Nature cancer最新文献

{"title":"Cellular hierarchies of embryonal tumors with multilayered rosettes are shaped by oncogenic microRNAs and receptor–ligand interactions","authors":"Alexander Beck, Lisa Gabler-Pamer, Gustavo Alencastro Veiga Cruzeiro, Sander Lambo, Bernhard Englinger, McKenzie L. Shaw, Olivia A. Hack, Ilon Liu, Rebecca D. Haase, Carlos A. O. de Biagi Jr, Alicia Baumgartner, Andrezza Do Nascimento Silva, Marbod Klenner, Pia S. Freidel, Jochen Herms, Louisa von Baumgarten, Joerg C. Tonn, Niklas Thon, Katharina Bruckner, Sibylle Madlener, Lisa Mayr, Daniel Senfter, Andreas Peyrl, Irene Slavc, Daniela Lötsch, Christian Dorfer, Rene Geyregger, Nicole Amberg, Christine Haberler, Norman Mack, Benjamin Schwalm, Stefan M. Pfister, Andrey Korshunov, Lissa C. Baird, Edward Yang, Susan N. Chi, Sanda Alexandrescu, Johannes Gojo, Marcel Kool, Volker Hovestadt, Mariella G. Filbin","doi":"10.1038/s43018-025-00964-9","DOIUrl":"10.1038/s43018-025-00964-9","url":null,"abstract":"Embryonal tumor with multilayered rosettes (ETMR) is a pediatric brain tumor with dismal prognosis. Characteristic alterations of the chromosome 19 microRNA cluster (C19MC) are observed in most ETMR; however, the ramifications of C19MC activation and the complex cellular architecture of ETMR remain understudied. Here we analyze 11 ETMR samples from patients using single-cell transcriptomics and multiplexed spatial imaging. We reveal a spatially distinct cellular hierarchy that spans highly proliferative neural stem-like cells and more differentiated neuron-like cells. C19MC is predominantly expressed in stem-like cells and controls a transcriptional network governing stemness and lineage commitment, as resolved by genome-wide analysis of microRNA-mRNA binding. Systematic analysis of receptor–ligand interactions between malignant cell types reveals fibroblast growth factor receptor and Notch signaling as oncogenic pathways that can be successfully targeted in preclinical models and in one patient with ETMR. Our study provides fundamental insights into ETMR pathobiology and a powerful rationale for more effective targeted therapies. Beck et al. conducted single-cell and spatial profiling of embryonal tumors with multilayered rosettes, finding that malignant cellular hierarchies are driven by developmental programs and specific members of the chromosome 19 microRNA cluster.","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":"6 6","pages":"1035-1055"},"PeriodicalIF":28.5,"publicationDate":"2025-05-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12202505/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144151120","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":"Sex-specific gut microbiota and neutrophil senescence in bladder cancer","authors":"Luca Danelli","doi":"10.1038/s43018-025-00995-2","DOIUrl":"10.1038/s43018-025-00995-2","url":null,"abstract":"","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":"6 5","pages":"738-738"},"PeriodicalIF":28.5,"publicationDate":"2025-05-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144132684","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":"Tumour plasticity and immune dynamics promote resistance to neo-adjuvant treatment","authors":"","doi":"10.1038/s43018-025-00954-x","DOIUrl":"10.1038/s43018-025-00954-x","url":null,"abstract":"Esophageal adenocarcinoma (EAC) is challenging to treat because it frequently develops resistance to treatment. Multi-omic analyses of EAC during the course of treatment reveal phenotype plasticity of tumor cells and immune dynamics as mechanisms underlying therapy resistance that might have pharmacological relevance.","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":"6 5","pages":"751-752"},"PeriodicalIF":28.5,"publicationDate":"2025-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144128220","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":"Curating a single-cell data atlas for a deeper understanding of intra-tumor heterogeneity","authors":"","doi":"10.1038/s43018-025-00956-9","DOIUrl":"10.1038/s43018-025-00956-9","url":null,"abstract":"We built a repository of 124 tumor single-cell RNA-sequencing datasets and used it to systematically characterize the expression heterogeneity within tumors. These data and analyses together constitute the Curated Cancer Cell Atlas and are freely available for exploration and download via an enhanced online