Cancer CellPub Date : 2025-08-07DOI: 10.1016/j.ccell.2025.07.007
Tao Shi, Wei Liu, Yuting Luo, Kaijie Liang, Shiji Ren, Xueru Song, Fangcen Liu, Chun Lu, Daniel Hirschhorn, Hanbing Wang, Yipeng Zhang, Yiran Cai, Yue Wang, Yunfeng Pan, Wenqi Liu, Yang Nie, Ziliang Zhang, Lixia Yu, Shuai Ding, Baorui Liu, Jia Wei
{"title":"CHI3L3+ immature neutrophils inhibit anti-tumor immunity and impede immune checkpoint blockade therapy in bone metastases","authors":"Tao Shi, Wei Liu, Yuting Luo, Kaijie Liang, Shiji Ren, Xueru Song, Fangcen Liu, Chun Lu, Daniel Hirschhorn, Hanbing Wang, Yipeng Zhang, Yiran Cai, Yue Wang, Yunfeng Pan, Wenqi Liu, Yang Nie, Ziliang Zhang, Lixia Yu, Shuai Ding, Baorui Liu, Jia Wei","doi":"10.1016/j.ccell.2025.07.007","DOIUrl":"https://doi.org/10.1016/j.ccell.2025.07.007","url":null,"abstract":"Bone metastases remain incurable and respond poorly to immune checkpoint blockade (ICB) therapy. The impact of neutrophil maturation in cancer, particularly in refractory tumors including bone metastases, is not well understood. Here, we observed the predominance of immature neutrophils in the bone metastasis microenvironment of both mouse models and cancer patients. Dickkopf1 (DKK1) induces an immature-like functional state in neutrophils, which exhibit robust immunosuppressive capabilities to inhibit anti-tumor response of CD8<sup>+</sup> T cells. Mechanistically, the DKK1-CKAP4-STAT6 signaling pathway drives CHI3L3 expression, which is necessary for the immune suppression mediated by immature neutrophils in bone metastases. Moreover, blocking DKK1 promotes neutrophil maturation to improve the immune microenvironment, induces tumor shrinkage, and enhances ICB therapy response in multiple bone metastasis mouse models. These findings uncover a critical role for immature neutrophils in bone metastases and suggest a potential strategy for modulating neutrophils to improve cancer immunotherapy.","PeriodicalId":9670,"journal":{"name":"Cancer Cell","volume":"27 1","pages":""},"PeriodicalIF":50.3,"publicationDate":"2025-08-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144792331","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}
Cancer CellPub Date : 2025-08-07DOI: 10.1016/j.ccell.2025.07.022
Sonia A. Melo, Hikaru Sugimoto, Joyce T. O’Connell, Noritoshi Kato, Alberto Villanueva, August Vidal, Le Qiu, Edward Vitkin, Lev T. Perelman, Carlos A. Melo, Anthony Lucci, Cristina Ivan, George A. Calin, Raghu Kalluri
{"title":"Cancer Exosomes Perform Cell-Independent MicroRNA Biogenesis and Promote Tumorigenesis","authors":"Sonia A. Melo, Hikaru Sugimoto, Joyce T. O’Connell, Noritoshi Kato, Alberto Villanueva, August Vidal, Le Qiu, Edward Vitkin, Lev T. Perelman, Carlos A. Melo, Anthony Lucci, Cristina Ivan, George A. Calin, Raghu Kalluri","doi":"10.1016/j.ccell.2025.07.022","DOIUrl":"https://doi.org/10.1016/j.ccell.2025.07.022","url":null,"abstract":"(Cancer Cell <em>26</em>, 707–721; November 10, 2014)","PeriodicalId":9670,"journal":{"name":"Cancer Cell","volume":"86 1","pages":""},"PeriodicalIF":50.3,"publicationDate":"2025-08-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145009328","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}
Cancer CellPub Date : 2025-07-31DOI: 10.1016/j.ccell.2025.07.011
Shankha Satpathy, Natalie M. Clark, Yi-Ju Chen, Noshad Hosseini, Ya-Hsuan Chang, Yi Hsiao, Jonathan T. Lei, Francesca Petralia, Jin-Shing Chen, Yifat Geffen, David I. Heiman, Indranil Paul, Hanbyul Cho, Michelle Hollenberg, Giacomo B. Marino, Kuen-Tyng Lin, Rahul Mannan, C. Jackson White, Joe Allen, Shayan C. Avanessian, Zoran Andric
