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Linking macrophage metabolism to function in the tumor microenvironment.
IF 23.5 1区 医学
Nature cancer Pub Date : 2025-02-17 DOI: 10.1038/s43018-025-00909-2
Robbie Jin, Luke Neufeld, Tracy L McGaha
{"title":"Linking macrophage metabolism to function in the tumor microenvironment.","authors":"Robbie Jin, Luke Neufeld, Tracy L McGaha","doi":"10.1038/s43018-025-00909-2","DOIUrl":"https://doi.org/10.1038/s43018-025-00909-2","url":null,"abstract":"<p><p>Macrophages are present at high frequency in most solid tumor types, and their relative abundance negatively correlates with therapy responses and survival outcomes. Tissue-resident macrophages are highly tuned to integrate tissue niche signals, and multiple factors within the idiosyncratic tumor microenvironment (TME) drive macrophages to polarization states that favor immune suppression, tumor growth and metastasis. These diverse functional states are underpinned by extensive and complex rewiring of tumor-associated macrophage (TAM) metabolism. In this Review, we link distinct and specific macrophage functional states within the TME to major, phenotype-sustaining metabolic programs and discuss the metabolic impact of macrophage-modulating therapeutic interventions.</p>","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":" ","pages":""},"PeriodicalIF":23.5,"publicationDate":"2025-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143441503","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}
引用次数: 0
Targeting ADAR1 with a small molecule for the treatment of prostate cancer.
IF 23.5 1区 医学
Nature cancer Pub Date : 2025-02-10 DOI: 10.1038/s43018-025-00907-4
Xiao Wang, Jiaxing Li, Yasheng Zhu, Hongtao Shen, Jiayu Ding, Ting Zeng, Wenjian Min, Shun-Qing Liang, Lei Huang, Zhongrui Shi, Hao Shen, Fei Huang, Kai Yuan, Wenbin Kuang, Minghui Ji, Chengliang Sun, Yi Hou, Liping Wang, Weijiao Chen, Yuzhang Jiang, Haiping Hao, Yibei Xiao, Peng Yang
{"title":"Targeting ADAR1 with a small molecule for the treatment of prostate cancer.","authors":"Xiao Wang, Jiaxing Li, Yasheng Zhu, Hongtao Shen, Jiayu Ding, Ting Zeng, Wenjian Min, Shun-Qing Liang, Lei Huang, Zhongrui Shi, Hao Shen, Fei Huang, Kai Yuan, Wenbin Kuang, Minghui Ji, Chengliang Sun, Yi Hou, Liping Wang, Weijiao Chen, Yuzhang Jiang, Haiping Hao, Yibei Xiao, Peng Yang","doi":"10.1038/s43018-025-00907-4","DOIUrl":"https://doi.org/10.1038/s43018-025-00907-4","url":null,"abstract":"<p><p>Despite the initial response to androgen signaling therapy, most cases of prostate cancer (PCa) eventually relapse and remain incurable. The specific function of ADAR1 that governs PCa progression and specific inhibitors of ADAR are underexplored. In this study, we demonstrate that highly expressed ADAR1 is a crucial oncogenic target in PCa and develop an effective small-molecule ADAR1 inhibitor, ZYS-1, with marked antitumor efficacy and a favorable safety profile. Either genetic or pharmacological inhibition of ADAR1 dramatically suppressed PCa growth and metastasis and potentiated the antitumor immune response. Moreover, ZYS-1 can enhance the antitumor effect of immunotherapy. We also reveal that ADAR1 represses the translation of MTDH in an editing-dependent manner, which drives cell proliferation and invasion in PCa. Collectively, our findings suggest that ADAR1 is a druggable target in PCa and highlight the widespread applicability of ADAR1 inhibitors for a broad spectrum of malignancies.</p>","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":" ","pages":""},"PeriodicalIF":23.5,"publicationDate":"2025-02-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143391346","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}
引用次数: 0
FLASH radiation reprograms lipid metabolism and macrophage immunity and sensitizes medulloblastoma to CAR-T cell therapy.
