Pub Date : 2026-01-27DOI: 10.1038/s41568-025-00901-z
Amirreza Bitaraf,Maria Camila Jimenez,Chinmayee Kakirde,Eric K Lau
Fucosylation, the conjugation of glycoproteins and glycolipids with the dietary sugar L-fucose, can have key functional and regulatory roles across a range of normal biological and developmental processes. Although the full repertoire of fucosylated proteins and their direct influence on signalling and cellular behaviour remains incompletely understood, it is not surprising that deregulated fucosylation has been increasingly associated with disease contexts, particularly cancer. Importantly, fucosylation regulates the biology of immune and other stromal cells, and emerging studies have elucidated how pathological aberrations in fucosylation can deregulate signalling that governs cellular interactions in the tumour microenvironment, thereby influencing tumour progression and therapeutic responses. Accordingly, fucosylated glycoproteins and glycans have been reported to exhibit potential biomarker utility, associating with cancer type and staging. Notably, fucosylation appears to be therapeutically actionable, as simply administering L-fucose orally can suffice to suppress tumour growth and stimulate antitumour immune responses in preclinical models. However, given that the blockade of fucosylation machinery can elicit similar antitumour effects reflects the diversity of cell-intrinsic and cell-extrinsic roles that fucosylation can divergently have across the tumour microenvironment. Here, we review recent glycobiology discoveries that shed light on the complexity of fucosylation, its mechanistic roles in immune and tumour biology, and how it might be strategically leveraged for the treatment of cancer.
{"title":"L-Fucose: a dietary sugar with multifaceted potential in the biology and therapy of cancer.","authors":"Amirreza Bitaraf,Maria Camila Jimenez,Chinmayee Kakirde,Eric K Lau","doi":"10.1038/s41568-025-00901-z","DOIUrl":"https://doi.org/10.1038/s41568-025-00901-z","url":null,"abstract":"Fucosylation, the conjugation of glycoproteins and glycolipids with the dietary sugar L-fucose, can have key functional and regulatory roles across a range of normal biological and developmental processes. Although the full repertoire of fucosylated proteins and their direct influence on signalling and cellular behaviour remains incompletely understood, it is not surprising that deregulated fucosylation has been increasingly associated with disease contexts, particularly cancer. Importantly, fucosylation regulates the biology of immune and other stromal cells, and emerging studies have elucidated how pathological aberrations in fucosylation can deregulate signalling that governs cellular interactions in the tumour microenvironment, thereby influencing tumour progression and therapeutic responses. Accordingly, fucosylated glycoproteins and glycans have been reported to exhibit potential biomarker utility, associating with cancer type and staging. Notably, fucosylation appears to be therapeutically actionable, as simply administering L-fucose orally can suffice to suppress tumour growth and stimulate antitumour immune responses in preclinical models. However, given that the blockade of fucosylation machinery can elicit similar antitumour effects reflects the diversity of cell-intrinsic and cell-extrinsic roles that fucosylation can divergently have across the tumour microenvironment. Here, we review recent glycobiology discoveries that shed light on the complexity of fucosylation, its mechanistic roles in immune and tumour biology, and how it might be strategically leveraged for the treatment of cancer.","PeriodicalId":19055,"journal":{"name":"Nature Reviews Cancer","volume":"7 1","pages":""},"PeriodicalIF":78.5,"publicationDate":"2026-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146056381","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 : 2026-01-23DOI: 10.1038/s41568-026-00909-z
Julia A. Beatty, Thomas Tu
{"title":"Cat viruses as windows into human oncogenesis","authors":"Julia A. Beatty, Thomas Tu","doi":"10.1038/s41568-026-00909-z","DOIUrl":"https://doi.org/10.1038/s41568-026-00909-z","url":null,"abstract":"","PeriodicalId":19055,"journal":{"name":"Nature Reviews Cancer","volume":"182 1","pages":""},"PeriodicalIF":78.5,"publicationDate":"2026-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146032801","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 : 2026-01-23DOI: 10.1038/s41568-025-00903-x
Laurel B Darragh,Sana D Karam
Radiation therapy can directly kill cancer cells, while simultaneously modulating the immune response. The advent of immune checkpoint blockade (ICB) provided compelling rationale for combination with radiation therapy to improve systemic tumour control. Although this strategy has improved survival in specific contexts, including cervical cancer and head and neck squamous cell carcinoma, the majority of combination trials have not demonstrated clinical benefit and predictive biomarkers remain elusive. These heterogeneous outcomes reflect fundamental gaps in understanding how radiation parameters influence immunological responses. Technological advances enabling diverse radiation delivery protocols have revealed that dose and fractionation profoundly impact the balance between immunostimulation and immunosuppression. Emerging evidence indicates that radiation protocols optimized for cytotoxic effects may not be optimal for immunological synergy with ICB. In this Review, we examine how radiation dose, fractionation and treatment volume shape local and systemic immunity, reconciling mechanistic insights with divergent clinical trial outcomes. We provide rationale for transitioning from empirical combinations towards immunologically informed radiation protocols that could help realize the full potential of radioimmunotherapy combinations.
