Pub Date : 2025-12-04DOI: 10.1016/j.ccell.2025.10.014
Michael Rade, David Fandrei, Markus Kreuz, Sabine Seiffert, Anja Grahnert, Maik Friedrich, Thomas Wiemers, Patrick Born, Luise Fischer, Heike Weidner, Lorenz C. Hofbauer, Ronny Baber, Song Yau Wang, Enrica Bach, Sandra Hoffmann, Jonathan Scolnick, Mirco Friedrich, Farid Keramati, Peter Brazda, Zsolt Sebestyen, Maximilian Merz
Chimeric antigen receptor (CAR) T cell therapies targeting B cell maturation antigen (BCMA) are transforming treatment for relapsed or refractory multiple myeloma (RRMM). We analyze 61 RRMM patients receiving idecabtagene vicleucel (Ide-cel; n = 34) or ciltacabtagene autoleucel (Cilta-cel; n = 27) and find that Cilta-cel achieves higher complete response (CR) rates (78% vs. 38%) and longer progression-free survival. Using a longitudinal single-cell multi-omics atlas of 135 blood samples, we show that Cilta-cel induces expansion of CD4+ cytotoxic T cells associated with CR and immune-related toxicities, whereas non-CR CD8+ T cells display impaired effector programs. Among non-B cells, plasmacytoid dendritic cells (pDCs) show the highest BCMA expression and BCMA-targeted agents eradicate a blastic plasmacytoid dendritic cell neoplasm line, suggesting a novel therapeutic avenue for this disease. Greater reductions in soluble BCMA correlate with enhanced CAR T expansion and systemic inflammation. These findings reveal cellular mechanisms driving differential efficacy and toxicity of BCMA-directed immunotherapy.
靶向B细胞成熟抗原（BCMA）的嵌合抗原受体（CAR） T细胞疗法正在改变复发或难治性多发性骨髓瘤（RRMM）的治疗方法。我们分析了61例接受idecabtagene vicleucel （Ide-cel, n = 34）或ciltacabtagene autotoleucel （Cilta-cel, n = 27）治疗的RRMM患者，发现Cilta-cel获得了更高的完全缓解（CR）率（78%对38%）和更长的无进展生存期。利用135份血液样本的纵向单细胞多组学图谱，我们发现cilta -cell诱导与CR和免疫相关毒性相关的CD4+细胞毒性T细胞扩增，而非CR CD8+ T细胞显示受损的效应程序。在非b细胞中，浆细胞样树突状细胞（pDCs）显示出最高的BCMA表达，BCMA靶向药物可根除母细胞浆细胞样树突状肿瘤系，为该疾病的治疗提供了新的途径。可溶性BCMA的减少与CAR - T扩增和全身性炎症相关。这些发现揭示了驱动bcma定向免疫治疗差异疗效和毒性的细胞机制。
{"title":"A longitudinal single-cell atlas to predict outcome and toxicity after BCMA-directed CAR T cell therapy in multiple myeloma","authors":"Michael Rade, David Fandrei, Markus Kreuz, Sabine Seiffert, Anja Grahnert, Maik Friedrich, Thomas Wiemers, Patrick Born, Luise Fischer, Heike Weidner, Lorenz C. Hofbauer, Ronny Baber, Song Yau Wang, Enrica Bach, Sandra Hoffmann, Jonathan Scolnick, Mirco Friedrich, Farid Keramati, Peter Brazda, Zsolt Sebestyen, Maximilian Merz","doi":"10.1016/j.ccell.2025.10.014","DOIUrl":"https://doi.org/10.1016/j.ccell.2025.10.014","url":null,"abstract":"Chimeric antigen receptor (CAR) T cell therapies targeting B cell maturation antigen (BCMA) are transforming treatment for relapsed or refractory multiple myeloma (RRMM). We analyze 61 RRMM patients receiving idecabtagene vicleucel (Ide-cel; <em>n</em> = 34) or ciltacabtagene autoleucel (Cilta-cel; <em>n</em> = 27) and find that Cilta-cel achieves higher complete response (CR) rates (78% vs. 38%) and longer progression-free survival. Using a longitudinal single-cell multi-omics atlas of 135 blood samples, we show that Cilta-cel induces expansion of CD4<sup>+</sup> cytotoxic T cells associated with CR and immune-related toxicities, whereas non-CR CD8<sup>+</sup> T cells display impaired effector programs. Among non-B cells, plasmacytoid dendritic cells (pDCs) show the highest BCMA expression and BCMA-targeted agents eradicate a blastic plasmacytoid dendritic cell neoplasm line, suggesting a novel therapeutic avenue for this disease. Greater reductions in soluble BCMA correlate with enhanced CAR T expansion and systemic inflammation. These findings reveal cellular mechanisms driving differential efficacy and toxicity of BCMA-directed immunotherapy.","PeriodicalId":9670,"journal":{"name":"Cancer Cell","volume":"7 1","pages":""},"PeriodicalIF":50.3,"publicationDate":"2025-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145664472","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}