IF 23.5 1区 医学
Nature cancer Pub Date : 2025-02-05 DOI: 10.1038/s43018-025-00905-6
Haiwei Ni, Zachary J Reitman, Wei Zou, Md Naushad Akhtar, Ritama Paul, Menggui Huang, Duo Zhang, Hao Zheng, Ruitao Zhang, Ruiying Ma, Gina Ngo, Lin Zhang, Eric S Diffenderfer, S Azar Oliaei Motlagh, Michele M Kim, Andy J Minn, Jay F Dorsey, Jessica B Foster, James Metz, Constantinos Koumenis, David G Kirsch, Yanqing Gong, Yi Fan
{"title":"FLASH radiation reprograms lipid metabolism and macrophage immunity and sensitizes medulloblastoma to CAR-T cell therapy.","authors":"Haiwei Ni, Zachary J Reitman, Wei Zou, Md Naushad Akhtar, Ritama Paul, Menggui Huang, Duo Zhang, Hao Zheng, Ruitao Zhang, Ruiying Ma, Gina Ngo, Lin Zhang, Eric S Diffenderfer, S Azar Oliaei Motlagh, Michele M Kim, Andy J Minn, Jay F Dorsey, Jessica B Foster, James Metz, Constantinos Koumenis, David G Kirsch, Yanqing Gong, Yi Fan","doi":"10.1038/s43018-025-00905-6","DOIUrl":"https://doi.org/10.1038/s43018-025-00905-6","url":null,"abstract":"<p><p>FLASH radiotherapy holds promise for treating solid tumors given the potential lower toxicity in normal tissues but its therapeutic effects on tumor immunity remain largely unknown. Using a genetically engineered mouse model of medulloblastoma, we show that FLASH radiation stimulates proinflammatory polarization in tumor macrophages. Single-cell transcriptome analysis shows that FLASH proton beam radiation skews macrophages toward proinflammatory phenotypes and increases T cell infiltration. Furthermore, FLASH radiation reduces peroxisome proliferator-activated receptor-γ (PPARγ) and arginase 1 expression and inhibits immunosuppressive macrophage polarization under stimulus-inducible conditions. Mechanistically, FLASH radiation abrogates lipid oxidase expression and oxidized low-density lipid generation to reduce PPARγ activity, while standard radiation induces reactive oxygen species-dependent PPARγ activation in macrophages. Notably, FLASH radiotherapy improves infiltration and activation of chimeric antigen receptor (CAR) T cells and sensitizes medulloblastoma to GD2 CAR-T cell therapy. Thus, FLASH radiotherapy reprograms macrophage lipid metabolism to reverse tumor immunosuppression. Combination FLASH-CAR radioimmunotherapy may offer exciting opportunities for solid tumor treatment.</p>","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":" ","pages":""},"PeriodicalIF":23.5,"publicationDate":"2025-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143255823","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}
引用次数: 0
Breaking frontiers with multidisciplinary cancer research
IF 23.5 1区 医学
Nature cancer Pub Date : 2025-01-30 DOI: 10.1038/s43018-024-00875-1
Carlos Caldas, Xiaoyuan Chen, Li Ding, Jakob Nikolas Kather, Maurizio Scaltriti
{"title":"Breaking frontiers with multidisciplinary cancer research","authors":"Carlos Caldas,&nbsp;Xiaoyuan Chen,&nbsp;Li Ding,&nbsp;Jakob Nikolas Kather,&nbsp;Maurizio Scaltriti","doi":"10.1038/s43018-024-00875-1","DOIUrl":"10.1038/s43018-024-00875-1","url":null,"abstract":"Five experts share their thoughts on key areas of focus in multidisciplinary cancer research for the upcoming years. They discuss the research approaches, tools, technologies, collaborations and way of thinking the lab of the future should integrate.","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":"6 1","pages":"13-15"},"PeriodicalIF":23.5,"publicationDate":"2025-01-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143066832","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}
引用次数: 0
Resistance mechanisms and therapeutic strategies of CDK4 and CDK6 kinase targeting in cancer
IF 23.5 1区 医学
Nature cancer Pub Date : 2025-01-30 DOI: 10.1038/s43018-024-00893-z
James J. Asciolla, Xuewei Wu, Christos Adamopoulos, Evripidis Gavathiotis, Poulikos I. Poulikakos
