Nature cancer最新文献

{"title":"Characterization of cis-regulatory elements and functional variants in colorectal cancer using epigenomics and CRISPRi screenings.","authors":"Zequn Lu, Can Chen, Heng Zhang, Bin Li, Yizhuo Liu, Jiayi Guo, Runying Xu, Ke Shi, Qianying Ma, Ming Zhang, Yimin Cai, Jinyu Huang, Hui Geng, Linyun Fan, Caibo Ning, Yanmin Li, Shuoni Chen, Wen Tian, Kexin Hu, Haijie Li, Xiaojun Yang, Chaoqun Huang, Yongchang Wei, Xu Zhu, Xiangpan Li, Zhen Xiong, Ming Cai, Xiaoyang Wang, Shaokai Zhang, Hongda Chen, Min Dai, Kun Chen, Mingjuan Jin, Meng Jin, Ying Zhu, Jianbo Tian, Xiaoping Miao","doi":"10.1038/s43018-025-01031-z","DOIUrl":"https://doi.org/10.1038/s43018-025-01031-z","url":null,"abstract":"<p><p>Genetic variants associated with colorectal cancer (CRC) are primarily noncoding and reside in cis-regulatory elements (CREs), yet their underlying mechanisms remain elusive. Here we established a dynamic epigenetic atlas using multiomics data from 533 colorectal tissues spanning normal to advanced adenoma to cancer, identifying 7,492 differential CREs linked to 5,490 target genes. High-throughput CRISPR interference screening revealed 265 functional CREs involved in CRC cell proliferation. A polygenic risk score (PRS) based on functional CRE variants effectively predicted CRC and precancerous lesions among 476,770 individuals. Notably, the functional variant rs10871066 was significantly associated with increased risk of precancerous lesions and CRC (odds ratio = 1.27, P = 1.03 × 10^-13). Mechanistically, rs10871066 triggers silencer-to-enhancer switching mediated by FOXP1 and TCF7L2, distally upregulating KLF5 to activate oncogenic pathways and PIBF1 to suppress natural killer cell cytotoxicity. Our study provides a comprehensive resource of dynamic epigenomic atlas, a functionally informed PRS for risk prediction and insights into epigenetic mechanisms underlying CRC development.</p>","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":" ","pages":""},"PeriodicalIF":28.5,"publicationDate":"2025-08-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144961855","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":"Colorectal cancer cells hijack a brain-gut polysynaptic circuit from the lateral septum to enteric neurons to sustain tumor growth.","authors":"Ying Li, Hao Yu, Zi-Ming Li, Kai-Wen Yin, Shi-Yang Jin, Chao-Chao Chen, Ming-Shi Tan, Chuan-Jie Zhang, Xun-Hua Liu, Wei-Peng Li, Jian-Ming Yang, Ai-Jun Zhou, Xiang Zhang, En-De Ni, Meng-Ling Wang, Hui Mo, Chao Qin, Jian Hu, Shu-Ji Li, Tian-Ming Gao, Jian-Ming Li","doi":"10.1038/s43018-025-01033-x","DOIUrl":"10.1038/s43018-025-01033-x","url":null,"abstract":"<p><p>The bidirectional interaction between the brain and peripheral tumors is critical but poorly understood. Here we show GABAergic neurons in the lateral septum, a key brain region implicated in emotional regulation, connect via a polysynaptic circuit to enteric cholinergic neurons that send nerve fibers into the tumor microenvironment, which were then hijacked by colorectal cancer cells to sustain tumor growth in mice. Functionally, activation of this septo-enteric circuit induces GABA release from enteric cholinergic neurons, which in turn activates epsilon-subunit-containing GABA_A receptors on tumor cells. Notably, chronic restraint stress potentiates activity within this circuit, exacerbating tumor progression. Clinically, patients with colorectal cancer exhibiting elevated neuronal activity in the septal region present with larger primary tumors. Collectively, our findings uncover a stress-sensitive septo-enteric polysynaptic pathway exploited by cancer cells to promote tumor growth, underscoring the previously unrecognized role of lateral septum-mediated neural circuitry and psychological stress in cancer progression.