Cancer CellPub Date : 2025-07-10DOI: 10.1016/j.ccell.2025.06.011
Ana Galan-Cobo, Natalie I. Vokes, Yu Qian, David Molkentine, Kavya Ramkumar, Alvaro G. Paula, Marlese Pisegna, Daniel J. McGrail, Alissa Poteete, Sungnam Cho, Minh Truong Do, Amirali Karimi, Yifan Kong, Anisha Solanki, Ankur Karmokar, Nicolas Floc’h, Adina Hughes, Rebecca Sargeant, Lucy Young, Li Shen, John V. Heymach
{"title":"KEAP1 and STK11/LKB1 alterations enhance vulnerability to ATR inhibition in KRAS mutant non-small cell lung cancer","authors":"Ana Galan-Cobo, Natalie I. Vokes, Yu Qian, David Molkentine, Kavya Ramkumar, Alvaro G. Paula, Marlese Pisegna, Daniel J. McGrail, Alissa Poteete, Sungnam Cho, Minh Truong Do, Amirali Karimi, Yifan Kong, Anisha Solanki, Ankur Karmokar, Nicolas Floc’h, Adina Hughes, Rebecca Sargeant, Lucy Young, Li Shen, John V. Heymach","doi":"10.1016/j.ccell.2025.06.011","DOIUrl":"https://doi.org/10.1016/j.ccell.2025.06.011","url":null,"abstract":"<em>KRAS</em> mutations frequently co-occur with alterations in <em>STK11</em>/LKB1 and/or <em>KEAP1</em>, defining an aggressive subset of lung cancers resistant to immuno- and chemotherapy. While LKB1 loss is associated with vulnerability to DNA damage response-based therapies, the impact of <em>KEAP1</em> alterations remains unknown. We demonstrate that KEAP1-NRF2 pathway drives a compensatory modulation of ATR-CHK1 signaling, enhancing vulnerability to ATR inhibitors (ATRi), particularly in the setting of increased replication stress associated with LKB1 loss. ATRi shows enhanced anti-tumor activity in LKB1 and/or KEAP1-deficient non-small cell lung cancer (NSCLC) models and synergizes with gemcitabine. ATRi also enhances antitumor immunity and mitigates the immunosuppressed phenotype of LKB1/KEAP1-deficient tumors. In the HUDSON trial, LKB1/KEAP1-deficient NSCLC patients demonstrate enhanced benefits to the ATRi ceralasertib plus durvalumab. These findings suggest that alterations in the KEAP1-NRF2 pathway and/or LKB1 are associated with enhanced sensitivity to ATRi and could serve as biomarkers for predicting response to ATRi combination regimens.","PeriodicalId":9670,"journal":{"name":"Cancer Cell","volume":"35 1","pages":""},"PeriodicalIF":50.3,"publicationDate":"2025-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144594656","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.2025.06.010
Julia Chronopoulos, Maria Crespo, Triantafyllos Chavakis
{"title":"Central trained immunity in the context of bladder cancer immunotherapy","authors":"Julia Chronopoulos, Maria Crespo, Triantafyllos Chavakis","doi":"10.1016/j.ccell.2025.06.010","DOIUrl":"https://doi.org/10.1016/j.ccell.2025.06.010","url":null,"abstract":"Two articles in <em>Immunity</em> and <em>Cancer Cell</em> describe that bladder cancer immunotherapy with Bacillus Calmette-Guerin (BCG) alone or in combination with β-glucan, another agonist of trained immunity (TRIM), involves reprogramming of bone marrow (BM) hematopoiesis. These findings provide additional evidence of the therapeutic potential of BM-mediated TRIM against cancer.","PeriodicalId":9670,"journal":{"name":"Cancer Cell","volume":"20 1","pages":""},"PeriodicalIF":50.3,"publicationDate":"2025-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144547561","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":"Distinct follicular T cell subsets regulate lymphoma progression and outcomes","authors":"Yoshiaki Abe, Junko Zenkoh, Akinori Kanai, Daisuke Ikeda, Daisuke Kaji, Aya Sawa, Ryota Matsuoka, Kei Asayama, Rikako Tabata, Ryota Ishii, Manabu Fujisawa, Kenichi Makishima, Sakurako Suma, Yasuhito Suehara, Keiichiro Hattori, Tatsuhiro Sakamoto, Hidekazu Nishikii, Chikashi Yoshida, Hiroko Bando, Ayako Suzuki, Mamiko Sakata-Yanagimoto","doi":"10.1016/j.ccell.2025.06.013","DOIUrl":"https://doi.org/10.1016/j.ccell.2025.06.013","url":null,"abstract":"Follicular lymphoma (FL) is characterized by the expansion of neoplastic follicle structures and is suggested to have a distinctive form of T cell immunity. However, the heterogeneity and role of follicular T cells beyond T follicular helper (T<sub>FH</sub>) cells remain largely unexplored in FL. Here, we performed multi-omics analyses of follicular T cells in FL leveraging pan-cancer single-cell mapping, spatially resolved single-cell transcriptomics and multiplex protein profiling, and functional characterization. We identified transcriptionally and spatially distinct non-T<sub>FH</sub> follicular T cell subsets that expand in FL. These subsets exhibit enhanced anti-tumorigenic properties and form unique spatial niches. Their phenotypes were replicated under interleukin-21–predominant conditions, revealing discrete self-regulatory cellular ecosystems that generate these subsets and may underlie FL clinical behaviors. Furthermore, these subsets robustly stratify FL prognoses, independently of existing prognostic markers. Our findings highlight previously unrecognized immunity that could advance our understanding of lymphoma and improve patient management.","PeriodicalId":9670,"journal":{"name":"Cancer Cell","volume":"1 1","pages":""},"PeriodicalIF":50.3,"publicationDate":"2025-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144547559","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":"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}
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