{"title":"Resistance mechanisms and therapeutic strategies of CDK4 and CDK6 kinase targeting in cancer","authors":"James J. Asciolla,&nbsp;Xuewei Wu,&nbsp;Christos Adamopoulos,&nbsp;Evripidis Gavathiotis,&nbsp;Poulikos I. Poulikakos","doi":"10.1038/s43018-024-00893-z","DOIUrl":"10.1038/s43018-024-00893-z","url":null,"abstract":"Cyclin-dependent kinases (CDKs) 4 and 6 (CDK4/6) are important regulators of the cell cycle. Selective CDK4/6 small-molecule inhibitors have shown clinical activity in hormonal receptor-positive (HR+) metastatic breast cancer, but their effectiveness remains limited in other cancer types. CDK4/6 degradation and improved selectivity across CDK paralogs are approaches that could expand the effectiveness of CDK4/6 targeting. Recent studies also suggest the use of CDK4/6-targeting agents in cancer immunotherapy. In this Review, we highlight recent advancements in the mechanistic understanding and development of pharmacological approaches targeting CDK4/6. Collectively, these developments pose new challenges and opportunities for rationally designing more effective treatments. Asciolla, Wu et al. review advances in CDK4 and CDK6 targeting and current challenges and opportunities, highlighting novel strategies to overcome treatment resistance and the role of the immune system in therapy response.","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":"6 1","pages":"24-40"},"PeriodicalIF":23.5,"publicationDate":"2025-01-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143066836","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}
引用次数: 0
Decoding pan-cancer treatment outcomes using multimodal real-world data and explainable artificial intelligence.
IF 23.5 1区 医学
Nature cancer Pub Date : 2025-01-30 DOI: 10.1038/s43018-024-00891-1
Julius Keyl, Philipp Keyl, Grégoire Montavon, René Hosch, Alexander Brehmer, Liliana Mochmann, Philipp Jurmeister, Gabriel Dernbach, Moon Kim, Sven Koitka, Sebastian Bauer, Nikolaos Bechrakis, Michael Forsting, Dagmar Führer-Sakel, Martin Glas, Viktor Grünwald, Boris Hadaschik, Johannes Haubold, Ken Herrmann, Stefan Kasper, Rainer Kimmig, Stephan Lang, Tienush Rassaf, Alexander Roesch, Dirk Schadendorf, Jens T Siveke, Martin Stuschke, Ulrich Sure, Matthias Totzeck, Anja Welt, Marcel Wiesweg, Hideo A Baba, Felix Nensa, Jan Egger, Klaus-Robert Müller, Martin Schuler, Frederick Klauschen, Jens Kleesiek
{"title":"Decoding pan-cancer treatment outcomes using multimodal real-world data and explainable artificial intelligence.","authors":"Julius Keyl, Philipp Keyl, Grégoire Montavon, René Hosch, Alexander Brehmer, Liliana Mochmann, Philipp Jurmeister, Gabriel Dernbach, Moon Kim, Sven Koitka, Sebastian Bauer, Nikolaos Bechrakis, Michael Forsting, Dagmar Führer-Sakel, Martin Glas, Viktor Grünwald, Boris Hadaschik, Johannes Haubold, Ken Herrmann, Stefan Kasper, Rainer Kimmig, Stephan Lang, Tienush Rassaf, Alexander Roesch, Dirk Schadendorf, Jens T Siveke, Martin Stuschke, Ulrich Sure, Matthias Totzeck, Anja Welt, Marcel Wiesweg, Hideo A Baba, Felix Nensa, Jan Egger, Klaus-Robert Müller, Martin Schuler, Frederick Klauschen, Jens Kleesiek","doi":"10.1038/s43018-024-00891-1","DOIUrl":"https://doi.org/10.1038/s43018-024-00891-1","url":null,"abstract":"<p><p>Despite advances in precision oncology, clinical decision-making still relies on limited variables and expert knowledge. To address this limitation, we combined multimodal real-world data and explainable artificial intelligence (xAI) to introduce AI-derived (AID) markers for clinical decision support. We used xAI to decode the outcome of 15,726 patients across 38 solid cancer entities based on 350 markers, including clinical records, image-derived body compositions, and mutational tumor profiles. xAI determined the prognostic contribution of each clinical marker at the patient level and identified 114 key markers that accounted for 90% of the neural network's decision process. Moreover, xAI enabled us to uncover 1,373 prognostic interactions between markers. Our approach was validated in an independent cohort of 3,288 patients with lung cancer from a US nationwide electronic health record-derived database. These results show the potential of xAI to transform the assessment of clinical variables and enable personalized, data-driven cancer care.</p>","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":" ","pages":""},"PeriodicalIF":23.5,"publicationDate":"2025-01-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143066830","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}
