Nature cancer最新文献

{"title":"Will it be a turning point?","authors":"Sarah-Maria Fendt","doi":"10.1038/s43018-025-01011-3","DOIUrl":"https://doi.org/10.1038/s43018-025-01011-3","url":null,"abstract":"","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":" ","pages":""},"PeriodicalIF":23.5,"publicationDate":"2025-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144554021","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}

{"title":"Efficacy of pembrolizumab and vorinostat combination in patients with recurrent and/or metastatic squamous cell carcinomas: a phase 2 basket trial.","authors":"Edith Borcoman, Bastien Cabarrou, Miguel Francisco, Frédéric Bigot, François Ghiringhelli, Damien Vansteene, François Legrand, Maral Halladjian, Célia Dupain, Olivia Le Saux, Clelia Coutzac, Christian Borel, Raphael Chaltiel, Benoit You, Carlos Gomez-Roca, Sophie Cousin, Elodie Coquan, Aurélien Lambert, Esma Saada-Bouzid, Xavier Durando, Mathilde Saint-Ghislain, Gianmaria Frige, Elena Guerini-Rocco, Maria Manuela Tonini, Ivan Bièche, Zahra Castel-Ajgal, Grégoire Marret, Marie-Paule Sablin, Emmanuelle Jeannot, Fabrice Andre, Thomas Filleron, Marta Jimenez, Luca Mazzarella, Nicolas Servant, Maud Kamal, Christophe Le Tourneau","doi":"10.1038/s43018-025-01004-2","DOIUrl":"https://doi.org/10.1038/s43018-025-01004-2","url":null,"abstract":"<p><p>Immune checkpoint inhibitors improve the treatment of many solid tumors and have shown encouraging results in advanced squamous cell carcinoma (SCC), yet only a minority of patients respond to immune checkpoint inhibitor monotherapy. We conducted the PEVOsq trial, an open-label, nonrandomized, multicenter, basket phase 2 trial to evaluate the combination of pembrolizumab and vorinostat in recurrent/metastatic SCC of various origins. The primary endpoint was the objective response rate (ORR) in each tumor cohort during treatment as per the investigators' assessment. Secondary endpoints included safety and antitumor activity evaluation in terms of centrally confirmed ORR, progression-free survival, overall survival and duration of response. In the efficacy population (n = 107), the ORR was met in cervical (39%), anal (31%) and vulvar/vaginal (19%) cancer cohorts, but not in head and neck SCC (19%) or penile (18%) cancer cohorts (overall ORR = 26%). Median progression-free survival was 4.0 months (95% confidence interval: 2.6-4.3), and median overall survival was 11.1 months (95% confidence interval: 9.2-17.4). In the safety population, 101 (91%) of 111 patients developed at least one treatment-related adverse event, with 39% and 5.4% of patients experiencing at least one grade 3 and grade 4 treatment-related adverse event, respectively. Vorinostat-related toxicity prompted a dose reduction/interruption in 66% of patients. Whole-exome sequencing analyses revealed several potential predictive biomarkers of response to treatment. Further studies in a larger number of patients are required to validate these findings. ClinicalTrials.gov identifier: NCT04357873 .</p>","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":" ","pages":""},"PeriodicalIF":23.5,"publicationDate":"2025-06-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144528987","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}

{"title":"Self-amplifying NRF2-EZH2 epigenetic loop converts KRAS-initiated progenitors to invasive pancreatic cancer.","authors":"Laura Antonucci, Na Li, Angeles Duran, Isidoro Cobo, Chiara Nicoletti, Kosuke Watari, Shuvro Prokash Nandi, Feng Zhu, Yongmei Zhao, Irene Riahi, Motoyuki Tsuda, Vidhi M Shah, Terry Morgan, Trent Waugh, Luca Caputo, Yuan Liu, Alexandra Rundberg Nilsson, Hongxu Xian, Jelena Todoric, Li Gu, Elsa Sanchez-Lopez, Guido Eibl, Emily A Vucic, Michal Krawczyk, Qianlan Xu, Andrew M Lowy, Georgia Hatzivassiliou, Merone Roose-Girma, Dorota Skowronska-Krawczyk, David A Scott, Dafna Bar-Sagi, Pablo Tamayo, Ying Wu, Rosalie C Sears, Christopher K Glass, Ludmil B Alexandrov, Pier Lorenzo Puri, David W Dawson, Yinling Hu, Maria T Diaz-Meco, Jorge Moscat, Michael Karin","doi":"10.1038/s43018-025-01003-3","DOIUrl":"10.1038/s43018-025-01003-3","url":null,"abstract":"<p><p>Pancreatic ductal adenocarcinoma (PDAC) emerges from mutant KRAS-harboring but dormant low-grade pancreatic intraepithelial neoplasia (PanIN). To examine the role of oxidative stress, a putative PDAC risk factor, we established an organoid-based transformation system. Although the prototypic oxidant H₂O₂ induced organoid transformation, its effect was nonmutational and was mediated by the oxidant-responsive transcription factor NRF2, which induced the histone methyltransferase EZH2. Congruently, nonoxidizing NRF2 activators triggered organoid malignant conversion through NRF2 and EZH2, establishing a hitherto unknown epigenetic mechanism underlying PanIN-to-PDAC progression. While NRF2 induced EZH2 gene transcription in mouse and human PDAC, EZH2, a general repressor, coactivated transcription of NRF2-encoding NFE2L2 and interacted with other transcription factors to induce genes that sustain PDAC metabolic demands. The self-amplifying NRF2-EZH2 epigenetic loop also accounted for inflammation-driven PanIN-to-PDAC progression in vivo and was upregulated in established human PDAC, whose malignancy was maintained by NRF2 binding to the EZH2 promoter.</p>","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":" ","pages":""},"PeriodicalIF":23.5,"publicationDate":"2025-06-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144528988","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}

