immunotherapy efficacy, T cell exhaustion — which is characterized by repression of the effector functions and proliferative potential of T cells — has emerged as a common mechanism among various cancers. Here, we review transcriptional and epigenetic mechanisms that control T cell exhaustion. We discuss how T cell subset-specific gene regulatory programmes limit immunotherapy success and theorize on the development of next-generation strategies for increasing the clinical breadth, efficacy and durability of T cell immunotherapy. Transcriptional and epigenetic mechanisms governing T cell exhaustion substantially impact immunotherapy effectiveness. In this Review, Kang et al. outline epigenetic regulatory programmes that influence T cell differentiation fates, proposing strategies to enhance clinical outcomes and immunotherapy durability in cancer through improved understanding of T cell biology.","PeriodicalId":19055,"journal":{"name":"Nature Reviews Cancer","volume":"26 1","pages":"46-61"},"PeriodicalIF":66.8,"publicationDate":"2025-10-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145373814","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 : 2025-10-24DOI: 10.1038/s41568-025-00887-8
Gabrielle Brewer
Metabolic dysfunction-associated steatotic liver disease (MASLD) is an independent risk factor for developing extra-hepatic cancers. Now, Li et al. uncover an exosome-driven metabolic connection between the steatotic liver and the breast that fosters cancer progression.
{"title":"You’ve got exosomes","authors":"Gabrielle Brewer","doi":"10.1038/s41568-025-00887-8","DOIUrl":"10.1038/s41568-025-00887-8","url":null,"abstract":"Metabolic dysfunction-associated steatotic liver disease (MASLD) is an independent risk factor for developing extra-hepatic cancers. Now, Li et al. uncover an exosome-driven metabolic connection between the steatotic liver and the breast that fosters cancer progression.","PeriodicalId":19055,"journal":{"name":"Nature Reviews Cancer","volume":"25 12","pages":"883-883"},"PeriodicalIF":66.8,"publicationDate":"2025-10-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145368424","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 : 2025-10-24DOI: 10.1038/s41568-025-00878-9
Marie-Catherine Vozenin, Pierre Montay-Gruel, Pelagia Tsoutsou, Charles L. Limoli
FLASH radiotherapy has the potential to improve both patient quality of life and outcomes by delivering radiation at ultrahigh dose rates to effectively target tumours while sparing healthy tissues. However, the differential sensitivity of healthy tissues versus tumours to FLASH radiotherapy remains unexplained. In this Perspective, we hypothesize that FLASH radiotherapy distinguishes healthy tissues from tumours based on subtle functional and structural biological differences. We identify commonalities present in the various healthy tissues that are spared by FLASH radiotherapy that might be lost during tumorigenesis. We also propose that a specific class of proteins, termed long-lived proteins, define a critical radiolytic target that are present in nearly every healthy tissue that is FLASH radiotherapy resistant yet are absent in tumours. We extend this structural hypothesis further by suggesting that tumour and extracellular matrix rigidity affects sensitivity to changes in radiotherapy dose rate, where more rigid and dense desmoplastic tumours are more sensitive to FLASH radiotherapy than those possessing more elasticity. Substantiating these concepts experimentally may provide a new and generalized mechanism of action of radiation effects and may therefore inform clinical trial designs by identifying those tumour subclasses expected to exhibit optimal responses to FLASH radiotherapy. FLASH radiotherapy demonstrates reduced complications in healthy tissues while effectively targeting tumours. In this Perspective, Vozenin et al. review the clinical implications, mechanistic basis and provide novel hypotheses for FLASH efficacy.