{"title":"Integrative analysis of lung adenocarcinoma across diverse ethnicities and exposures","authors":"Shankha Satpathy, Natalie M. Clark, Yi-Ju Chen, Noshad Hosseini, Ya-Hsuan Chang, Yi Hsiao, Jonathan T. Lei, Francesca Petralia, Jin-Shing Chen, Yifat Geffen, David I. Heiman, Indranil Paul, Hanbyul Cho, Michelle Hollenberg, Giacomo B. Marino, Kuen-Tyng Lin, Rahul Mannan, C. Jackson White, Joe Allen, Shayan C. Avanessian, Zoran Andric","doi":"10.1016/j.ccell.2025.07.011","DOIUrl":"https://doi.org/10.1016/j.ccell.2025.07.011","url":null,"abstract":"Lung adenocarcinomas (LUAD) are a pressing global health problem with enduring lethality and rapidly shifting epidemiology. Proteogenomic studies integrating proteomics and post-translational modifications with genomics can identify clinical strata and oncogenic mechanisms, but have been underpowered to examine effects of ethnicity, smoking and environmental exposures, or sex on this heterogeneous disease. This comprehensive proteogenomic analysis of LUAD tumors and matched normal adjacent tissues from 406 patients across diverse geographic and demographic backgrounds explores the impact of understudied driver mutations, prognostic role of chromosomal instability, patterns of immune signaling, differential and sex-specific effects of endogenous mutagens and environmental carcinogens, and pathobiology of early-stage tumors with “late-like” characteristics. Candidate protein biomarkers are proposed for unstable tumors with highly fragmented genomes and for carcinogen exposures, and a LUAD subtype-specific atlas of therapeutic vulnerabilities is presented. These observations and the associated data resource advance the objective of precision management strategies for this devastating disease.","PeriodicalId":9670,"journal":{"name":"Cancer Cell","volume":"131 1","pages":""},"PeriodicalIF":50.3,"publicationDate":"2025-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144748120","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}
Cancer CellPub Date : 2025-07-31DOI: 10.1016/j.ccell.2025.05.001
Analisa DiFeo
{"title":"Immune memory shapes ovarian cancer recurrence","authors":"Analisa DiFeo","doi":"10.1016/j.ccell.2025.05.001","DOIUrl":"https://doi.org/10.1016/j.ccell.2025.05.001","url":null,"abstract":"Despite current progress, many patients with ovarian cancer (OC) often relapse after therapy. In this issue of <em>Cancer Cell</em>, Ghisoni et al. integrate multiomic and functional analyses to provide a roadmap for biomarker-driven therapy in OC and suggest that immune phenotyping could be incorporated into clinical stratification.","PeriodicalId":9670,"journal":{"name":"Cancer Cell","volume":"44 1","pages":""},"PeriodicalIF":50.3,"publicationDate":"2025-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144747835","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}
Cancer CellPub Date : 2025-07-31DOI: 10.1016/j.ccell.2025.07.008
Charles S. Dai, Avanish Mishra, Jon Edd, Mehmet Toner, Shyamala Maheswaran, Daniel A. Haber