portal.","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":"6 6","pages":"922-923"},"PeriodicalIF":28.5,"publicationDate":"2025-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144128212","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":"Tumor antigens preferentially derive from unmutated genomic sequences in melanoma and non-small cell lung cancer","authors":"Anca Apavaloaei, Qingchuan Zhao, Leslie Hesnard, Maxime Cahuzac, Chantal Durette, Jean-David Larouche, Marie-Pierre Hardy, Krystel Vincent, Sylvie Brochu, Jean-Philippe Laverdure, Joël Lanoix, Mathieu Courcelles, Patrick Gendron, Mathieu Lajoie, Maria Virginia Ruiz Cuevas, Eralda Kina, Julie Perrault, Juliette Humeau, Grégory Ehx, Sébastien Lemieux, Ian R. Watson, Daniel E. Speiser, Michal Bassani-Sternberg, Pierre Thibault, Claude Perreault","doi":"10.1038/s43018-025-00979-2","DOIUrl":"10.1038/s43018-025-00979-2","url":null,"abstract":"Melanoma and non-small cell lung cancer (NSCLC) display exceptionally high mutational burdens. Hence, immune targeting in these cancers has primarily focused on tumor antigens (TAs) predicted to derive from nonsynonymous mutations. Using comprehensive proteogenomic analyses, we identified 589 TAs in cutaneous melanoma (n = 505) and NSCLC (n = 90). Of these, only 1% were derived from mutated sequences, which was explained by a low RNA expression of most nonsynonymous mutations and their localization outside genomic regions proficient for major histocompatibility complex (MHC) class I-associated peptide generation. By contrast, 99% of TAs originated from unmutated genomic sequences specific to cancer (aberrantly expressed tumor-specific antigens (aeTSAs), n = 220), overexpressed in cancer (tumor-associated antigens (TAAs), n = 165) or specific to the cell lineage of origin (lineage-specific antigens (LSAs), n = 198). Expression of aeTSAs was epigenetically regulated, and most were encoded by noncanonical genomic sequences. aeTSAs were shared among tumor samples, were immunogenic and could contribute to the response to immune checkpoint blockade observed in previous studies, supporting their immune targeting across cancers. Based on a proteogenomic analysis, Perreault and colleagues report that the majority of predicted tumor antigens originate from unmutated genomic sequences in melanoma and non-small cell lung cancer.","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":"6 8","pages":"1419-1437"},"PeriodicalIF":28.5,"publicationDate":"2025-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12380612/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144128216","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":"Classifying InDel signatures in tumors","authors":"Tiffanie Chouleur","doi":"10.1038/s43018-025-00999-y","DOIUrl":"10.1038/s43018-025-00999-y","url":null,"abstract":"","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":"6 5","pages":"739-739"},"PeriodicalIF":28.5,"publicationDate":"2025-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144128166","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":"Resistance to TIL therapy in lung cancer mediated by clonal T cell loss and neoantigen escape","authors":"","doi":"10.1038/s43018-025-00947-w","DOIUrl":"10.1038/s43018-025-00947-w","url":null,"abstract":"By tracking tumor antigens and tumor-reactive T cell clones in serial tumor and blood samples, we identify key mechanisms of resistance to tumor-infiltrating lymphocyte (TIL) therapy of lung cancer. Loss of antitumor reactivity and exhaustion by infused TILs was associated with therapy resistance. New tumors that emerged lacked the original antigens or tumor-reactive T cells, which suggests adaptive resistance.","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":"6 5","pages":"749-750"},"PeriodicalIF":28.5,"publicationDate":"2025-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144120343","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":"Age-associated nicotinamide adenine dinucleotide decline drives CAR-T cell failure","authors":"Helen Carrasco Hope, Jana de Sostoa, Pierpaolo Ginefra, Massimo Andreatta, Yi-Hsuan Chiang, Catherine Ronet, Christine Pich-Bavastro, Jesús Corria Osorio, François Kuonen, Johan Auwerx, Patrizia D’Amelio, Ping-Chih Ho, Santiago J. Carmona, George Coukos, Denis Migliorini, Nicola Vannini","doi":"10.1038/s43018-025-00982-7","DOIUrl":"10.1038/s43018-025-00982-7","url":null,"abstract":"Chimeric antigen receptor (CAR) T cell