{"title":"Mechanisms, challenges and opportunities for FLASH radiotherapy in cancer","authors":"Marie-Catherine Vozenin, Pierre Montay-Gruel, Pelagia Tsoutsou, Charles L. Limoli","doi":"10.1038/s41568-025-00878-9","DOIUrl":"10.1038/s41568-025-00878-9","url":null,"abstract":"FLASH radiotherapy has the potential to improve both patient quality of life and outcomes by delivering radiation at ultrahigh dose rates to effectively target tumours while sparing healthy tissues. However, the differential sensitivity of healthy tissues versus tumours to FLASH radiotherapy remains unexplained. In this Perspective, we hypothesize that FLASH radiotherapy distinguishes healthy tissues from tumours based on subtle functional and structural biological differences. We identify commonalities present in the various healthy tissues that are spared by FLASH radiotherapy that might be lost during tumorigenesis. We also propose that a specific class of proteins, termed long-lived proteins, define a critical radiolytic target that are present in nearly every healthy tissue that is FLASH radiotherapy resistant yet are absent in tumours. We extend this structural hypothesis further by suggesting that tumour and extracellular matrix rigidity affects sensitivity to changes in radiotherapy dose rate, where more rigid and dense desmoplastic tumours are more sensitive to FLASH radiotherapy than those possessing more elasticity. Substantiating these concepts experimentally may provide a new and generalized mechanism of action of radiation effects and may therefore inform clinical trial designs by identifying those tumour subclasses expected to exhibit optimal responses to FLASH radiotherapy. FLASH radiotherapy demonstrates reduced complications in healthy tissues while effectively targeting tumours. In this Perspective, Vozenin et al. review the clinical implications, mechanistic basis and provide novel hypotheses for FLASH efficacy.","PeriodicalId":19055,"journal":{"name":"Nature Reviews Cancer","volume":"26 1","pages":"62-75"},"PeriodicalIF":66.8,"publicationDate":"2025-10-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145357804","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 : 2025-10-16DOI: 10.1038/s41568-025-00885-w
Mervi Aavikko,Aoxing Liu,Mark Daly
{"title":"Unlocking the potential of FinnGen to advance cancer research.","authors":"Mervi Aavikko,Aoxing Liu,Mark Daly","doi":"10.1038/s41568-025-00885-w","DOIUrl":"https://doi.org/10.1038/s41568-025-00885-w","url":null,"abstract":"","PeriodicalId":19055,"journal":{"name":"Nature Reviews Cancer","volume":"11 1","pages":""},"PeriodicalIF":78.5,"publicationDate":"2025-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145305624","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 : 2025-10-15DOI: 10.1038/s41568-025-00879-8
Chao Mao, Dadi Jiang, Albert C. Koong, Boyi Gan
Resistance to cell death is a hallmark of cancer, driving tumour progression and limiting therapeutic efficacy. Metabolic cell death pathways have been identified as unique vulnerabilities in cancer, with ferroptosis being the most extensively studied, alongside the more recently discovered pathways of cuproptosis and disulfidptosis — each triggered by distinct metabolic perturbations. In this Review, we examine the molecular mechanisms and regulatory networks that govern these forms of metabolic cell death in cancer cells. We further examine the potential crosstalk between these pathways and discuss how insights gained and challenges encountered from extensive studies on ferroptosis can guide future research and therapeutic strategies targeting cuproptosis and disulfidptosis in cancer treatment. We highlight the complexity and dual roles of metabolic cell death in cancer and offer our perspective on how to leverage these cell death processes to develop innovative, targeted cancer therapies. In this Review, Mao et al. discuss the regulation and interplay of the metabolic cell death pathways ferroptosis, disulfidptosis and cuproptosis and explore how these mechanisms can be harnessed for cancer therapies.
