{"title":"Chemotherapy awakens dormant cancer cells in lung by inducing neutrophil extracellular traps","authors":"Dasa He, Qiuyao Wu, Pu Tian, Yin Liu, Zhenchang Jia, Zhenwei Li, Yuan Wang, Yuchen Jin, Wenqian Luo, Ling Li, Peiyuan Zhang, Qianlu Jin, Wenjing Zhao, Weiguo Hu, Yajun Liang, Bin Zhou, Qifeng Yang, Yi-zhou Jiang, Zhi-Ming Shao, Guohong Hu","doi":"10.1016/j.ccell.2025.06.007","DOIUrl":"https://doi.org/10.1016/j.ccell.2025.06.007","url":null,"abstract":"Disseminated tumor cells (DTCs) can remain in a non-proliferative, dormant state for years in distant organs, but the exogenous causes triggering their reactivation and metastatic colonization are unclear. Here, we demonstrate that chemotherapeutic drugs, including doxorubicin and cisplatin, enhance proliferation and lung metastasis of dormant breast cancer cells. Using a recombinase-based dormancy tracing system, DormTracer, we confirm chemotherapy-induced reactivation of dormant DTCs leading to metastatic relapse. Mechanistically, chemotherapy induces fibroblast senescence, which promotes formation of neutrophil extracellular traps (NETs) through secreted proteins. NETs promote dormant DTC proliferation through extracellular matrix remodeling. Importantly, combining senolytic drugs, dasatinib and quercetin, with doxorubicin inhibits post-therapy DTC reactivation and suppresses metastatic relapse. This study provides direct evidence of dormancy awakening and reveals a mechanism underlying detrimental effect of chemotherapy on metastasis, highlighting potential strategies to improve cancer treatment.","PeriodicalId":9670,"journal":{"name":"Cancer Cell","volume":"10 1","pages":""},"PeriodicalIF":50.3,"publicationDate":"2025-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144547562","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 : 2025-07-03DOI: 10.1016/j.ccell.2025.06.008
András Piffkó, Sean P. Pitroda, Ralph R. Weichselbaum
{"title":"The dark side of radiotherapy","authors":"András Piffkó, Sean P. Pitroda, Ralph R. Weichselbaum","doi":"10.1016/j.ccell.2025.06.008","DOIUrl":"https://doi.org/10.1016/j.ccell.2025.06.008","url":null,"abstract":"Radiotherapy (RT), while pivotal in cancer control, may paradoxically promote metastasis through systemic effects. Emerging evidence implicates RT-induced growth factors and immune modulation—especially via amphiregulin-epidermal growth factor receptor (EGFR) signaling—in facilitating metastatic outgrowth at distant sites. This effect underscores the need to refine RT strategies, identify high-risk patients, and explore therapeutic combinations targeting myeloid cells and EGFR pathways to mitigate pro-metastatic consequences and optimize outcomes in the immunotherapy era.","PeriodicalId":9670,"journal":{"name":"Cancer Cell","volume":"9 1","pages":""},"PeriodicalIF":50.3,"publicationDate":"2025-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144547443","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 : 2025-07-03DOI: 10.1016/j.ccell.2025.06.012
Krijn K. Dijkstra, Roberto Vendramin, Despoina Karagianni, Maartje Witsen, Felipe Gálvez-Cancino, Mark S. Hill, Kane A. Foster, Vittorio Barbè, Mihaela Angelova, Robert E. Hynds, David R. Pearce, Carlos Martínez-Ruiz, James R.M. Black, Ariana Huebner, Oriol Pich, Andrew Rowan, Marcellus Augustine, Clare Puttick, David A. Moore, Lydia L. Liu, Charles Swanton
{"title":"Subclonal immune evasion in non-small cell lung cancer","authors":"Krijn K. Dijkstra, Roberto Vendramin, Despoina Karagianni, Maartje Witsen, Felipe Gálvez-Cancino, Mark S. Hill, Kane A. Foster, Vittorio Barbè, Mihaela Angelova, Robert E. Hynds, David R. Pearce, Carlos Martínez-Ruiz, James R.M. Black, Ariana Huebner, Oriol Pich, Andrew Rowan, Marcellus Augustine, Clare Puttick, David A. Moore, Lydia L. Liu, Charles Swanton","doi":"10.1016/j.ccell.2025.06.012","DOIUrl":"https://doi.org/10.1016/j.ccell.2025.06.012","url":null,"abstract":"Cancers rarely respond completely to immunotherapy. While tumors consist of multiple genetically distinct clones, whether this affects the potential for immune escape remains unclear due to an inability to isolate and propagate individual subclones from human cancers. Here, we leverage the multi-region TRACERx lung cancer evolution study to generate a patient-derived organoid – T cell co-culture