</p>","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":" ","pages":""},"PeriodicalIF":28.5,"publicationDate":"2025-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144961905","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":"A sphingolipid-derived paclitaxel nanovesicle enhances efficacy of combination therapies in triple-negative breast cancer and pancreatic cancer.","authors":"Zhiren Wang, Wenpan Li, Yanhao Jiang, Teng Ma, Mengwen Li, Shuang Wu, Tuyen Ba Tran, Leyla Estrella Cordova, Ethan Lin, Aaron James Scott, Jennifer Erdrich, Joyce Schroeder, Pavani Chalasani, Jianqin Lu","doi":"10.1038/s43018-025-01029-7","DOIUrl":"10.1038/s43018-025-01029-7","url":null,"abstract":"<p><p>Taxol and Abraxane, the US Food and Drug Administration-approved paclitaxel (PTX) formulations, have revealed hypersensitivity due to excipients and mediocre efficacy due to insufficient tumor penetration, respectively. Here we developed a sphingolipid-derived PTX nanovesicle (paclitaxome) via covalently conjugating PTX to sphingomyelin, which improved pharmacokinetics and enhanced efficacy in metastatic triple-negative breast cancer and pancreatic cancer female mice and reduced myelosuppression. To bolster tumor penetration and reduce phagocytosis, we engineered a cationization-enabled transcytosis machinery by installing an ultra-pH-sensitive azepane (AZE) probe into paclitaxome and masked nanovesicle surface with a CD47 'self' peptide (CD47p). The resulting CD47p/AZE-paclitaxome synchronized the co-delivery of gemcitabine or carboplatin to boost tumor inhibition and eradicate metastasis in late-stage KPC-Luc pancreatic cancer model and prevent tumor relapse and extend survival in postsurgical 4T1-Luc2 triple-negative breast cancer model in female mice. CD47p/AZE-paclitaxome also outperformed previous promising PTX nanoformulations. Finally, the series of nanoparticle modifications was applied to camptothecin, demonstrating its generalizability.</p>","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":" ","pages":""},"PeriodicalIF":28.5,"publicationDate":"2025-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144961897","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":"Evolutionary trajectories of IDH-mutant astrocytoma identify molecular grading markers related to cell cycling.","authors":"Wies R Vallentgoed, Youri Hoogstrate, Karin A van Garderen, Levi van Hijfte, Erik van Dijk, Mathilde C M Kouwenhoven, Johanna M Niers, Kaspar Draaisma, Ivonne Martin, Wendy W J de Leng, C Mircea S Tesileanu, Iris de Heer, Maud Diepeveen, Anna Lavrova, Paul P Eijk, Marcel Bühler, Wolfgang Wick, Paul M Clement, Marc Sanson, Enrico Franceschi, Thierry Gorlia, Vassilis Golfinopoulos, Michael Weller, Tobias Weiss, Pierre A Robe, Johan M Kros, Marion Smits, Mark van de Wiel, Bauke Ylstra, Roel G W Verhaak, Martin J van den Bent, Bart A Westerman, Pieter Wesseling, Pim J French","doi":"10.1038/s43018-025-01023-z","DOIUrl":"10.1038/s43018-025-01023-z","url":null,"abstract":"<p><p>The evolutionary processes that drive malignant progression of IDH-mutant astrocytomas remain unclear. Here, we performed multiomics on matched initial and recurrent tumor samples from a cohort of 105 patients and overlaid the data with detailed clinical annotation. We identified overlapping features associated with malignant progression that are derived from three molecular mechanisms: cell cycling, tumor cell (de)differentiation and remodeling of the extracellular matrix. Together, they provide a rationale of the underlying biology of tumor malignancy. DNA methylation levels decreased over time, predominantly in tumors with malignant transformation, and co-occurred with poor prognostic genetic events. We identified a DNA methylation-based signature strongly associated with survival, which allows objective, molecular-based grading of IDH-mutant astrocytomas to aid clinical decision making. Our findings were validated on large, independent cohorts of IDH-mutant astrocytoma samples. Lastly, in this retrospective study, we found little effect of radiotherapy or chemotherapy on the molecular features associated with malignant progression.