Nature cancer最新文献

A high-MAPK, low-WNT cell state drives metastatic dissemination in colorectal cancer. 高mapk、低wnt细胞状态驱动结直肠癌转移传播。

IF 28.5 1区医学

Nature cancer Pub Date : 2026-05-07 DOI: 10.1038/s43018-026-01155-w

Melanie Heinlein, Ginny X Li, Noelyn Kljavin, Amanda R Moore, Brian Biehs, Liming Tao, Soufiane Boumahdi, Farnaz Mohammadi, Minyi Shi, Yuxin Liang, Hartmut Koeppen, Nicolò Riggi, Robert Piskol, Frederic J de Sauvage

{"title":"A high-MAPK, low-WNT cell state drives metastatic dissemination in colorectal cancer.","authors":"Melanie Heinlein, Ginny X Li, Noelyn Kljavin, Amanda R Moore, Brian Biehs, Liming Tao, Soufiane Boumahdi, Farnaz Mohammadi, Minyi Shi, Yuxin Liang, Hartmut Koeppen, Nicolò Riggi, Robert Piskol, Frederic J de Sauvage","doi":"10.1038/s43018-026-01155-w","DOIUrl":"https://doi.org/10.1038/s43018-026-01155-w","url":null,"abstract":"Colorectal cancer (CRC), a leading cause of cancer-related mortality due to distant metastases, is largely driven by activating mutations in the WNT and mitogen-activated protein kinase (MAPK) pathways. Understanding the mechanism underlying the metastatic process is essential for developing effective treatments. Using serial in vivo orthotopic passaging, we developed an immunocompetent mouse model of metastatic CRC. Highly metastatic tumor cells exhibited chromosomal amplifications in MAPK pathway genes, resulting in increased MAPK pathway activity and suppression of WNT-associated transcriptional programs, including stem cell genes. Pharmacological inhibition of mutant KRASG12D led to a reduction in the MAPK-high-WNT-low transcriptional state and decreased both lung and liver metastases. Analysis of CRC patient data revealed that the metastatic gene signature associated with the MAPK-high-WNT-low state correlated with poorer survival outcomes. These findings underscore the plasticity of metastasis-initiating cells in CRC driven by the opposing roles of MAPK and WNT signaling, despite their synergy observed during colon tumorigenesis.","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":" ","pages":""},"PeriodicalIF":28.5,"publicationDate":"2026-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147840373","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

Safety and activity of RO7300490, a bispecific CD40 agonist targeted to fibroblast activation protein, in patients with advanced solid tumors: a single-arm, multicenter, first-in-human, phase 1 trial. 靶向成纤维细胞活化蛋白的双特异性CD40激动剂RO7300490在晚期实体瘤患者中的安全性和活性：单臂、多中心、首次人体1期试验

IF 28.5 1区医学

Nature cancer Pub Date : 2026-05-01 DOI: 10.1038/s43018-026-01157-8

Ignacio Melero, Bernhard Reis, Corinne Rusterholz, Alexandra Epp, Nicole A Kratochwil, Chun Wu, Michael Hettich, Georgios Kazantzidis, Natascha Rieder, Petra C Schwalie, Solveig Badillo, Nadine Kumpesa, Andreas Thommen, Danielle J Vugts, Victor Moreno, Julia Lostes Bardaji, Eduardo Castanon Alvarez, Carlos E de Andrea, Iben Spanggaard, Dae Ho Lee, James Spicer, Fiona Thistlethwaite, Do-Youn Oh, Antoine Hollebecque, Olivera Cirovic, Stefan N Symeonides