platform that allows the functional analysis of subclonal immune escape at single clone resolution. We establish organoid lines from 11 separate tumor regions from three patients, followed by isolation of 81 individual clonal sublines. Co-culture with tumor infiltrating lymphocytes (TIL) or natural killer (NK) cells reveals cancer-intrinsic and subclonal immune escape in all 3 patients. Immune evading subclones represent genetically distinct lineages with a unique evolutionary history. This indicates that immune evading and non-evading subclones can be isolated from the same tumor, suggesting that subclonal tumor evolution directly affects immune escape.","PeriodicalId":9670,"journal":{"name":"Cancer Cell","volume":"7 1","pages":""},"PeriodicalIF":50.3,"publicationDate":"2025-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144547560","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":"Engineering myeloid cells for cancer immunotherapy","authors":"Jianzhu Chen, Yingjie Zhao, Xiaotong Chen, Jiayao Yan, Fuguo Liu, Rizwan Romee","doi":"10.1016/j.ccell.2025.06.014","DOIUrl":"https://doi.org/10.1016/j.ccell.2025.06.014","url":null,"abstract":"Macrophages naturally infiltrate tumors, modulate tumor microenvironment, phagocytose tumor cells, and present antigens to induce T cell responses. These properties have been leveraged to develop chimeric antigen receptor-macrophages (CAR-Ms) for cancer immunotherapy. We discuss key findings from CAR-M studies to assess their potential to overcome major limitations of current CAR-T cell therapies and outline research directions to optimize CAR-Ms as a safe, efficacious, and cost-effective cancer immunotherapy.","PeriodicalId":9670,"journal":{"name":"Cancer Cell","volume":"647 1","pages":""},"PeriodicalIF":50.3,"publicationDate":"2025-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144547563","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 : 2025-06-26DOI: 10.1016/j.ccell.2025.06.005
{"title":"Gene context drift identifies drug targets to mitigate cancer treatment resistance","authors":"","doi":"10.1016/j.ccell.2025.06.005","DOIUrl":"https://doi.org/10.1016/j.ccell.2025.06.005","url":null,"abstract":"Cancer treatment often fails because combinations of different therapies evoke complex resistance mechanisms that are hard to predict. We introduce RE…","PeriodicalId":9670,"journal":{"name":"Cancer Cell","volume":"248 1","pages":""},"PeriodicalIF":50.3,"publicationDate":"2025-06-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144488371","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 : 2025-06-26DOI: 10.1016/j.ccell.2025.06.004
Lisa Schweizer, Hilary A. Kenny, Rahul Krishnan, Lucy Kelliher, Agnes J. Bilecz, Janna Heide, Leonhard Donle, Aasa Shimizu, Andreas Metousis, Rachelle Mendoza, Thierry M. Nordmann, Sarah Rauch, Sabrina Richter, Yan Li, Florian A. Rosenberger, Maximilian T. Strauss, Katherine C. Kurnit, Marvin Thielert, Edwin Rodriguez, Johannes B. Müller-Reif, Ernst Lengyel
{"title":"Spatial proteo-transcriptomic profiling reveals the molecular landscape of borderline ovarian tumors and their invasive progression","authors":"Lisa Schweizer, Hilary A. Kenny, Rahul Krishnan, Lucy Kelliher, Agnes J. Bilecz, Janna Heide, Leonhard Donle, Aasa Shimizu, Andreas Metousis, Rachelle Mendoza, Thierry M. Nordmann, Sarah Rauch, Sabrina Richter, Yan Li, Florian A. Rosenberger, Maximilian T. Strauss, Katherine C. Kurnit, Marvin Thielert, Edwin Rodriguez, Johannes B. Müller-Reif, Ernst Lengyel","doi":"10.1016/j.ccell.2025.06.004","DOIUrl":"https://doi.org/10.1016/j.ccell.2025.06.004","url":null,"abstract":"Epithelial serous borderline tumors (SBT) are non-invasive neoplastic ovarian lesions that may recur as chemo-resistant low-grade serous cancer (LGSC). While genetic alterations suggest a common origin, the transition from SBT to LGSC remains poorly understood. Here, we integrate cell-type resolved spatial proteomics and transcriptomics to elucidate the evolution from SBT to LGSC and its corresponding metastases in both stroma and tumor. The transition occurs within the epithelial compartment through an intermediary stage with micropapillary features, during which LGSC overexpresses c-Met and several brain-specific proteins. Within the tumor microenvironment, interconnectivity between cancer