Nature cancer最新文献

{"title":"MCSP+ metastasis founder cells activate immunosuppression early in human melanoma metastatic colonization","authors":"Severin Guetter, Courtney König, Huiqin Koerkel-Qu, Aleksandra Markiewicz, Sebastian Scheitler, Marie Katzer, Mark Berneburg, Philipp Renner, Beatrix Cucuruz, Leonhard Guttenberger, Veronika Naimer, Kathrin Weidele, Steffi Treitschke, Christian Werno, Hanna Jaser, Tonia Bargmann, Armin Braun, Florian Weber, Katja Evert, Alexander Rochwarger, Christian M. Schürch, Katharina Limm, Peter J. Oefner, Reinhard Rachel, Felix Baumann, Jens Warfsmann, Lisa Schmidleithner, Kathrin Guetter, Parvaneh Mohammadi, Anja Ulmer, Sebastian Haferkamp, Christoph A. Klein, Melanie Werner-Klein","doi":"10.1038/s43018-025-00963-w","DOIUrl":"10.1038/s43018-025-00963-w","url":null,"abstract":"To investigate the early, poorly understood events driving metastatic progression, we searched for the earliest detectable disseminated cancer cells (DCCs), also often referred to as disseminated tumor cells (DTCs), in sentinel lymph node (SLN) biopsies of 492 patients with stage I–III melanoma. Using micromanipulator-assisted isolation of rare DCCs, single-cell mRNA and DNA sequencing, codetection by indexing immunofluorescence imaging and survival analysis, we identified melanoma-associated chondroitin sulfate proteoglycan (MCSP)+ melanoma cells as metastasis founder cells (MFCs). We found that DCCs entering SLNs predominantly exhibited a transitory phenotype that, upon interferon-γ exposure triggered by CD8 T cells, dedifferentiated into a neural-crest-like phenotype. This was accompanied by increased production of small extracellular vesicles (sEVs) carrying the immunomodulatory proteins CD155 and CD276 but rarely programmed cell death protein 1 ligand 1. The sEVs suppressed CD8 T cell proliferation and function, facilitating colony formation. Targeting MCSP+ MFCs or their immune escape mechanisms could be key to curing melanoma early by preventing manifestation of metastasis. Guetter et al. identify a melanoma-associated chondroitin sulfate proteoglycan-positive subpopulation of metastasis founder cells from lymph node biopsies of patients with melanoma and observe that they mediate immune evasion and predict systemic metastasis and poor outcomes.","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":"6 6","pages":"1017-1034"},"PeriodicalIF":28.5,"publicationDate":"2025-05-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12202500/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144086423","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":"Evolutionary and immune microenvironment dynamics during neoadjuvant treatment of esophageal adenocarcinoma","authors":"Melissa Barroux, Jacob Househam, Eszter Lakatos, Tahel Ronel, Ann-Marie Baker, Henrike Salié, Maximilian Mossner, Kane Smith, Chris Kimberley, Salpie Nowinski, Alison Berner, Vinaya Gunasri, Martin Borgmann, Sven Liffers, Marnix Jansen, Giulio Caravagna, Katja Steiger, Julia Slotta-Huspenina, Wilko Weichert, Luis Zapata, Eleftheria Giota, Sylvie Lorenzen, Markus Alberstmeier, Benny Chain, Helmut Friess, Bertram Bengsch, Roland M. Schmid, Jens T. Siveke, Michael Quante, Trevor A. Graham","doi":"10.1038/s43018-025-00955-w","DOIUrl":"10.1038/s43018-025-00955-w","url":null,"abstract":"Locally advanced esophageal adenocarcinoma remains difficult to treat and the ecological and evolutionary dynamics responsible for resistance and recurrence are incompletely understood. Here, we performed longitudinal multiomic analysis of patients with esophageal adenocarcinoma in the MEMORI trial. Multi-region multi-timepoint whole-exome and paired transcriptome sequencing was performed on 27 patients before, during and after neoadjuvant treatment. We found major transcriptomic changes during treatment with upregulation of immune, stromal and oncogenic pathways. Genetic data revealed that clonal sweeps through treatment were rare. Imaging mass cytometry and T cell receptor sequencing revealed remodeling of the tumor microenvironment during treatment. The presence of genetic immune escape, a less-cytotoxic T cell phenotype and a lack of clonal T cell expansions were linked to poor treatment response. In summary, there were widespread transcriptional and environmental changes through treatment, with limited clonal replacement, suggestive of phenotypic plasticity. Graham and colleagues analyzed locally advanced esophageal adenocarcinoma clinical trial patient samples and identified major changes in gene expression profiles and immune microenvironment composition independent of changes in clonal composition.","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":"6 