{"title":"Radiation as an immune modulator: mechanisms and implications for combination with immunotherapy.","authors":"Laurel B Darragh,Sana D Karam","doi":"10.1038/s41568-025-00903-x","DOIUrl":"https://doi.org/10.1038/s41568-025-00903-x","url":null,"abstract":"Radiation therapy can directly kill cancer cells, while simultaneously modulating the immune response. The advent of immune checkpoint blockade (ICB) provided compelling rationale for combination with radiation therapy to improve systemic tumour control. Although this strategy has improved survival in specific contexts, including cervical cancer and head and neck squamous cell carcinoma, the majority of combination trials have not demonstrated clinical benefit and predictive biomarkers remain elusive. These heterogeneous outcomes reflect fundamental gaps in understanding how radiation parameters influence immunological responses. Technological advances enabling diverse radiation delivery protocols have revealed that dose and fractionation profoundly impact the balance between immunostimulation and immunosuppression. Emerging evidence indicates that radiation protocols optimized for cytotoxic effects may not be optimal for immunological synergy with ICB. In this Review, we examine how radiation dose, fractionation and treatment volume shape local and systemic immunity, reconciling mechanistic insights with divergent clinical trial outcomes. We provide rationale for transitioning from empirical combinations towards immunologically informed radiation protocols that could help realize the full potential of radioimmunotherapy combinations.","PeriodicalId":19055,"journal":{"name":"Nature Reviews Cancer","volume":"3 1","pages":""},"PeriodicalIF":78.5,"publicationDate":"2026-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146033564","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 : 2026-01-20DOI: 10.1038/s41568-026-00907-1
Kenny Zhuoran Wu,N Gopalakrishna Iyer,Chin-Ann Johnny Ong,Eliza Li Shan Fong
{"title":"Tumour explants as next-generation models of cancer.","authors":"Kenny Zhuoran Wu,N Gopalakrishna Iyer,Chin-Ann Johnny Ong,Eliza Li Shan Fong","doi":"10.1038/s41568-026-00907-1","DOIUrl":"https://doi.org/10.1038/s41568-026-00907-1","url":null,"abstract":"","PeriodicalId":19055,"journal":{"name":"Nature Reviews Cancer","volume":"231 1","pages":""},"PeriodicalIF":78.5,"publicationDate":"2026-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146005371","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 : 2026-01-16DOI: 10.1038/s41568-025-00905-9
Frank Arnold,Annachiara Del Vecchio,Zainab Hussain,Mara H Sherman
A fibroinflammatory microenvironment coevolves with many tumour types and profoundly influences disease progression and response to therapy. Pancreatic cancer is the archetype of a fibroinflammatory tumour, with non-malignant stromal elements comprising the volumetric majority of the tumour tissue. A convergence of three factors - technological advances enabling deep understanding of heterocellular crosstalk in these complex tumours; therapeutic advances revealing meaningful vulnerabilities in this notoriously chemoresistant, immunosuppressive disease; and conceptual advances towards distilling the conserved features and key functions of stromal elements amid this complexity - has positioned the field in a promising era for discovery, wherein our ever-improving understanding of the pancreatic tumour microenvironment is poised for translational impact. Emerging pan-cancer analyses highlight features of tumour microenvironments conserved not only among pancreatic cancer specimens but also across anatomic sites, such that lessons learnt about the organization of tumour tissue architecture and the role of oncogenic KRAS signalling in this process in other tumours have shaped our understanding of heterocellular dependencies in pancreatic cancer and vice versa. Here, we review recent developments sculpting our current understanding of the diverse features of the pancreatic tumour microenvironment and emerging means to leverage these developments for the benefit of patients with pancreatic cancer.