and stromal cells, along with enzymes degrading a packed extracellular matrix, suggests functional collaboration among various cell types. We functionally validated 16 drug targets identified through integrated spatial transcriptomics and proteomics. Combined treatment targeting CDK4/6 (milciclib) and FOLR1 (mirvetuximab) achieved significant tumor reduction <em>in vivo</em>, representing a promising therapeutic strategy for LGSC.","PeriodicalId":9670,"journal":{"name":"Cancer Cell","volume":"46 1","pages":""},"PeriodicalIF":50.3,"publicationDate":"2025-06-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144488375","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 : 2025-06-26DOI: 10.1016/j.ccell.2025.06.006
Jin Qian, Chenkai Ma, Quin T. Waterbury, Xiaofei Zhi, Christine S. Moon, Ruhong Tu, Hiroki Kobayashi, Feijing Wu, Biyun Zheng, Yi Zeng, Hualong Zheng, Yosuke Ochiai, Ruth A. White, David W. Harle, Jonathan S. LaBella, Leah B. Zamechek, Lucas ZhongMing Hu, Ryan H. Moy, Arnold S. Han, Bruce L. Daugherty, Timothy C. Wang
{"title":"A CXCR4 partial agonist improves immunotherapy by targeting immunosuppressive neutrophils and cancer-driven granulopoiesis","authors":"Jin Qian, Chenkai Ma, Quin T. Waterbury, Xiaofei Zhi, Christine S. Moon, Ruhong Tu, Hiroki Kobayashi, Feijing Wu, Biyun Zheng, Yi Zeng, Hualong Zheng, Yosuke Ochiai, Ruth A. White, David W. Harle, Jonathan S. LaBella, Leah B. Zamechek, Lucas ZhongMing Hu, Ryan H. Moy, Arnold S. Han, Bruce L. Daugherty, Timothy C. Wang","doi":"10.1016/j.ccell.2025.06.006","DOIUrl":"https://doi.org/10.1016/j.ccell.2025.06.006","url":null,"abstract":"Pathologically activated immunosuppressive neutrophils impair cancer immunotherapy efficacy. The chemokine receptor CXCR4, a central regulator of hematopoiesis and neutrophil biology, represents an attractive target. Here, we fuse a secreted CXCR4 partial agonist, trefoil factor 2 (TFF2), to mouse serum albumin (MSA) and demonstrate that TFF2-MSA peptide synergizes with anti-PD-1 to inhibit primary tumor growth and distant metastases and prolongs survival in gastric cancer (GC) mouse models. Using histidine decarboxylase (<em>Hdc</em>)-GFP transgenic mice to track polymorphonuclear myeloid-derived suppressor cell (PMN-MDSC) <em>in vivo</em>, we find that TFF2-MSA selectively reduces the <em>Hdc</em>-GFP<sup>+</sup>CXCR4<sup>high</sup> immunosuppressive neutrophils, thereby boosting CD8<sup>+</sup> T cell-mediated tumor killing with anti-PD-1. Importantly, TFF2-MSA reduces bone marrow granulopoiesis, contrasting with CXCR4 antagonism, which fails to confer therapeutic benefits. In GC patients, elevated CXCR4<sup>+</sup>LOX-1<sup>+</sup> low-density neutrophils correlate with lower circulating TFF2 levels. Collectively, our studies introduce a strategy that utilizes CXCR4 partial agonism to restore anti-PD-1 sensitivity by targeting immunosuppressive neutrophils and granulopoiesis.","PeriodicalId":9670,"journal":{"name":"Cancer Cell","volume":"653 1","pages":""},"PeriodicalIF":50.3,"publicationDate":"2025-06-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144488372","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 : 2025-06-26DOI: 10.1016/j.ccell.2025.05.017
Fan Huang, Zengli Liu, Yan Song, Ganyu Wang, Anda Shi, Tianli Chen, Shaohui Huang, Shuo Lian, Kangshuai Li, Yongchang Tang, Lijie Zheng, Guoli Sheng, Nuoqi Zhang, Fan Yang, Chang Pan, Weiqiang Jing, Zongli Zhang, Yunfei Xu
{"title":"Bile acids activate cancer-associated fibroblasts and induce an immunosuppressive microenvironment in cholangiocarcinoma","authors":"Fan Huang, Zengli Liu, Yan Song, Ganyu Wang, Anda Shi, Tianli Chen, Shaohui Huang, Shuo Lian, Kangshuai Li, Yongchang Tang, Lijie Zheng, Guoli Sheng, Nuoqi Zhang, Fan Yang, Chang Pan, Weiqiang Jing, Zongli Zhang, Yunfei Xu","doi":"10.1016/j.ccell.2025.05.017","DOIUrl":"https://doi.org/10.1016/j.ccell.2025.05.017","url":null,"abstract":"Cholangiocarcinoma (CCA) is a highly lethal malignancy originating from the biliary tract and characterized with exposure to high levels of bile acids (BAs). Immunotherapies have demonstrated limited efficacy in CCA, but the underlying mechanism remains elusive. In this study, we reveal that the excessive BAs specifically activate GPBAR1 on cancer-associated fibroblasts (CAFs) to express high levels