{"title":"Charting human hematopoiesis to understand B cell leukemia.","authors":"Allison L Boyd, Mickie Bhatia","doi":"10.1038/s43018-025-00980-9","DOIUrl":"https://doi.org/10.1038/s43018-025-00980-9","url":null,"abstract":"","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":" ","pages":""},"PeriodicalIF":23.5,"publicationDate":"2025-06-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144512212","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}

{"title":"Profiling antigen-binding affinity of B cell repertoires in tumors by deep learning predicts immune-checkpoint inhibitor treatment outcomes.","authors":"Bing Song, Kaiwen Wang, Saiyang Na, Jia Yao, Farjana J Fattah, Alexandra L Martin, Mitchell S von Itzstein, Donghan M Yang, Jialiang Liu, Yaming Xue, Chaoying Liang, Yuzhi Guo, Indu Raman, Chengsong Zhu, Jonathan E Dowell, Jade Homsi, Sawsan Rashdan, Shengjie Yang, Mary E Gwin, Tuoqi Wu, David Hsiehchen, Yvonne Gloria-McCutchen, Catherine Pei-Ju Lu, Prithvi Raj, Xiao-Chen Bai, Jun Wang, Jose Conejo-Garcia, Yang Xie, Junzhou Huang, David E Gerber, Tao Wang","doi":"10.1038/s43018-025-01001-5","DOIUrl":"https://doi.org/10.1038/s43018-025-01001-5","url":null,"abstract":"<p><p>The capability to profile the landscape of antigen-binding affinities of a vast number of antibodies (B cell receptors, BCRs) will provide a powerful tool to reveal biological insights. However, experimental approaches for detecting antibody-antigen interactions are costly and time-consuming and can only achieve low-to-mid throughput. In this work, we developed Cmai (contrastive modeling for antigen-antibody interactions) to address the prediction of binding between antibodies and antigens that can be scaled to high-throughput sequencing data. We devised a biomarker based on the output from Cmai to map the antigen-binding affinities of BCR repertoires. We found that the abundance of tumor antigen-targeting antibodies is predictive of immune-checkpoint inhibitor (ICI) treatment response. We also found that, during immune-related adverse events (irAEs) caused by ICI, humoral immunity is preferentially responsive to intracellular antigens from the organs affected by the irAEs. We used Cmai to construct a BCR-based irAE risk score, which predicted the timing of the occurrence of irAEs.</p>","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":" ","pages":""},"PeriodicalIF":23.5,"publicationDate":"2025-06-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144512216","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}

{"title":"Innate immunity drives epithelial cell plasticity during prostate tumor formation.","authors":"","doi":"10.1038/s43018-025-01000-6","DOIUrl":"https://doi.org/10.1038/s43018-025-01000-6","url":null,"abstract":"","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":" ","pages":""},"PeriodicalIF":23.5,"publicationDate":"2025-06-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144512213","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}

{"title":"Vascular collapse leads to muscle wasting in cancer cachexia.","authors":"Denis C Guttridge, Teresa A Zimmers","doi":"10.1038/s43018-025-01002-4","DOIUrl":"https://doi.org/10.1038/s43018-025-01002-4","url":null,"abstract":"","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":" ","pages":""},"PeriodicalIF":23.5,"publicationDate":"2025-06-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144512217","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}

{"title":"Multipotent lineage potential in B cell acute lymphoblastic leukemia is associated with distinct cellular origins and clinical features.","authors":"Ilaria Iacobucci, Andy G X Zeng, Qingsong Gao, Laura Garcia-Prat, Pradyumna Baviskar, Sayyam Shah, Alex Murison, Veronique Voisin, Michelle Chan-Seng-Yue, Cheng Cheng, Chunxu Qu, Colin Bailey, Matthew Lear, Matthew T Witkowski, Xin Zhou, Airen Zaldivar Peraza, Karishma Gangwani, Anjali S Advani, Selina M Luger, Mark R Litzow, Jacob M Rowe, Elisabeth M Paietta, Wendy Stock, John E Dick, Charles G Mullighan","doi":"10.1038/s43018-025-00987-2","DOIUrl":"10.1038/s43018-025-00987-2","url":null,"abstract":"<p><p>Developmental origins and their associations with lineage plasticity and treatment response in B-cell progenitor acute lymphoblastic leukemia (B-ALL) are mostly unexplored. Here, we integrated single-cell transcriptome sequencing (scRNA-seq) of 89 B-ALL samples with a single-cell atlas of normal human B cell development incorporating functional and molecular assays. We observed subtype- and sample-dependent correlation with normal developmental stage, with intra-subtype and intra-patient heterogeneity. We show that subtypes prone to shift from the B-lineage (for example BCR::ABL1, KMT2A-R and DUX4-R B-ALL) are enriched for multipotent progenitors and show this developmental stage exhibits CEBPA activation and retains myeloid potential, providing a mechanistic explanation for this clinical observation. We developed a 'multipotency score' most enriched in subtypes exhibiting lineage plasticity that was independently associated with inferior survival. Thus, multipotent B-ALL states reflect the early progenitor origins of a subset of patients with B-ALL and may be relevant for understanding lineage shifting following conventional chemotherapy or immunotherapies.</p>","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":" ","pages":""},"PeriodicalIF":23.5,"publicationDate":"2025-06-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144512214","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}