</p>","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":" ","pages":""},"PeriodicalIF":28.5,"publicationDate":"2025-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144883219","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":"Prospects for ferroptosis therapies in cancer","authors":"Jessalyn M. Ubellacker,&nbsp;Scott J. Dixon","doi":"10.1038/s43018-025-01037-7","DOIUrl":"10.1038/s43018-025-01037-7","url":null,"abstract":"Ferroptosis is a nonapoptotic form of cell death characterized by lethal membrane lipid peroxidation. This mechanism was first characterized in cancer cells well over a decade ago, and there is much enthusiasm for the concept that certain cancers may be treated by inducing ferroptosis. However, therapies that engage ferroptosis have yet to enter clinical testing. In this Review, we highlight the gap between our rapidly expanding knowledge of the ferroptosis mechanism and its translation into cancer therapies. We discuss the known challenges that may be slowing ferroptosis therapies from reaching the clinic. Ubellacker and Dixon summarize the latest discoveries on ferroptosis in cancer, covering the molecular and cellular pathways underlying sensitivity and resistance to this type of cell death, as well as potential translational applications in cancer therapeutics.","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":"6 8","pages":"1326-1336"},"PeriodicalIF":28.5,"publicationDate":"2025-08-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144874210","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":"Innovative ways to target (K)RAS dependencies","authors":"Heathcliff Dorado García","doi":"10.1038/s43018-025-01040-y","DOIUrl":"10.1038/s43018-025-01040-y","url":null,"abstract":"","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":"6 8","pages":"1300-1300"},"PeriodicalIF":28.5,"publicationDate":"2025-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144847661","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":"SWIFT-seq enables comprehensive single-cell transcriptomic profiling of circulating tumor cells in multiple myeloma and its precursors","authors":"Elizabeth D. Lightbody,&nbsp;Romanos Sklavenitis-Pistofidis,&nbsp;Ting Wu,&nbsp;Junko Tsuji,&nbsp;Danielle T. Firer,&nbsp;Michael P. Agius,&nbsp;Ankit K. Dutta,&nbsp;Hadley Barr,&nbsp;Sungjae Kim,&nbsp;Jean-Baptiste Alberge,&nbsp;Sarah Nersesian,&nbsp;Tim Coorens,&nbsp;Nicholas J. Haradhvala,&nbsp;Nang Kham Su,&nbsp;Cody J. Boehner,&nbsp;Michelle P. Aranha,&nbsp;Mahshid Rahmat,&nbsp;Yoshinobu Konishi,&nbsp;Laura Hevenor,&nbsp;Katherine Towle,&nbsp;Erica Horowitz,&nbsp;Jacqueline Perry,&nbsp;Maya Davis,&nbsp;Kelly A. Walsh,&nbsp;Christian J. Cea-Curry,&nbsp;Grace Fleming,&nbsp;Michael E. Vinyard,&nbsp;Daniel Heilpern-Mallory,&nbsp;Habib El-Khoury,&nbsp;Annie Cowan,&nbsp;John E. Ready,&nbsp;Catherine R. Marinac,&nbsp;Gad Getz,&nbsp;Irene M. Ghobrial","doi":"10.1038/s43018-025-01006-0","DOIUrl":"10.1038/s43018-025-01006-0","url":null,"abstract":"Multiple myeloma is a bone marrow (BM) plasma cell malignancy preceded by precursor conditions. BM biopsies are conducted infrequently and can yield inconclusive results due to technical limitations. Profiling circulating tumor cells (CTCs) may enable noninvasive routine clinical assessments but remains challenging. Here, to address this, we describe a single-cell sequencing workflow to interrogate few tumor cells (SWIFT-seq), and employ single-cell RNA sequencing and B cell receptor sequencing