5","pages":"820-837"},"PeriodicalIF":28.5,"publicationDate":"2025-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12122370/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144079240","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":"CHD1 status drives divergent metabolic pathways in SPOP-mutant prostate cancer","authors":"Jacob J. Orme, Emmanuel S. Antonarakis, Scott M. Dehm","doi":"10.1038/s43018-025-00959-6","DOIUrl":"10.1038/s43018-025-00959-6","url":null,"abstract":"CHD1 loss is common in SPOP-mutant prostate cancer; however, this combined phenotype has not yet been clearly defined. Genetically engineered mouse models of prostate cancer with Chd1 loss and Spop mutation now reveal a mechanism of castration resistance driven by enhanced intracellular cholesterol and androgen biosynthesis.","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":"6 5","pages":"740-742"},"PeriodicalIF":28.5,"publicationDate":"2025-05-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144028276","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":"CHD1 loss reprograms SREBP2-driven cholesterol synthesis to fuel androgen-responsive growth and castration resistance in SPOP-mutated prostate tumors","authors":"Feiyu Chen, Haoyan Li, Yin Wang, Ximing Tang, Kevin Lin, Qidong Li, Chenling Meng, Wei Shi, Javier Leo, Xin Liang, Jie Zhang, Vivien Van, Iqbal Mahmud, Bo Wei, Philip L. Lorenzi, Maria G. Raso, Ana Aparicio, Yue Lu, Daniel E. Frigo, Boyi Gan, Di Zhao","doi":"10.1038/s43018-025-00952-z","DOIUrl":"10.1038/s43018-025-00952-z","url":null,"abstract":"Despite undergoing castration, most individuals with prostate cancer (PCa) experience progression to castration-resistant PCa (CRPC), in which the androgen receptor (AR) remains an important driver. Concurrent genetic alterations in SPOP and CHD1 define a unique subtype of PCa, but their interactions in tumor progression and therapy response remain unclear. Here, we provide genetic evidence supporting that CHD1 loss accelerates disease progression and confers resistance to castration in males with SPOP-mutated PCa. By leveraging genetic engineering and multiomics, we uncovered a noncanonical function of CHD1 in lipid metabolism reprogramming via repressing the SREBP2 transcriptome. Loss of CHD1 induces cholesterol production, supplies intratumoral androgen biosynthesis and enhances AR activity, leading to castration resistance of SPOP-mutated PCa. Combining anti-androgen therapy with cholesterol-lowering drugs showed synergistic and durable activity against CRPC harboring CHD1 loss and SPOP mutations. These findings advance our understanding of an emerging PCa subtype and offer biomarker-driven combinatorial treatment strategies for men with CRPC. Chen at al. show that CHD1 loss in SPOP-mutated prostate tumors confers castration resistance by increasing SREBP2-mediated cholesterol synthesis and subsequent androgen supply, an effect counteracted by combined androgen and cholesterol inhibition.","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":"6 5","pages":"854-873"},"PeriodicalIF":28.5,"publicationDate":"2025-05-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144005998","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":"Atezolizumab plus personalized neoantigen vaccination in urothelial cancer: a phase 1 trial","authors":"Mansi Saxena, Jonathan F. Anker, Julia Kodysh, Timothy O’Donnell, Anna M. Kaminska, Marcia Meseck, Olivia Hapanowicz, Scot Anthony Niglio, Andres M. Salazar, Hardik R. Shah, Yayoi Kinoshita, Rachel Brody, Alex Rubinsteyn, Robert P. Sebra, Nina Bhardwaj, Matthew D. Galsky","doi":"10.1038/s43018-025-00966-7","DOIUrl":"10.1038/s43018-025-00966-7","url":null,"abstract":"Features of constrained adaptive immunity and high neoantigen burden have been correlated with response to immune checkpoint inhibitors (ICIs). In an attempt to stimulate antitumor immunity, we evaluated atezolizumab (anti-programmed cell death protein 1 ligand 1) in combination with PGV001, a personalized neoantigen vaccine, in participants with urothelial cancer. The primary endpoints were feasibility (as defined by neoantigen identification, peptide synthesis, vaccine production time and vaccine administration) and safety. Secondary endpoints included objective response rate, duration of response and progression-free survival for participants treated in the metastatic setting, time to progression for participants treated in the adjuvant setting, overall survival and vaccine-induced neoantigen-specific T cell immunity. A vaccine was successfully prepared (median 20.3 weeks) for 10 of 12 enrolled participants. All