{"title":"Safety and activity of RO7300490, a bispecific CD40 agonist targeted to fibroblast activation protein, in patients with advanced solid tumors: a single-arm, multicenter, first-in-human, phase 1 trial.","authors":"Ignacio Melero, Bernhard Reis, Corinne Rusterholz, Alexandra Epp, Nicole A Kratochwil, Chun Wu, Michael Hettich, Georgios Kazantzidis, Natascha Rieder, Petra C Schwalie, Solveig Badillo, Nadine Kumpesa, Andreas Thommen, Danielle J Vugts, Victor Moreno, Julia Lostes Bardaji, Eduardo Castanon Alvarez, Carlos E de Andrea, Iben Spanggaard, Dae Ho Lee, James Spicer, Fiona Thistlethwaite, Do-Youn Oh, Antoine Hollebecque, Olivera Cirovic, Stefan N Symeonides","doi":"10.1038/s43018-026-01157-8","DOIUrl":"https://doi.org/10.1038/s43018-026-01157-8","url":null,"abstract":"CD40 activation on dendritic cells (DCs) enhances tumor antigen cross-priming of tumor-specific cytotoxic T lymphocytes, strengthening anticancer immune responses. RO7300490 is a fibroblast activation protein (FAP)-targeted CD40 agonist antibody. In this phase I study, 80 patients with advanced and/or metastatic solid tumors received RO7300490 biweekly (dose range 16-1,100 mg). The primary objective was to evaluate safety and tolerability. Secondary/exploratory objectives included pharmacokinetics, antitumor activity and pharmacodynamics. Treatment-related adverse events (TRAEs) occurred in 53 patients (66.3%) and were mostly grade 1-2. Grade 3-4 TRAEs (3.8%) and TRAEs leading to discontinuation (2.5%) were uncommon. No grade 5 TRAEs were reported. RO7300490 showed target-mediated drug disposition, with sustained exposure at higher doses. No objective responses and limited clinical activity (disease control rate 42.5%) were observed despite rapid and persistent tumor uptake of radiolabeled RO7300490. Intratumoral pharmacodynamic activity was demonstrated by a significant increase in DC-LAMP+ DC density in paired tumor biopsies. An increase in B cell density was also observed, along with the formation of pretertiary lymphoid structures, co-organized in focal micro-neighborhoods with DCs. In summary, treatment with a tumor-targeted CD40 agonist antibody is feasible, clinically manageable and induces immunomodulation of the tumor microenvironment. ClinicalTrials.gov registration: NCT04857138 .","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":" ","pages":""},"PeriodicalIF":28.5,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147817844","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

Tumor-localized CD40 agonism with MP0317, a FAP x CD40 DARPin, reprograms the tumor microenvironment in patients with advanced solid tumors: an open-label, nonrandomized, dose-escalation phase 1 study. 一项开放标签、非随机、剂量递增的1期研究：MP0317 （FAP x CD40 DARPin）对晚期实体瘤患者肿瘤微环境的重编程作用

IF 28.5 1区医学

Nature cancer Pub Date : 2026-05-01 DOI: 10.1038/s43018-026-01150-1

Neeltje Steeghs, Carlos Gomez-Roca, Iphigénie Korakis, Eelke Gort, Hilde De Winter, Nina Stojcheva, Vaia Stavropoulou, Jennifer Krieg, Paul Baverel, Elena Fernandez, Ana Maria Florescu, Lea Hoenig, Michael Peter Sanderson, Vladimir Kirkin, Philippe Legenne, Philippe Alexandre Cassier

{"title":"Tumor-localized CD40 agonism with MP0317, a FAP x CD40 DARPin, reprograms the tumor microenvironment in patients with advanced solid tumors: an open-label, nonrandomized, dose-escalation phase 1 study.","authors":"Neeltje Steeghs, Carlos Gomez-Roca, Iphigénie Korakis, Eelke Gort, Hilde De Winter, Nina Stojcheva, Vaia Stavropoulou, Jennifer Krieg, Paul Baverel, Elena Fernandez, Ana Maria Florescu, Lea Hoenig, Michael Peter Sanderson, Vladimir Kirkin, Philippe Legenne, Philippe Alexandre Cassier","doi":"10.1038/s43018-026-01150-1","DOIUrl":"https://doi.org/10.1038/s43018-026-01150-1","url":null,"abstract":"This phase 1, open-label, nonrandomized, dose-escalation study evaluated MP0317 (FAP x CD40 DARPin) in adults with advanced solid tumors. Forty-six patients across nine cohorts received MP0317 at doses ranging from 0.03 to 10 mg kg-1 intravenously weekly or every 3 weeks. The primary outcome measure was safety; secondary and exploratory outcome measures included antitumor activity, pharmacokinetics and pharmacodynamics. Most treatment-related adverse events were of grades 1 and 2 (95%); a maximum tolerated dose was not reached. One patient achieved an unconfirmed partial response and 14 patients had stable disease. MP0317 serum pharmacokinetics confirmed extended half-life properties; terminal half-life estimates increased with dose and ranged from 21.8 to 120 h. Paired tumor biopsies confirmed colocalization of MP0317 with fibroblast activation protein and CD40. Activation of the CD40 pathway in the tumor microenvironment was shown by increased infiltration of antigen-presenting, plasma and follicular helper T cells, dendritic cell maturation, interferon-γ signaling and circulating immune markers. Collectively, these data confirm a favorable safety profile for MP0317 and support further clinical evaluation in combination with complementary immunotherapies. ClinicalTrials.gov registration: NCT05098405 .","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":" ","pages":""},"PeriodicalIF":28.5,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147817903","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 tumor heterogeneity and plasticity 解码肿瘤的异质性和可塑性