We report the results of LINUX (NCT05594095), a multicenter, randomized, controlled phase II platform trial aiming to identify effective precision treatments for hormone receptor-positive/human epidermal growth factor receptor 2-negative metastatic breast cancer after resistance to cyclin-dependent kinase 4/6 inhibitor. A total of 105 patients were categorized into four similarity network fusion (SNF) subtypes by artificial intelligence-assisted classification and randomly assigned to receive subtyping-based precision therapy (N = 70) or treatment of physician’s choice (N = 35). Results demonstrate superior primary endpoint of objective response rates in the subtyping-based groups compared to controls: 10% versus 0% for SNF1, 65% versus 30% for SNF2, 40% versus 30% for SNF3, and 70% versus 20% for SNF4. Grade 3–4 treatment-related adverse events occurred in 37% of both groups. These findings highlight the clinical benefits of subtyping-based precision therapies, particularly for SNF2 and SNF4 subtypes, warranting further validation in phase III trials.
{"title":"Precision treatment with artificial intelligence assisted subtyping enhances therapeutic efficacy in HR+/HER2− breast cancer: The LINUXtrial","authors":"Lei Fan, Wen-Juan Zhang, Hui-Ping Li, Xiao-Hua Zeng, Yue-E Teng, Yue Gong, Xi Jin, Shen Zhao, Tao Sun, Wen-Yan Chen, Shu-Sen Wang, Jin Yang, Zhi-Gang Zhuang, Su-Jie Ni, Zhi-Xian He, De-Yuan Fu, Chuan-Gui Song, Zheng Lv, Qian-Nan Liang, Bao-Hua Yu, Zhi-Ming Shao","doi":"10.1016/j.ccell.2025.11.003","DOIUrl":"https://doi.org/10.1016/j.ccell.2025.11.003","url":null,"abstract":"We report the results of LINUX (<span><span>NCT05594095</span><svg aria-label=\"Opens in new window\" focusable=\"false\" height=\"20\" viewbox=\"0 0 8 8\"><path d=\"M1.12949 2.1072V1H7V6.85795H5.89111V2.90281L0.784057 8L0 7.21635L5.11902 2.1072H1.12949Z\"></path></svg></span>), a multicenter, randomized, controlled phase II platform trial aiming to identify effective precision treatments for hormone receptor-positive/human epidermal growth factor receptor 2-negative metastatic breast cancer after resistance to cyclin-dependent kinase 4/6 inhibitor. A total of 105 patients were categorized into four similarity network fusion (SNF) subtypes by artificial intelligence-assisted classification and randomly assigned to receive subtyping-based precision therapy (<em>N</em> = 70) or treatment of physician’s choice (<em>N</em> = 35). Results demonstrate superior primary endpoint of objective response rates in the subtyping-based groups compared to controls: 10% versus 0% for SNF1, 65% versus 30% for SNF2, 40% versus 30% for SNF3, and 70% versus 20% for SNF4. Grade 3–4 treatment-related adverse events occurred in 37% of both groups. These findings highlight the clinical benefits of subtyping-based precision therapies, particularly for SNF2 and SNF4 subtypes, warranting further validation in phase III trials.","PeriodicalId":9670,"journal":{"name":"Cancer Cell","volume":"12 1","pages":""},"PeriodicalIF":50.3,"publicationDate":"2025-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145673659","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}
Pub Date : 2025-12-04DOI: 10.1016/j.ccell.2025.11.004
Carlos de la Calle-Fabregat, Elsa Bernard, Florent Ginhoux
Clonal hematopoiesis (CH), an expansion of hematopoietic clones harboring somatic mutations, is common in patients with solid tumors and associates with poor outcomes. In this issue of Cancer Cell, a study shows that, in response to immunotherapy, TET2-mutant CH enhances macrophage antigen presentation and CD8⁺ T cell activation, thereby improving therapeutic efficacy.
