Cancer CellPub Date : 2025-07-10DOI: 10.1016/j.ccell.2025.06.016
Shin-Heng Chiou, Diane Tseng
{"title":"Blood TCRs go to town with early NPC detection","authors":"Shin-Heng Chiou, Diane Tseng","doi":"10.1016/j.ccell.2025.06.016","DOIUrl":"https://doi.org/10.1016/j.ccell.2025.06.016","url":null,"abstract":"In this issue of <em>Cancer Cell</em>, Zhang et al. report an innovative approach utilizing patients’ blood T cell receptor (TCR) sequences for the early detection of nasopharyngeal cancer. This study highlights the potential of harnessing highly public TCRs in the peripheral blood as biomarkers for virally associated malignancies.","PeriodicalId":9670,"journal":{"name":"Cancer Cell","volume":"1 1","pages":""},"PeriodicalIF":50.3,"publicationDate":"2025-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144594754","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 : 2025-07-10DOI: 10.1016/j.ccell.2025.06.015
Catalina Rozalén, Irene Sangrador, Silvia Avalle, Sandra Blasco-Benito, Panagiota Tzortzi, María Sanz-Flores, José Ángel Palomeque, Pau Torren-Duran, Mariona Dalmau, Helena Brunel, Albert Coll-Manzano, Iván Pérez-Núñez, Tamara Martos, Sonia Servitja, Sandra Pérez-Buira, José Ignacio Chacón, Ángel Guerrero-Zotano, Eduardo Martínez de Dueñas, Yolanda Guillén, Laura Comerma, Toni Celià-Terrassa
{"title":"TIM3+ breast cancer cells license immune evasion during micrometastasis outbreak","authors":"Catalina Rozalén, Irene Sangrador, Silvia Avalle, Sandra Blasco-Benito, Panagiota Tzortzi, María Sanz-Flores, José Ángel Palomeque, Pau Torren-Duran, Mariona Dalmau, Helena Brunel, Albert Coll-Manzano, Iván Pérez-Núñez, Tamara Martos, Sonia Servitja, Sandra Pérez-Buira, José Ignacio Chacón, Ángel Guerrero-Zotano, Eduardo Martínez de Dueñas, Yolanda Guillén, Laura Comerma, Toni Celià-Terrassa","doi":"10.1016/j.ccell.2025.06.015","DOIUrl":"https://doi.org/10.1016/j.ccell.2025.06.015","url":null,"abstract":"In metastasis, the dynamics of tumor-immune interactions during micrometastasis remain unclear. Identifying the vulnerabilities of micrometastases before outbreaking into macrometastases can reveal therapeutic opportunities for metastasis. Here, we report a function of T cell immunoglobulin and mucin domain 3 (TIM3) in tumor cells during micrometastasis using breast cancer (BC) metastasis mouse models. TIM3 is highly upregulated in micrometastases, promoting survival, stemness, and immune escape. TIM3<sup>+</sup> tumor cells are specifically selected during early seeding of micrometastasis. Mechanistically, TIM3 increases β-catenin/interleukin-1β (IL-1β) signaling, leading to stemness and immune-evasion by inducing immunosuppressive γδ T cells and reducing CD8 T cells during micrometastasis. Clinical data confirm increased TIM3<sup>+</sup> tumor cells in BC metastasis and TIM3<sup>+</sup> tumor cells as a biomarker of poor outcome in BC patients. (Neo)adjuvant TIM3 blockade reduces the metastatic seeding and incidence in preclinical models. These findings unveil a specific mechanism of micrometastasis immune-evasion and the potential use of TIM3 blockade for subclinical metastasis.","PeriodicalId":9670,"journal":{"name":"Cancer Cell","volume":"153 1","pages":""},"PeriodicalIF":50.3,"publicationDate":"2025-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144594753","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 : 2025-07-10DOI: 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.2025.06.009
Tracy O'Connor, Xiaolan Zhou, Jan Kosla, Arlind Adili, Maria Garcia Beccaria, Elena Kotsiliti, Dominik Pfister, Anna-Lena Johlke, Ankit Sinha, Roman Sankowski, Markus Schick, Richard Lewis, Nikolaos Dokalis, Bastian Seubert, Bastian Höchst, Donato Inverso, Danijela Heide, Wenlong Zhang, Petra Weihrich, Katrin Manske, Dirk Wohlleber, Martina Anton, Alexander Hoellein, Gitta Seleznik, Juliane Bremer, Sabine Bleul, Hellmut G Augustin, Florian Scherer, Uwe Koedel, Achim Weber, Ulrike Protzer, Reinhold Förster, Thomas Wirth, Adriano Aguzzi, Felix Meissner, Marco Prinz, Bernd Baumann, Uta E Höpken, Percy A Knolle, Louisa von Baumgarten, Ulrich Keller, Mathias Heikenwalder
{"title":"Age-Related Gliosis Promotes Central Nervous System Lymphoma through CCL19-Mediated Tumor Cell Retention.","authors":"Tracy O'Connor, Xiaolan Zhou, Jan Kosla, Arlind Adili, Maria Garcia Beccaria, Elena Kotsiliti, Dominik Pfister, Anna-Lena Johlke, Ankit Sinha, Roman Sankowski, Markus Schick, Richard Lewis, Nikolaos Dokalis, Bastian Seubert, Bastian Höchst, Donato Inverso, Danijela Heide, Wenlong Zhang, Petra Weihrich, Katrin Manske, Dirk Wohlleber, Martina Anton, Alexander Hoellein, Gitta Seleznik, Juliane Bremer, Sabine Bleul, Hellmut G Augustin, Florian Scherer, Uwe Koedel, Achim Weber, Ulrike Protzer, Reinhold Förster, Thomas Wirth, Adriano Aguzzi, Felix Meissner, Marco Prinz, Bernd Baumann, Uta E Höpken, Percy A Knolle, Louisa von Baumgarten, Ulrich Keller, Mathias Heikenwalder","doi":"10.1016/j.ccell.2025.06.009","DOIUrl":"https://doi.org/10.1016/j.ccell.2025.06.009","url":null,"abstract":"","PeriodicalId":9670,"journal":{"name":"Cancer Cell","volume":" ","pages":""},"PeriodicalIF":48.8,"publicationDate":"2025-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144564621","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}
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