IF 28.5 1区医学

Nature cancer Pub Date : 2026-04-29 DOI: 10.1038/s43018-026-01166-7

引用次数: 0

Dual targeting of PI3Kγ and STING overcomes regulatory B cell- and myeloid cell-driven immune suppression in pancreatic cancer. PI3Kγ和STING的双重靶向克服了胰腺癌中B细胞和髓细胞驱动的调节免疫抑制。

IF 28.5 1区医学

Nature cancer Pub Date : 2026-04-28 DOI: 10.1038/s43018-026-01158-7

Chengyi Li, Fang Ke, Hongyi Zhao, Shuai Mao, Mahamadou Djibo, Linqi Huang, Miao He, Meilin Wang, Hanning Wen, Zhongwei Liu, Zhixin Yu, Zhihong Qi, Ana R Xavier, Minal Nenwani, Bo Wen, Nicole Peterson, Vaibhav Sahai, Deepak Nagrath, Carrie L Lucas, Matthias P Wymann, Wei Gao, Lawrence Fong, Duxin Sun

{"title":"Dual targeting of PI3Kγ and STING overcomes regulatory B cell- and myeloid cell-driven immune suppression in pancreatic cancer.","authors":"Chengyi Li, Fang Ke, Hongyi Zhao, Shuai Mao, Mahamadou Djibo, Linqi Huang, Miao He, Meilin Wang, Hanning Wen, Zhongwei Liu, Zhixin Yu, Zhihong Qi, Ana R Xavier, Minal Nenwani, Bo Wen, Nicole Peterson, Vaibhav Sahai, Deepak Nagrath, Carrie L Lucas, Matthias P Wymann, Wei Gao, Lawrence Fong, Duxin Sun","doi":"10.1038/s43018-026-01158-7","DOIUrl":"https://doi.org/10.1038/s43018-026-01158-7","url":null,"abstract":"Both regulatory B (Breg) and myeloid cells in tumors and lymph nodes drive immune suppression in pancreatic cancer. Current strategies to counter immune suppression emphasize myeloid cells but overlook Breg cells. We discovered that STING agonist expanded Breg cells depended on PI3Kγ but not PI3Kδ in pancreatic cancer, whereas activating myeloid cells were independent of PI3Kγ. Inhibition of PI3Kγ, but not PI3Kδ, decreased STING-induced IRF3 phosphorylation and Breg cell expansion in pancreatic cancer, while sustaining STING-induced IRF3 phosphorylation to activate myeloid cells. We developed a dual targeting compound and its albumin nanoformulation Nano-273, which stimulated STING to activate myeloid cells and inhibited PI3Kγ to decrease STING-induced Breg cell expansion. Nano-273 delivered the drug to tumors and lymph nodes to overcome myeloid cell- and Breg cell-mediated immune suppression in pancreatic cancer. Nano-273, combined with anti-programmed cell death protein 1, achieved durable efficacy in transgenic KPC mice with pancreatic cancer, offering potential for pancreatic cancer treatment.","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":" ","pages":""},"PeriodicalIF":28.5,"publicationDate":"2026-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147776400","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

Artificial intelligence model boosts lung nodule diagnostic accuracy in clinical trial. 人工智能模型在临床试验中提高肺结节诊断的准确性。