participants initiating treatment completed the priming cycle. The most common treatment-related adverse events were grade 1 injection site reactions, fatigue and fever. At a median follow-up of 39 months, three of four participants treated in the adjuvant setting were free of recurrence and two of five participants treated in the metastatic setting with measurable disease achieved an objective response. All participants demonstrated on-treatment emergence of neoantigen-specific T cell responses. Neoantigen vaccination plus ICI was feasible and safe, meeting its endpoints, and warrants further investigation. ClinicalTrials.gov registration: NCT03359239 . Galsky and colleagues report the results of a phase 1 clinical trial of anti-programmed cell death protein 1 ligand 1 atezolizumab in combination with PGV001, a personalized neoantigen vaccine, in participants with urothelial cancer.","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":"6 6","pages":"988-999"},"PeriodicalIF":28.5,"publicationDate":"2025-05-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144010065","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":"Personalized neoantigen vaccines in urologic malignancies","authors":"Behzad Jazayeri, Roger Li","doi":"10.1038/s43018-025-00944-z","DOIUrl":"10.1038/s43018-025-00944-z","url":null,"abstract":"Personalized neoantigen vaccines utilize mutation-driven neoantigens to induce tumor-specific immune responses. This strategy is now shown to be feasible and safe, with preliminary evidence of efficacy and immunogenicity in patients with urothelial cancer or renal-cell carcinoma.","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":"6 6","pages":"916-918"},"PeriodicalIF":28.5,"publicationDate":"2025-05-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144002010","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":"The Curated Cancer Cell Atlas provides a comprehensive characterization of tumors at single-cell resolution","authors":"Michael Tyler, Avishai Gavish, Chaya Barbolin, Roi Tschernichovsky, Rouven Hoefflin, Michael Mints, Sidharth V. Puram, Itay Tirosh","doi":"10.1038/s43018-025-00957-8","DOIUrl":"10.1038/s43018-025-00957-8","url":null,"abstract":"Recent years have seen a rapid proliferation of single-cell cancer studies, yet most of these studies profiled few tumors, limiting their statistical power. Combining data and results across studies holds great promise but also involves various challenges. We recently began to address these challenges by curating a large collection of cancer single-cell RNA-sequencing datasets, leveraging it for systematic analyses of tumor heterogeneity. Here we greatly extend this repository to 124 datasets for over 40 cancer types, together comprising 2,836 samples, with improved data annotations, visualizations and exploration. Using this vast cohort, we generate an updated map of recurrent expression programs in malignant cells and systematically quantify context-dependent gene expression and cell-cycle patterns across cell types and cancer types. These data, annotations and analysis results are all freely available for exploration and download through the Curated Cancer Cell Atlas, a central community resource that opens new avenues in cancer research. Tyler et al. introduce a curated collection of 124 multicancer, single-cell RNA-sequencing datasets with 2,836 samples and present recurrent cancer cell expression metaprograms, quantifying context-dependent expression and proliferation across cell and cancer types.","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":"6 6","pages":"1088-1101"},"PeriodicalIF":28.5,"publicationDate":"2025-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144005122","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":"Impaired T cell and neoantigen retention in time-serial analysis of metastatic non-small cell lung cancer in patients unresponsive to TIL cell therapy","authors":"Chao Wang, Xiaoqing Yu, Jamie K. Teer, Jiqiang Yao, Dongliang Du, Xiaoxian Liu, Zachary J. Thompson, Min Hsuan Wang, Eric A. Welsh, Danish Memon, Timothy A. Chan, Vladimir Makarov, Carmen M. Anadon, Lamees Saeed, Theresa A. Boyle, Bin Fang, John M. Koomen, Cheryl Cox, Ana M. Landin, Sean J. Yoder, Sungjune Kim, Dung-Tsa Chen, Shari A. Pilon-Thomas, Jose R. Conejo-Garcia, Scott J. Antonia, Eric B. Haura, Benjamin C. Creelan","doi":"10.1038/s43018-025-00946-x","DOIUrl":"10.1038/s43018-025-00946-x","url":null,"abstract":"Cell therapy with tumor-infiltrating lymphocytes (TILs) has yielded durable responses for multiple cancer types, but the causes of therapeutic resistance remain largely unknown. Here multidimensional