{"title":"When blood mutations turn beneficial","authors":"Carlos de la Calle-Fabregat, Elsa Bernard, Florent Ginhoux","doi":"10.1016/j.ccell.2025.11.004","DOIUrl":"https://doi.org/10.1016/j.ccell.2025.11.004","url":null,"abstract":"Clonal hematopoiesis (CH), an expansion of hematopoietic clones harboring somatic mutations, is common in patients with solid tumors and associates with poor outcomes. In this issue of <em>Cancer Cell</em>, a study shows that, in response to immunotherapy, <em>TET2</em>-mutant CH enhances macrophage antigen presentation and CD8⁺ T cell activation, thereby improving therapeutic efficacy.","PeriodicalId":9670,"journal":{"name":"Cancer Cell","volume":"155 1","pages":""},"PeriodicalIF":50.3,"publicationDate":"2025-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145673654","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}
Pub Date : 2025-12-04DOI: 10.1016/j.ccell.2025.11.001
Weijie Guo, Jingyun Luan, Xuejie Huang, Daniel Leon, Sophie Gang, Benjamin Nicholson, Breanna Bertacchi, Diana Bolotin, Mark W. Lingen, Alexander T. Pearson, Evgeny Izumchenko, Ari J. Rosenberg, Nishant Agrawal, Everett E. Vokes, Siwakorn Punyawatthananukool, Shuh Narumiya, Matthias Gunzer, Iván Ballesteros, Andrés Hidalgo, Yuxuan Miao
The heterogeneous nature of tumor-associated neutrophils (TANs) has been recognized, but how different cell states of TANs emerge, evolve, distribute, and impact cancer immunotherapy efficacy remain elusive. Using single-cell RNA sequencing, spatial transcriptomics, and genetic manipulations, we show that anti-PDL1 + CD40 agonist immunotherapy can induce interferon responses in TANs, allowing them to regain anti-tumor activities in squamous cell carcinomas (SCCs). In contrast, TANs residing at the tumor-stroma interface can preserve their immune-suppressive state. Importantly, we identify a group of SOX2High tumor-initiating stem cells (tSCs) at the tumor-stroma interface that upregulate fatty acid desaturase 1 (Fads1) to produce arachidonic acid (AA). This tSC-specific pathway enhances the prostaglandin E2 (PGE2) signaling in TANs, which can disrupt the interferon response and prevent the interferon-induced anti-tumor functions in TANs. By fine-tuning the plasticity of neutrophils, tSCs shape neutrophil heterogeneity and sculpt a protective micro-niche to survive from immunotherapy and drive cancer relapse.