IF 28.5 1区医学

Nature cancer Pub Date : 2026-04-27 DOI: 10.1038/s43018-026-01148-9

引用次数: 0

Epithelial-to-mesenchymal transition as a central driver of tumor cell plasticity 上皮-间质转化是肿瘤细胞可塑性的主要驱动因素

IF 28.5 1区医学

Nature cancer Pub Date : 2026-04-24 DOI: 10.1038/s43018-026-01154-x

Raul Jimenez-Castaño, M. Angela Nieto

引用次数: 0

Oncolytic viruses and cytokine-based gene therapies reprogram the tumor microenvironment. 溶瘤病毒和基于细胞因子的基因疗法重新编程肿瘤微环境。

IF 28.5 1区医学

Nature cancer Pub Date : 2026-04-24 DOI: 10.1038/s43018-026-01153-y

Joshua D Bernstock, Lennard Spanehl, E Antonio Chiocca

引用次数: 0

New payloads drive next-gen antibody–drug conjugates 新的有效载荷驱动新一代抗体-药物结合物

IF 28.5 1区医学

Nature cancer Pub Date : 2026-04-23 DOI: 10.1038/s43018-026-01152-z

Melanie Senior

引用次数: 0

DeepFAN, a transformer-based model for human-artificial intelligence collaborative assessment of incidental pulmonary nodules in CT scans: a multireader, multicase trial. DeepFAN，一个基于变压器的人-人工智能协同评估CT扫描中偶发肺结节的模型：一个多阅读器，多病例试验。

IF 28.5 1区医学

Nature cancer Pub Date : 2026-04-22 DOI: 10.1038/s43018-026-01147-w

Zhenchen Zhu, Ge Hu, Weixiong Tan, Kai Gao, Chao Sun, Zhen Zhou, Kepei Xu, Wei Han, Meixia Shang, Xiaoming Qiu, Yiqing Tan, Jinhua Wang, Zhoumeng Ying, Li Peng, Wei Song, Lan Song, Zhengyu Jin, Nan Hong, Yizhou Yu

{"title":"DeepFAN, a transformer-based model for human-artificial intelligence collaborative assessment of incidental pulmonary nodules in CT scans: a multireader, multicase trial.","authors":"Zhenchen Zhu, Ge Hu, Weixiong Tan, Kai Gao, Chao Sun, Zhen Zhou, Kepei Xu, Wei Han, Meixia Shang, Xiaoming Qiu, Yiqing Tan, Jinhua Wang, Zhoumeng Ying, Li Peng, Wei Song, Lan Song, Zhengyu Jin, Nan Hong, Yizhou Yu","doi":"10.1038/s43018-026-01147-w","DOIUrl":"https://doi.org/10.1038/s43018-026-01147-w","url":null,"abstract":"The widespread adoption of computed tomography has increased the detection of lung nodules. However, deep learning methods for classification of benign and malignant nodules often fail to comprehensively integrate global and local features, and most of these methods have not been validated through clinical trials. Here we developed DeepFAN, a transformer-based model trained on more than 10,000 pathology-confirmed nodules, and conducted a multireader, multicase clinical trial (Chinese Clinical Trial Registry: ChiCTR2400084624) to evaluate its efficacy in assisting junior radiologists. DeepFAN achieved diagnostic area under the curve (AUC) values of 0.939 (95% CI 0.930-0.948) on an internal test set and 0.954 (95% CI 0.934-0.973) on a clinical trial dataset involving 400 cases across three independent medical institutions. Explainability analysis indicated higher contributions from global than local features. The average performance of 12 readers improved significantly: by 10.9% (95% CI 8.3-13.5%) for AUC, 10.0% (95% CI 8.9-11.1%) for accuracy, 7.6% (95% CI 6.1-9.2%) for sensitivity and 12.6% (95% CI 10.9-14.3%) for specificity (all P < 0.001). Nodule-level interreader diagnostic consistency improved from fair to moderate (overall κ: 0.313 versus 0.421; P = 0.019). These results indicate that DeepFAN can effectively assist junior radiologists and could help to homogenize diagnostic quality and reduce unnecessary follow-up of patients with indeterminate pulmonary nodules.","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":" ","pages":""},"PeriodicalIF":28.5,"publicationDate":"2026-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147775779","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