引用次数: 0
The editors’ point of view
IF 23.5 1区 医学
Nature cancer Pub Date : 2025-01-30 DOI: 10.1038/s43018-024-00901-2
Julieta Alfonso, Tiffanie Chouleur, Luca Danelli, Heathcliff Dorado García, Vincenzo Giacco, Lisa Hoffmann-Haas, Ioanna Pavlaki, Eleni Skourti, Alexia-Ileana Zaromytidou
{"title":"The editors’ point of view","authors":"Julieta Alfonso,&nbsp;Tiffanie Chouleur,&nbsp;Luca Danelli,&nbsp;Heathcliff Dorado García,&nbsp;Vincenzo Giacco,&nbsp;Lisa Hoffmann-Haas,&nbsp;Ioanna Pavlaki,&nbsp;Eleni Skourti,&nbsp;Alexia-Ileana Zaromytidou","doi":"10.1038/s43018-024-00901-2","DOIUrl":"10.1038/s43018-024-00901-2","url":null,"abstract":"The editors of Nature Cancer share their thoughts on five years of the journal: the science, what being an editor means to them, and what lies ahead.","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":"6 1","pages":"10-12"},"PeriodicalIF":23.5,"publicationDate":"2025-01-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143066837","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}
引用次数: 0
Embracing the unexpected to make progress against cancer
IF 23.5 1区 医学
Nature cancer Pub Date : 2025-01-30 DOI: 10.1038/s43018-024-00887-x
Alexia-Ileana Zaromytidou
{"title":"Embracing the unexpected to make progress against cancer","authors":"Alexia-Ileana Zaromytidou","doi":"10.1038/s43018-024-00887-x","DOIUrl":"10.1038/s43018-024-00887-x","url":null,"abstract":"Lillian Siu is director of the Phase I Clinical Trials Program, codirector of the Robert and Maggie Bras and Family Drug Development Program, clinical lead for the Tumor Immunotherapy Program, and the BMO Chair in Precision Cancer Genomics at the Princess Margaret Cancer Centre, University Health Network in Toronto, Canada. She is also a professor of medicine at the University of Toronto and AACR President-Elect 2024–2025. We caught up with her to discuss her career and developments in the clinical oncology field.","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":"6 1","pages":"3-5"},"PeriodicalIF":23.5,"publicationDate":"2025-01-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143066833","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}
引用次数: 0
Thriving in diverse ecosystems
IF 23.5 1区 医学
Nature cancer Pub Date : 2025-01-30 DOI: 10.1038/s43018-024-00888-w
Alexia-Ileana Zaromytidou
{"title":"Thriving in diverse ecosystems","authors":"Alexia-Ileana Zaromytidou","doi":"10.1038/s43018-024-00888-w","DOIUrl":"10.1038/s43018-024-00888-w","url":null,"abstract":"Johanna A. Joyce is a professor at the University of Lausanne and a member of the Ludwig Institute for Cancer Research. She is also president-elect of the European Association for Cancer Research (EACR). We spoke to her about her work on the tumor microenvironment and with the cancer community.","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":"6 1","pages":"6-9"},"PeriodicalIF":23.5,"publicationDate":"2025-01-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143066839","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}
引用次数: 0
Five years of Nature Cancer
IF 23.5 1区 医学
Nature cancer Pub Date : 2025-01-30 DOI: 10.1038/s43018-025-00911-8
{"title":"Five years of Nature Cancer","authors":"","doi":"10.1038/s43018-025-00911-8","DOIUrl":"10.1038/s43018-025-00911-8","url":null,"abstract":"To mark the fifth anniversary of Nature Cancer, we launch a Series of Reviews and opinion pieces that will run throughout this year. We take this opportunity to reflect on the journal’s first five years and what comes next.","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":"6 1","pages":"1-2"},"PeriodicalIF":23.5,"publicationDate":"2025-01-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s43018-025-00911-8.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143066834","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}
引用次数: 0
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