{"title":"Heterocellular crosstalk and architecture of the pancreatic tumour microenvironment.","authors":"Frank Arnold,Annachiara Del Vecchio,Zainab Hussain,Mara H Sherman","doi":"10.1038/s41568-025-00905-9","DOIUrl":"https://doi.org/10.1038/s41568-025-00905-9","url":null,"abstract":"A fibroinflammatory microenvironment coevolves with many tumour types and profoundly influences disease progression and response to therapy. Pancreatic cancer is the archetype of a fibroinflammatory tumour, with non-malignant stromal elements comprising the volumetric majority of the tumour tissue. A convergence of three factors - technological advances enabling deep understanding of heterocellular crosstalk in these complex tumours; therapeutic advances revealing meaningful vulnerabilities in this notoriously chemoresistant, immunosuppressive disease; and conceptual advances towards distilling the conserved features and key functions of stromal elements amid this complexity - has positioned the field in a promising era for discovery, wherein our ever-improving understanding of the pancreatic tumour microenvironment is poised for translational impact. Emerging pan-cancer analyses highlight features of tumour microenvironments conserved not only among pancreatic cancer specimens but also across anatomic sites, such that lessons learnt about the organization of tumour tissue architecture and the role of oncogenic KRAS signalling in this process in other tumours have shaped our understanding of heterocellular dependencies in pancreatic cancer and vice versa. Here, we review recent developments sculpting our current understanding of the diverse features of the pancreatic tumour microenvironment and emerging means to leverage these developments for the benefit of patients with pancreatic cancer.","PeriodicalId":19055,"journal":{"name":"Nature Reviews Cancer","volume":"37 1","pages":""},"PeriodicalIF":78.5,"publicationDate":"2026-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145986336","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 : 2026-01-12DOI: 10.1038/s41568-025-00900-0
Daniel Truhn,Shekoofeh Azizi,James Zou,Leonor Cerda-Alberich,Faisal Mahmood,Jakob Nikolas Kather
Since 2022, artificial intelligence (AI) methods have progressed far beyond their established capabilities of data classification and prediction. Large language models (LLMs) can perform logical reasoning, enabling them to plan and orchestrate complex workflows. By using this planning ability and equipped with the ability to act upon their environment, LLMs can function as agents. Agents are (semi-)autonomous systems capable of sensing, learning and acting upon their environments. As such, they can interact with external knowledge or external software and can execute sequences of tasks with minimal or no human input. In cancer research and oncology, evidence for the capability of AI agents is rapidly emerging. From autonomously optimizing drug design and development to proposing therapeutic strategies for clinical cases, AI agents can handle complex, multistep problems that were not addressable by previous generations of AI systems. Despite rapid developments, many translational and clinical cancer researchers still lack clarity regarding the precise capabilities, limitations, and ethical or regulatory frameworks associated with AI agents. Here we provide a primer on AI agents for cancer researchers and oncologists. We illustrate how this technology is set apart from and goes beyond traditional AI systems. We discuss existing and emerging applications in cancer research and address real-world challenges from the perspective of academic, clinical and industrial research.