{"title":"Exploiting metabolic cell death for cancer therapy","authors":"Chao Mao, Dadi Jiang, Albert C. Koong, Boyi Gan","doi":"10.1038/s41568-025-00879-8","DOIUrl":"10.1038/s41568-025-00879-8","url":null,"abstract":"Resistance to cell death is a hallmark of cancer, driving tumour progression and limiting therapeutic efficacy. Metabolic cell death pathways have been identified as unique vulnerabilities in cancer, with ferroptosis being the most extensively studied, alongside the more recently discovered pathways of cuproptosis and disulfidptosis — each triggered by distinct metabolic perturbations. In this Review, we examine the molecular mechanisms and regulatory networks that govern these forms of metabolic cell death in cancer cells. We further examine the potential crosstalk between these pathways and discuss how insights gained and challenges encountered from extensive studies on ferroptosis can guide future research and therapeutic strategies targeting cuproptosis and disulfidptosis in cancer treatment. We highlight the complexity and dual roles of metabolic cell death in cancer and offer our perspective on how to leverage these cell death processes to develop innovative, targeted cancer therapies. In this Review, Mao et al. discuss the regulation and interplay of the metabolic cell death pathways ferroptosis, disulfidptosis and cuproptosis and explore how these mechanisms can be harnessed for cancer therapies.","PeriodicalId":19055,"journal":{"name":"Nature Reviews Cancer","volume":"26 1","pages":"27-45"},"PeriodicalIF":66.8,"publicationDate":"2025-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145296109","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 : 2025-10-10DOI: 10.1038/s41568-025-00864-1
Adam Wahida, Marcus Conrad
Resisting cell death is a pivotal hallmark of cancer and one of several increasingly actionable functional capabilities acquired by cancer cells to sustain their malignant state. Since the early 2000s, the discovery of multiple regulated cell death programmes has intensified interest in targeting these maladaptive traits that cancer cells employ to resist cellular demise. Among these, ferroptosis — the lethal outcome of iron-dependent (phospho)lipid peroxidation — stands apart from other regulated cell death mechanisms, as it is persistently suppressed while lacking an activating signal. In cancer research, ferroptosis has garnered considerable attention, with growing evidence suggesting that its deregulation intersects with other hallmarks of malignancy, thus positioning it as a pleiotropic target. However, in the absence of approved ferroptosis-based drugs and despite substantial advances in understanding the metabolic manoeuvres of cancer cells to evade ferroptosis, its heralded translational value remains somewhat speculative at this stage. This Review reconciles the biochemical foundation of ferroptosis, the evidence supporting its role in cancer biology and the potential strategies for rationalizing targeted therapies to induce ferroptosis-prone states in malignancies. Building on this foundation, we explore contentious issues surrounding ferroptosis, including its implications for immunogenicity and redox imbalances in cancer. Finally, we address critical considerations such as therapeutic windows and biomarkers of ferroptosis, which are prerequisites for successful translation into clinical oncology. Although ferroptosis, an iron-dependent form of regulated cell death, is emerging as a therapeutic vulnerability in cancer, clinical translation is hindered by context-dependent regulation, a lack of predictive biomarkers and challenges in clinical trial design. In this Review, Wahida and Conrad examine the biological basis of ferroptosis, including its immunogenic potential, and outline the necessary steps towards translating ferroptosis-based therapies into the clinic.
{"title":"Decoding ferroptosis for cancer therapy","authors":"Adam Wahida, Marcus Conrad","doi":"10.1038/s41568-025-00864-1","DOIUrl":"10.1038/s41568-025-00864-1","url":null,"abstract":"Resisting cell death is a pivotal hallmark of cancer and one of several increasingly actionable functional capabilities acquired by cancer cells to sustain their malignant state. Since the early 2000s, the discovery of multiple regulated cell death programmes has intensified interest in targeting these maladaptive traits that cancer cells employ to resist cellular demise. Among these, ferroptosis — the lethal outcome of iron-dependent (phospho)lipid peroxidation — stands apart from other regulated cell death mechanisms, as it is persistently suppressed while lacking an activating signal. In cancer research, ferroptosis has garnered considerable attention, with growing evidence suggesting that its deregulation intersects with other hallmarks of malignancy, thus positioning it as a pleiotropic target. However, in the absence of approved ferroptosis-based drugs and despite substantial advances in understanding the metabolic manoeuvres of cancer cells to evade ferroptosis, its heralded translational value remains somewhat speculative at this stage. This Review reconciles the biochemical foundation of ferroptosis, the evidence supporting its role in cancer biology and the potential strategies for rationalizing targeted therapies to induce ferroptosis-prone states in malignancies. Building on this foundation, we explore contentious issues surrounding ferroptosis, including its implications for immunogenicity and redox imbalances in cancer. Finally, we address critical considerations such as therapeutic windows and biomarkers of ferroptosis, which are prerequisites for successful translation into clinical oncology. Although ferroptosis, an iron-dependent form of regulated cell death, is emerging as a therapeutic vulnerability in cancer, clinical translation is hindered by context-dependent regulation, a lack of predictive biomarkers and challenges in clinical trial design. In this Review, Wahida and Conrad examine the biological basis of ferroptosis, including its immunogenic potential, and outline the necessary steps towards translating ferroptosis-based therapies into the clinic.","PeriodicalId":19055,"journal":{"name":"Nature Reviews Cancer","volume":"25 12","pages":"910-924"},"PeriodicalIF":66.8,"publicationDate":"2025-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145275494","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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