{"title":"p95HER2, a truncated form of the HER2 oncoprotein, drives an immunosuppressive program in HER2⁺ breast cancer that limits trastuzumab deruxtecan efficacy.","authors":"Dong Hu, Xiaoshuang Lyu, Zheqi Li, Prasanna Ekambaram, Anushka Dongre, Tanner Freeman, Marion Joy, Jennifer M Atkinson, Daniel D Brown, Zongyou Cai, Neil M Carleton, Hannah E Crentsil, John Little, Felicia Kemp, Linda R Klei, Maria Beecher, Jeff Sperinde, Weidong Huang, Heikki Joensuu, Ashok Srinivasan, Katherine L Pogue-Geile, Ying Wang, Huichen Feng, Lisa D Eli, Alshad S Lalani, Jian Zou, George C Tseng, Tullia C Bruno, Adrian V Lee, Steffi Oesterreich, Norman Wolmark, Carmen J Allegra, Samuel A Jacobs, Linda M McAllister-Lucas, Peter C Lucas","doi":"10.1038/s43018-025-00969-4","DOIUrl":"https://doi.org/10.1038/s43018-025-00969-4","url":null,"abstract":"<p><p>Resistance to human epidermal growth factor receptor 2 (HER2)-targeted therapies and immuno-oncology agents poses a major challenge in treating HER2-positive breast cancer. Here we demonstrate that p95HER2, a truncated form of HER2, drives immune evasion in HER2-positive female breast cancer, enhancing tumor growth and conferring therapy resistance. This stems from the unique ability of p95HER2 to promote cancer cell-intrinsic programmed death ligand 1 expression and secretion of immunosuppressive mediators including interleukin 6. In preclinical models, this impairs the efficacy of trastuzumab deruxtecan, a HER2-directed antibody-drug conjugate (ADC) that relies on immunogenic responses to cell death for full efficacy. Importantly, we find that neratinib potently directs proteasomal degradation of p95HER2, relieving its immunosuppressive effects, and provide proof of concept that neratinib and/or agents targeting p95HER2 downstream mediators can restore antitumor immunity and trastuzumab deruxtecan efficacy. This study reveals a p95HER2-specific therapy resistance mechanism in HER2-positive female breast cancer and highlights the potential value of targeting p95HER2 to improve outcomes with ADCs or immuno-oncology agents.</p>","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":" ","pages":""},"PeriodicalIF":23.5,"publicationDate":"2025-06-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144512215","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}

{"title":"Concurrent inhibition of tumor growth and metastasis by a lipidated nanophotosensitizer tracing and disabling tumor extracellular vesicles.","authors":"Guifeng Miao, Zhanhao Shang, Xinyue Wang, Jibin Zhang, Mingheng Xu, Peiyi He, Qinjie Zhong, Xiaoxi Zhao, Guozhu Tan, Xiaorui Wang","doi":"10.1038/s43018-025-00997-0","DOIUrl":"https://doi.org/10.1038/s43018-025-00997-0","url":null,"abstract":"<p><p>Cancer cells promote tumor growth and metastasis through tumor extracellular vesicle (TEV)-mediated intercellular and intertissue communication. Inhibiting TEVs represents a promising strategy to suppress metastasis; however, effectively and selectively disabling TEVs remains challenging. Herein, we developed palmitic acid surface-displayed nanoparticles using an adjacent hydrophilic molecular engineering strategy. Unexpectedly, these lipidated nanoparticles were not only efficiently taken up and distributed within tumor cells but also coupled with TEV generation, enabling active tracing of TEVs. Exploiting their dual tumor spatial distribution (intracellular and intra-TEV), a lipidated nanophotosensitizer was constructed for metastasis therapy. Under near-infrared light irradiation at the primary tumor site, both intracellular and intra-TEV reactive oxygen species were generated synchronously. This led to photodynamic suppression of the primary tumor and blocked intercellular and intertissue communication by disabling TEVs, effectively inhibiting tumor growth and metastasis in multiple tumor models in female mice. Overall, this work reports a therapeutic paradigm for concurrently inhibiting tumor growth and metastasis.</p>","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":" ","pages":""},"PeriodicalIF":23.5,"publicationDate":"2025-06-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144485152","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}