on paired BM and CTCs from 101 patients and healthy donors. We establish a sequencing-based CTC enumeration strategy and develop a CTC classifier to infer cytogenetic abnormalities. Additionally, we leverage expression profiling to measure tumor proliferative index in CTCs, and demonstrate that clonal dynamics can be captured in CTCs. Last, we propose a circulatory dynamics model whereby tumor burden, proliferation, cytogenetics and a circulatory capacity signature influence CTC burden. Overall, SWIFT-seq may advance blood-based myeloma diagnostics, surveillance and prognostication, and reveal biological mechanisms of tumor dissemination. Lightbody et al. present SWIFT-seq, a single-cell RNA sequencing approach to profile circulating tumor cells from patients with multiple myeloma and its precursor conditions and leverage it to derive clinical and biological insights into the disease.","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":"6 9","pages":"1595-1611"},"PeriodicalIF":28.5,"publicationDate":"2025-08-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144804379","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":"Nanotechnology for immuno-oncology","authors":"Adam J. Grippin,&nbsp;DaeYong Lee,&nbsp;Eileen E. Parkes,&nbsp;Wen Jiang,&nbsp;Betty Y. S. Kim","doi":"10.1038/s43018-025-01025-x","DOIUrl":"10.1038/s43018-025-01025-x","url":null,"abstract":"Although the first generation of cancer immunotherapeutics produced unprecedented improvements in clinical outcomes for individuals with cancer, novel strategies to increase treatment specificity, delivery efficiency and pharmacokinetics are still needed. In this Review, we describe the potential advantages and current limitations of nanomaterials for cancer immunotherapy and highlight rational uses of nanosystems to generate potent and durable antitumor immune responses. We close with a review of the current state of clinical development of nanomedicine for cancer immunotherapy. Kim and colleagues provide an overview of the current state of the art of nanomaterials and their application in immuno-oncology, discussing preclinical development and the clinical landscape.","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":"6 8","pages":"1311-1325"},"PeriodicalIF":28.5,"publicationDate":"2025-08-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144799708","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":"Author Correction: RIOK1 phase separation restricts PTEN translation via stress granules activating tumor growth in hepatocellular carcinoma","authors":"Fanzheng Meng,&nbsp;Hairui Li,&nbsp;Yabin Huang,&nbsp;Chunxu Wang,&nbsp;Yufeng Liu,&nbsp;Chunting Zhang,&nbsp;Danlei Chen,&nbsp;Taofei Zeng,&nbsp;Shenyu Zhang,&nbsp;Yunyun Li,&nbsp;Bo Zhang,&nbsp;Chuandong Lang,&nbsp;Jie Xia,&nbsp;Wanxiang Xiong,&nbsp;Shixiang Pan,&nbsp;Xuedan Sun,&nbsp;Rick F. Thorne,&nbsp;Yao Liu,&nbsp;Jiabei Wang,&nbsp;Shugeng Zhang,&nbsp;Ruipeng Song,&nbsp;Jizhou Wang,&nbsp;Lianxin Liu","doi":"10.1038/s43018-025-01043-9","DOIUrl":"10.1038/s43018-025-01043-9","url":null,"abstract":"","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":"6 9","pages":"1612-1612"},"PeriodicalIF":28.5,"publicationDate":"2025-08-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s43018-025-01043-9.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144784790","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}

{"title":"Improved immune responses in lung cancer with radiotherapy and immune checkpoint inhibition.","authors":"","doi":"10.1038/s43018-025-01019-9","DOIUrl":"10.1038/s43018-025-01019-9","url":null,"abstract":"","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":" ","pages":""},"PeriodicalIF":28.5,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144765024","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}