{"title":"Circulating tumor cells: Blood-based detection, molecular biology, and clinical applications","authors":"Charles S. Dai, Avanish Mishra, Jon Edd, Mehmet Toner, Shyamala Maheswaran, Daniel A. Haber","doi":"10.1016/j.ccell.2025.07.008","DOIUrl":"https://doi.org/10.1016/j.ccell.2025.07.008","url":null,"abstract":"Circulating tumor cells (CTCs) are cancer cells, shed from primary tumors or metastases into the bloodstream. The first non-invasive “liquid biopsy” for cancer monitoring, CTCs have been largely surpassed by circulating tumor DNA (ctDNA) for clinical applications, given the ease of DNA sequencing without specialized cell isolation methods. However, emerging rare cell capture technologies that can process larger blood volumes and enable advanced single-cell analyses may enhance the range and potential of CTC-based biomarkers. CTCs are increasingly valuable for assessing tumor heterogeneity, guiding protein biomarker-driven cancer immune therapies, and assessing heterogeneous drug resistance, as well as for detecting minimal disease. CTCs, thus, remain central to understanding cancer dissemination and are poised to offer complementary diagnostic roles in the application of minimally invasive liquid biopsies for cancer. Here, we review recent advances in the study of these rare circulating cancer cells and discuss current limitations and future directions.","PeriodicalId":9670,"journal":{"name":"Cancer Cell","volume":"15 1","pages":""},"PeriodicalIF":50.3,"publicationDate":"2025-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144748118","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}
Cancer CellPub Date : 2025-07-31DOI: 10.1016/j.ccell.2025.07.005
Eleonora Ghisoni, Fabrizio Benedetti, Aspram Minasyan, Mathieu Desbuisson, Paula Cunnea, Alizée J. Grimm, Noémie Fahr, Charlotte Capt, Nicolas Rayroux, Flavia De Carlo, Doga C. Gulhan, Julien Dagher, David Barras, Matteo Morotti, Juan A. Marín-Jiménez, Bovannak Stewen Chap, Tania Santoro, Giulia Spagnol, Mapi Fleury, Katerina Fortis, Denarda Dangaj Laniti
{"title":"Myeloid cell networks govern re-establishment of original immune landscapes in recurrent ovarian cancer","authors":"Eleonora Ghisoni, Fabrizio Benedetti, Aspram Minasyan, Mathieu Desbuisson, Paula Cunnea, Alizée J. Grimm, Noémie Fahr, Charlotte Capt, Nicolas Rayroux, Flavia De Carlo, Doga C. Gulhan, Julien Dagher, David Barras, Matteo Morotti, Juan A. Marín-Jiménez, Bovannak Stewen Chap, Tania Santoro, Giulia Spagnol, Mapi Fleury, Katerina Fortis, Denarda Dangaj Laniti","doi":"10.1016/j.ccell.2025.07.005","DOIUrl":"https://doi.org/10.1016/j.ccell.2025.07.005","url":null,"abstract":"Immunotherapy has shown limited success in recurrent ovarian cancer (OC), with prognostic insights largely derived from treatment-naive tumors. We analyzed 697 tumor samples (566 primary and 131 recurrent) from 595 OC patients across five independent cohorts, capturing tumor-infiltrating lymphocytes (TILs) heterogeneity and identifying four immune phenotypes linked to prognosis and TIL:myeloid networks driving malignant progression. We found that in preclinical mouse models, mirroring inflamed human OCs, the recurrent <em>Brca1</em><sup>mut</sup> tumors maintained activated TILs:dendritic cells (DCs) niches but evaded immune control through upregulation of COX/PGE<sub>2</sub> signaling. Conversely, recurrent <em>Brca1</em><sup>wt</sup> tumors displayed loss of TILs:DCs niches and accumulated immunosuppressive tumor microenvironment (TME) networks featuring <em>Trem2/ApoE</em><sup>high</sup> tumor associated macrophages (TAMs) and <em>Nduf4l2</em><sup>high</sup>/<em>Galectin3</em><sup>high</sup> malignant states. Recurrent tumors recapitulate the immunogenic landscapes of original cancers. Our findings reveal BRCA-dependent TIL:myeloid crosstalk as key to persistent immunogenicity in recurrent OC and propose new targets to enhance chemotherapy efficacy.","PeriodicalId":9670,"journal":{"name":"Cancer Cell","volume":"37 1","pages":""},"PeriodicalIF":50.3,"publicationDate":"2025-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144748122","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}