analysis was performed on time-serial tumor and blood in a lung cancer TIL therapy trial. Using T cell receptor sequencing on both functionally expanded T cells and neoantigen-loaded tetramer-sorted T cells, we identified tumor antigen-specific T cell receptors. We then mapped clones into individual transcriptomes and found that tumor-reactive clonotypes expressed a dysfunctional program and lacked stem-like features among patients who lacked clinical benefit. Tracking tumor-reactive clonotypes over time, decay of antigen-reactive peripheral T cell clonotypes was associated with the emergence of progressive disease. Further, subclonal neoantigens previously targeted by infused T cells were subsequently absent within tumors at progression, suggesting potential adaptive resistance. Our findings suggest that targeting clonal antigens and circumventing dysfunctional states may be important for conferring clinical responses to TIL therapy. Wang et al. present T cell receptor sequencing of serial tumor and blood samples from TIL-treated patients with non-small cell lung cancer, identifying tumor-reactive clonotypes expressing dysfunctional programs in patients lacking clinical benefit.","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":"6 5","pages":"801-819"},"PeriodicalIF":28.5,"publicationDate":"2025-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144010080","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 population-based analysis of the molecular landscape of glioma in adolescents and young adults reveals insights into gliomagenesis","authors":"Julie Bennett, Adrian B. Levine, Liana Nobre, Logine Negm, Jiil Chung, Karen Fang, Monique Johnson, Martin Komosa, Stacey Krumholtz, Nuno Miguel Nunes, Mansuba Rana, Scott Ryall, Javal Sheth, Robert Siddaway, Tejus A. Bale, Eric Bouffet, Michael D. Cusimano, Sunit Das, Jay Detsky, Peter Dirks, Matthias A. Karajannis, Paul Kongkham, Alexandra Giantini-Larsen, Bryan Kincheon Li, Mary Jane Lim-Fat, Andrew L. Lin, Warren P. Mason, Alexandra Miller, James R. Perry, Arjun Sahgal, Sameer Farouk Sait, Derek S. Tsang, Gelareh Zadeh, Normand Laperriere, Lananh Nguyen, Andrew Gao, Julia Keith, David G. Munoz, Uri Tabori, Cynthia Hawkins","doi":"10.1038/s43018-025-00962-x","DOIUrl":"10.1038/s43018-025-00962-x","url":null,"abstract":"Gliomas are a major cause of cancer-related deaths in adolescents and young adults (AYAs; ages 15–39 years). Different molecular alterations drive gliomas in children and adults, leading to distinct biology and clinical consequences, but the implications of pediatric- versus adult-type alterations in AYAs are unknown. Our population-based analysis of 1,456 clinically and molecularly characterized gliomas in patients aged 0–39 years addresses this gap. Pediatric-type alterations were found in 31% of AYA gliomas and conferred superior outcomes compared to adult-type alterations. AYA low-grade gliomas with specific RAS–MAPK alterations exhibited senescence, tended to arise in different locations and were associated with superior outcomes compared to gliomas in children, suggesting different cellular origins. Hemispheric IDH-mutant, BRAF p.V600E and FGFR-altered gliomas were associated with the risk of malignant transformation, having worse outcomes with increased age. These insights into gliomagenesis may provide a rationale for earlier intervention for certain tumors to disrupt the typical behavior, leading to improved outcomes. Bennett et al. conducted a population-based study in adolescents and young adults with gliomas, revealing the specific molecular alterations and identifying potential subclassifications and targets.","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":"6 6","pages":"1102-1119"},"PeriodicalIF":28.5,"publicationDate":"2025-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144033970","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":"Palmitoylation regulates ferroptosis and anti-tumor immunity","authors":"Robin Demuynck, Mariia Saviuk, Dmitri V. Krysko","doi":"10.1038/s43018-025-00972-9","DOIUrl":"10.1038/s43018-025-00972-9","url":null,"abstract":"Comprehensive understanding of the molecular mechanisms that underlie ferroptosis is essential for the development of new anti-tumor therapies. Palmitoylation of GPX4 is now shown to increase its stability and change its cellular localization and thus promote resistance to ferroptosis in cancer.","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":"6 5","pages":"746-748"},"PeriodicalIF":28.5,"publicationDate":"2025-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144012092","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}