of CXCL10, enhancing epithelial-mesenchymal transition (EMT) and metastasis of CCA cells and creating an immunosuppressive tumor microenvironment (TME) by recruiting neutrophils in CCA. Interestingly, single-cell RNA sequencing analysis demonstrates that CAFs in CCA, but not other cancer types examined, specifically express GPBAR1, a receptor for BAs. GPBAR1-CXCL10 axis inhibition enhances the efficacy of pembrolizumab in multiple CCA preclinical models. High BA levels and upregulated GPBAR1 expression predict poor prognosis and inferior immunotherapy response. In summary, our study reveals an immunosuppressive mechanism of BAs and identifies GPBAR1 and CXCL10 as potential immunotherapeutic targets in CCA.","PeriodicalId":9670,"journal":{"name":"Cancer Cell","volume":"8 1","pages":""},"PeriodicalIF":50.3,"publicationDate":"2025-06-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144488374","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 : 2025-06-26DOI: 10.1016/j.ccell.2025.06.003
John M. Warrington, Nathan Singh
{"title":"Disarming myeloid resistance in CAR T therapy","authors":"John M. Warrington, Nathan Singh","doi":"10.1016/j.ccell.2025.06.003","DOIUrl":"https://doi.org/10.1016/j.ccell.2025.06.003","url":null,"abstract":"Uncovering mechanisms of resistance to chimeric antigen receptor (CAR) T cell therapy for B cell lymphoma is of paramount importance. In this issue of <em>Cancer Cell</em>, Stahl et al. identify a CSF1R<sup>+</sup> myelo-monocytic population that disrupts CAR T cell function and show that inhibition of CSF1R enhances efficacy of CD19-targeted CAR T cells.","PeriodicalId":9670,"journal":{"name":"Cancer Cell","volume":"95 1","pages":""},"PeriodicalIF":50.3,"publicationDate":"2025-06-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144488360","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 : 2025-06-19DOI: 10.1016/j.ccell.2025.05.016
Lyla J. Stanland, Hayden P. Huggins, Snehasudha S. Sahoo, Alessandro Porrello, Yogitha Chareddy, Salma H. Azam, Jillian L. Perry, Pradeep S. Pallan, Kristina Whately, Lincy Edatt, William D. Green, Matthew C. Fleming, Jonah Im, Christina Gutierrez-Ford, Imani Simmons, Alyaa Dawoud, Katherine I. Zhou, Vandanaa Jayaprakash, Rani S. Sellers, Gabriela de la Cruz, Chad V. Pecot
{"title":"A first-in-class EGFR-directed KRAS G12V selective inhibitor","authors":"Lyla J. Stanland, Hayden P. Huggins, Snehasudha S. Sahoo, Alessandro Porrello, Yogitha Chareddy, Salma H. Azam, Jillian L. Perry, Pradeep S. Pallan, Kristina Whately, Lincy Edatt, William D. Green, Matthew C. Fleming, Jonah Im, Christina Gutierrez-Ford, Imani Simmons, Alyaa Dawoud, Katherine I. Zhou, Vandanaa Jayaprakash, Rani S. Sellers, Gabriela de la Cruz, Chad V. Pecot","doi":"10.1016/j.ccell.2025.05.016","DOIUrl":"https://doi.org/10.1016/j.ccell.2025.05.016","url":null,"abstract":"Despite <em>KRAS</em><sup><em>G12V</em></sup> being the second most common <em>KRAS</em> mutation in cancer, no direct inhibitors targeting KRAS<sup>G12V</sup> have been approved. RNA interference (RNAi) has faced numerous obstacles as cancer therapeutic, including the lack of cancer-specific tissue targeting, rapid oligonucleotide nuclease degradation, and clearance from circulation. Recently, the use of targetable ligands conjugated to chemically modified siRNAs have shown remarkable promise in circumventing these barriers. In this study, we demonstrate that an EGFR-directed RNAi molecule (EFTX-G12V) is highly selective for <em>KRAS</em><sup><em>G12V</em></sup> and exhibits improved therapeutic activity over pan-KRAS targeting, including enhanced inhibition of several cancer hallmarks. Using a targeted RNAi delivery platform, we achieve effective tumor silencing of <em>KRAS</em><sup><em>G12V</em></sup> and significant anti-tumor activity across several cancer models. Our findings represent a technological advance in oncogene targeting using RNAi and provide new biologic insights in KRAS targeting with potential implications for safety and efficacy.","PeriodicalId":9670,"journal":{"name":"Cancer Cell","volume":"29 1","pages":""},"PeriodicalIF":50.3,"publicationDate":"2025-06-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144319500","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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