therapy is one of the most promising cancer treatments. However, different hurdles are limiting its application and efficacy. In this context, how aging influences CAR-T cell outcomes is largely unknown. Here we show that CAR-T cells generated from aged female mice present a mitochondrial dysfunction derived from nicotinamide adenine dinucleotide (NAD) depletion that leads to poor stem-like properties and limited functionality in vivo. Moreover, human data analysis revealed that both age and NAD metabolism determine the responsiveness to CAR-T cell therapy. Targeting NAD pathways, we were able to recover the mitochondrial fitness and functionality of CAR-T cells derived from older adults. Altogether, our study demonstrates that aging is a limiting factor to successful CAR-T cell responses. Repairing metabolic and functional obstacles derived from age, such as NAD decline, is a promising strategy to improve current and future CAR-T cell therapies. Vannini and colleagues report that an age-associated decline in nicotinamide adenine dinucleotide levels is associated with mitochondrial dysfunction and reduced antitumor efficacy of chimeric antigen receptor T cells derived from older adults.","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":"6 9","pages":"1524-1536"},"PeriodicalIF":28.5,"publicationDate":"2025-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s43018-025-00982-7.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144111200","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":"Sensitizing solid tumors to CAR-mediated cytotoxicity by lipid nanoparticle delivery of synthetic antigens","authors":"Lena Gamboa, Ali H. Zamat, Chloé A. Thiveaud, Hee Jun Lee, Elif Kulaksizoglu, Zizhen Zha, Noah S. Campbell, Ching Shen Chan, Sydney Fábrega, S. Abbey Oliver, Fang-Yi Su, Hathaichanok Phuengkham, Daryll Vanover, Hannah E. Peck, Anirudh Sivakumar, Shreyas N. Dahotre, Adrian M. Harris, Philip J. Santangelo, Gabriel A. Kwong","doi":"10.1038/s43018-025-00968-5","DOIUrl":"10.1038/s43018-025-00968-5","url":null,"abstract":"Chimeric antigen receptor (CAR) T cell immunotherapy relies on CAR targeting of tumor-associated antigens; however, heterogenous antigen expression, interpatient variation and off-tumor expression by healthy cells remain barriers. Here we develop synthetic antigens to sensitize solid tumors for recognition and elimination by CAR T cells. Unlike tumor-associated antigens, we design synthetic antigens that are orthogonal to endogenous proteins to eliminate off-tumor targeting and that have a small genetic footprint to facilitate efficient tumor delivery to tumors by lipid nanoparticles. Using a camelid single-domain antibody (VHH) as a synthetic antigen, we show that adoptive transfer of anti-VHH CAR T cells to female mice bearing VHH-expressing tumors reduced tumor burden in multiple syngeneic and xenograft models of cancer, improved survival, induced epitope spread, protected against tumor rechallenge and mitigated antigen escape in heterogenous tumors. Our work supports the in situ delivery of synthetic antigens to treat antigen-low or antigen-negative tumors with CAR T cells. Gamboa et al. develop a chimeric antigen receptor (CAR) T cell therapeutic strategy based on synthetic antigens that are delivered to the tumor by lipid nanoparticles and demonstrate the therapeutic efficacy of their approach using CAR T cells directed against the synthetic antigen.","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":"6 6","pages":"1073-1087"},"PeriodicalIF":28.5,"publicationDate":"2025-05-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144086442","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":"Fishing for melanoma metastasis-initiating cells in lymph nodes","authors":"Panagiotis Karras, Jean-Christophe Marine","doi":"10.1038/s43018-025-00973-8","DOIUrl":"10.1038/s43018-025-00973-8","url":null,"abstract":"The complex nature of metastasis-initiating cells (MICs) has long hindered our understanding of how cancer spreads and how to prevent it. A study now identifies a potential MIC population and a crucial role for extracellular vesicles in the immune-evasion tactics of these cells.","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":"6 6","pages":"919-921"},"PeriodicalIF":28.5,"publicationDate":"2025-05-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144086420","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}