{"title":"Artificial intelligence agents in cancer research and oncology.","authors":"Daniel Truhn,Shekoofeh Azizi,James Zou,Leonor Cerda-Alberich,Faisal Mahmood,Jakob Nikolas Kather","doi":"10.1038/s41568-025-00900-0","DOIUrl":"https://doi.org/10.1038/s41568-025-00900-0","url":null,"abstract":"Since 2022, artificial intelligence (AI) methods have progressed far beyond their established capabilities of data classification and prediction. Large language models (LLMs) can perform logical reasoning, enabling them to plan and orchestrate complex workflows. By using this planning ability and equipped with the ability to act upon their environment, LLMs can function as agents. Agents are (semi-)autonomous systems capable of sensing, learning and acting upon their environments. As such, they can interact with external knowledge or external software and can execute sequences of tasks with minimal or no human input. In cancer research and oncology, evidence for the capability of AI agents is rapidly emerging. From autonomously optimizing drug design and development to proposing therapeutic strategies for clinical cases, AI agents can handle complex, multistep problems that were not addressable by previous generations of AI systems. Despite rapid developments, many translational and clinical cancer researchers still lack clarity regarding the precise capabilities, limitations, and ethical or regulatory frameworks associated with AI agents. Here we provide a primer on AI agents for cancer researchers and oncologists. We illustrate how this technology is set apart from and goes beyond traditional AI systems. We discuss existing and emerging applications in cancer research and address real-world challenges from the perspective of academic, clinical and industrial research.","PeriodicalId":19055,"journal":{"name":"Nature Reviews Cancer","volume":"84 1","pages":""},"PeriodicalIF":78.5,"publicationDate":"2026-01-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145955937","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 : 2026-01-09DOI: 10.1038/s41568-025-00904-w
Daniela Senft
In a study published in Nature, Lourenço et al. demonstrate that strong oncogenic driver mutations undergo negative selection unless they occur in a permissive tissue context.
{"title":"When the time is right","authors":"Daniela Senft","doi":"10.1038/s41568-025-00904-w","DOIUrl":"10.1038/s41568-025-00904-w","url":null,"abstract":"In a study published in Nature, Lourenço et al. demonstrate that strong oncogenic driver mutations undergo negative selection unless they occur in a permissive tissue context.","PeriodicalId":19055,"journal":{"name":"Nature Reviews Cancer","volume":"26 2","pages":"82-82"},"PeriodicalIF":66.8,"publicationDate":"2026-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145938298","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 : 2026-01-05DOI: 10.1038/s41568-025-00894-9
Changzheng Lu,Wenyan Wang,Yang-Xin Fu
The cyclic guanosine monophosphate-adenosine monophosphate synthase (cGAS)-stimulator of interferon genes (STING) pathway has a crucial role in detecting tumour-derived DNA, whether the pathway is generated spontaneously or induced therapeutically. Activation of the cGAS-STING pathway triggers type I interferon signalling and pro-inflammatory responses in both tumour and immune cells, establishing a delicate balance between pathological inflammation and protective immune responses. Although preclinical studies have highlighted the promise of targeting the cGAS-STING pathway to enhance antitumour immunotherapy, clinical results have fallen short of expectations. In this Review, we outline key advances in understanding the tumour-promoting and tumour-suppressive effects mediated by the cGAS-STING pathway and discuss opportunities and challenges for its integration into future cancer immunotherapy.
{"title":"Opportunities and challenges of targeting cGAS-STING in cancer.","authors":"Changzheng Lu,Wenyan Wang,Yang-Xin Fu","doi":"10.1038/s41568-025-00894-9","DOIUrl":"https://doi.org/10.1038/s41568-025-00894-9","url":null,"abstract":"The cyclic guanosine monophosphate-adenosine monophosphate synthase (cGAS)-stimulator of interferon genes (STING) pathway has a crucial role in detecting tumour-derived DNA, whether the pathway is generated spontaneously or induced therapeutically. Activation of the cGAS-STING pathway triggers type I interferon signalling and pro-inflammatory responses in both tumour and immune cells, establishing a delicate balance between pathological inflammation and protective immune responses. Although preclinical studies have highlighted the promise of targeting the cGAS-STING pathway to enhance antitumour immunotherapy, clinical results have fallen short of expectations. In this Review, we outline key advances in understanding the tumour-promoting and tumour-suppressive effects mediated by the cGAS-STING pathway and discuss opportunities and challenges for its integration into future cancer immunotherapy.","PeriodicalId":19055,"journal":{"name":"Nature Reviews Cancer","volume":"29 1","pages":""},"PeriodicalIF":78.5,"publicationDate":"2026-01-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145897396","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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