Cancer CellPub Date : 2025-07-24DOI: 10.1016/j.ccell.2025.06.021
Yijuan Zhang, Li Ling, Rabi Murad, Swetha Maganti, Ambroise Manceau, Hannah A. Hetrick, Madelaine Neff, Cheska Marie Galapate, Shea F. Grenier, Florent Carrette, Karen Duong-Polk, Anindya Bagchi, David A. Scott, Yoav Altman, Jennifer L. Hope, Andrew M. Lowy, Linda M. Bradley, Cosimo Commisso
{"title":"Macropinocytosis maintains CAF subtype identity under metabolic stress in pancreatic cancer","authors":"Yijuan Zhang, Li Ling, Rabi Murad, Swetha Maganti, Ambroise Manceau, Hannah A. Hetrick, Madelaine Neff, Cheska Marie Galapate, Shea F. Grenier, Florent Carrette, Karen Duong-Polk, Anindya Bagchi, David A. Scott, Yoav Altman, Jennifer L. Hope, Andrew M. Lowy, Linda M. Bradley, Cosimo Commisso","doi":"10.1016/j.ccell.2025.06.021","DOIUrl":"https://doi.org/10.1016/j.ccell.2025.06.021","url":null,"abstract":"Pancreatic ductal adenocarcinoma (PDAC) tumors are glutamine deficient, and both tumor cells and cancer-associated fibroblasts (CAFs) rely on this amino acid to maintain fitness and induce macropinocytosis as an adaptive response. CAFs play a critical role in sculpting the tumor microenvironment, yet how adaptations to metabolic stress impact the stromal architecture remains elusive. In this study, we find that macropinocytosis sustains the myCAF phenotype under glutamine limitation by preventing inflammatory reprogramming. Our data demonstrate that metabolic stress induces an intrinsic inflammatory CAF (iCAF) program through MEK-ERK signaling. We find that blocking macropinocytosis <em>in vivo</em> promotes myCAF-to-iCAF transitions, remodeling the tumor stroma. Importantly, stromal remodeling driven by macropinocytosis inhibition—including iCAF enrichment, collagen reduction, immune cell infiltration, and vascular expansion—sensitizes PDAC tumors to immunotherapy and chemotherapy. Our findings reveal that inhibiting macropinocytosis promotes an inflammatory, less fibrotic tumor microenvironment that can be leveraged to improve therapeutic responses in PDAC.","PeriodicalId":9670,"journal":{"name":"Cancer Cell","volume":"23 1","pages":""},"PeriodicalIF":50.3,"publicationDate":"2025-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144693926","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}
Cancer CellPub Date : 2025-07-24DOI: 10.1016/j.ccell.2025.07.018
M. Stacey Ricci, Seok-Hyun Kim, Kazuhiro Ogi, John P. Plastaras, Jianhua Ling, Wenge Wang, Zhaoyu Jin, Yingqiu Y. Liu, David T. Dicker, Paul J. Chiao, Keith T. Flaherty, Charles D. Smith, Wafik S. El-Deiry
{"title":"Reduction of TRAIL-Induced Mcl-1 and cIAP2 by c-Myc or Sorafenib Sensitizes Resistant Human Cancer Cells to TRAIL-Induced Death","authors":"M. Stacey Ricci, Seok-Hyun Kim, Kazuhiro Ogi, John P. Plastaras, Jianhua Ling, Wenge Wang, Zhaoyu Jin, Yingqiu Y. Liu, David T. Dicker, Paul J. Chiao, Keith T. Flaherty, Charles D. Smith, Wafik S. El-Deiry","doi":"10.1016/j.ccell.2025.07.018","DOIUrl":"https://doi.org/10.1016/j.ccell.2025.07.018","url":null,"abstract":"No Abstract","PeriodicalId":9670,"journal":{"name":"Cancer Cell","volume":"704 1","pages":""},"PeriodicalIF":50.3,"publicationDate":"2025-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144701408","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}
Cancer CellPub Date : 2025-07-24DOI: 10.1016/j.ccell.2025.07.001
Anna C. Cole, Hannah M. Knochelmann, Megan M. Wyatt, Megen C. Wittling, Natalie K. Horvat, Aubrey S. Smith, Guillermo O. Rangel Rivera, Amalia M. Rivera Reyes, Bhavana Pavuluri, Soundharya Kumaresan, Pawel Muranski, Ayana T. Ruffin, Jeremy M. Boss, Gregory B. Lesinski, Chrystal M. Paulos
{"title":"Adoptively transferred Th17 cells cooperate with host B cells to achieve durable tumor immunity","authors":"Anna C. Cole, Hannah M. Knochelmann, Megan M. Wyatt, Megen C. Wittling, Natalie K. Horvat, Aubrey S. Smith, Guillermo O. Rangel Rivera, Amalia M. Rivera Reyes, Bhavana Pavuluri, Soundharya Kumaresan, Pawel Muranski, Ayana T. Ruffin, Jeremy M. Boss, Gregory B. Lesinski, Chrystal M. Paulos","doi":"10.1016/j.ccell.2025.07.001","DOIUrl":"https://doi.org/10.1016/j.ccell.2025.07.001","url":null,"abstract":"CD4<sup>+</sup> T helper cells play an important role in adoptive T cell therapy (ACT) success, but it remains unclear which subset is most therapeutic and how they eliminate tumors. We find that tumor-specific Th17 cells eradicate melanoma more effectively than other CD4<sup>+</sup> subsets and protect against distant metastases by unique orchestration of host immunity. Donor Th17 cells require host B cells —but not T cells— for tumor regression. Th17 cells induce B cell proliferation, activation, and differentiation, while B cells augment Th17 cell polyfunctionality by enhancing IL-21 production. Th17 and B cells colocalize in lymphoid tissues, where Th17 cells induce germinal centers and tumor-reactive antibodies via IL-21 production and CD40L costimulation. Furthermore, these tumor-specific antibodies provide partial protection against tumor challenge. Herein, we reveal that adoptively transferred Th17 cells cooperate with B cells to drive sustained immunity, demonstrating a role for endogenous B cell responses in effective CD4<sup>+</sup> ACT.","PeriodicalId":9670,"journal":{"name":"Cancer Cell","volume":"117 1","pages":""},"PeriodicalIF":50.3,"publicationDate":"2025-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144693784","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}
Cancer CellPub Date : 2025-07-24DOI: 10.1016/j.ccell.2025.07.004
Christina Nürnberg, Sophie Heuer, Frank Winkler
{"title":"When human cancer goes neural","authors":"Christina Nürnberg, Sophie Heuer, Frank Winkler","doi":"10.1016/j.ccell.2025.07.004","DOIUrl":"https://doi.org/10.1016/j.ccell.2025.07.004","url":null,"abstract":"Invasion along nerves is prognostically detrimental in pancreatic and other cancers, yet its microenvironmental composition in humans remains poorly understood. In this issue of <em>Cancer Cell</em>, Chen et al. present a patient-derived high-resolution spatial and molecular atlas to reveal significant effects of cancer cell invasion on neuro-immuno-oncological and other nerve features.","PeriodicalId":9670,"journal":{"name":"Cancer Cell","volume":"53 1","pages":""},"PeriodicalIF":50.3,"publicationDate":"2025-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144693650","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}
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