{"title":"Tumor-initiating stem cells fine-tune the plasticity of neutrophils to sculpt a protective niche","authors":"Weijie Guo, Jingyun Luan, Xuejie Huang, Daniel Leon, Sophie Gang, Benjamin Nicholson, Breanna Bertacchi, Diana Bolotin, Mark W. Lingen, Alexander T. Pearson, Evgeny Izumchenko, Ari J. Rosenberg, Nishant Agrawal, Everett E. Vokes, Siwakorn Punyawatthananukool, Shuh Narumiya, Matthias Gunzer, Iván Ballesteros, Andrés Hidalgo, Yuxuan Miao","doi":"10.1016/j.ccell.2025.11.001","DOIUrl":"https://doi.org/10.1016/j.ccell.2025.11.001","url":null,"abstract":"The heterogeneous nature of tumor-associated neutrophils (TANs) has been recognized, but how different cell states of TANs emerge, evolve, distribute, and impact cancer immunotherapy efficacy remain elusive. Using single-cell RNA sequencing, spatial transcriptomics, and genetic manipulations, we show that anti-PDL1 + CD40 agonist immunotherapy can induce interferon responses in TANs, allowing them to regain anti-tumor activities in squamous cell carcinomas (SCCs). In contrast, TANs residing at the tumor-stroma interface can preserve their immune-suppressive state. Importantly, we identify a group of SOX2<sup>High</sup> tumor-initiating stem cells (tSCs) at the tumor-stroma interface that upregulate fatty acid desaturase 1 (<em>Fads1</em>) to produce arachidonic acid (AA). This tSC-specific pathway enhances the prostaglandin E<sub>2</sub> (PGE<sub>2</sub>) signaling in TANs, which can disrupt the interferon response and prevent the interferon-induced anti-tumor functions in TANs. By fine-tuning the plasticity of neutrophils, tSCs shape neutrophil heterogeneity and sculpt a protective micro-niche to survive from immunotherapy and drive cancer relapse.","PeriodicalId":9670,"journal":{"name":"Cancer Cell","volume":"1 1","pages":""},"PeriodicalIF":50.3,"publicationDate":"2025-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145673653","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}
Pub Date : 2025-12-04DOI: 10.1016/j.ccell.2025.11.002
Martin Sill, Daniel Schrimpf, Areeba Patel, Dominik Sturm, Natalie Jäger, Philipp Sievers, Leonille Schweizer, Rouzbeh Banan, David Reuss, Abigail Suwala, Andrey Korshunov, Damian Stichel, Annika K. Wefers, Ann-Christin Hau, Henning Boldt, Patrick N. Harter, Zied Abdullaev, Jamal Benhamida, Daniel Teichmann, Arend Koch, Felix Sahm
DNA methylation-based classification is now central to contemporary neuro-oncology, as highlighted by the World Health Organization (WHO) classification of central nervous system (CNS) tumors. We present the Heidelberg CNS Tumor Methylation Classifier version 12.8 (v12.8), trained on 7,495 methylation profiles, which expands recognized entities from 91 classes in version 11 (v11) to 184 subclasses. This expansion is a result of newly identified tumor types discovered through our large online repository and global collaborations, underscoring CNS tumor heterogeneity. The random forest-based classifier achieves 95% subclass-level accuracy, with its well-calibrated probabilistic scores providing a reliable measure of confidence for each classification. Its hierarchical output structure enables interpretation across subclass, class, family, and superfamily levels, thereby supporting clinical decisions at multiple granularities. Comparative analyses demonstrate that v12.8 surpasses previous versions and conventional WHO-based approaches. These advances highlight the improved precision and practical utility of the updated classifier in personalized neuro-oncology.
{"title":"Advancing CNS tumor diagnostics with expanded DNA methylation-based classification","authors":"Martin Sill, Daniel Schrimpf, Areeba Patel, Dominik Sturm, Natalie Jäger, Philipp Sievers, Leonille Schweizer, Rouzbeh Banan, David Reuss, Abigail Suwala, Andrey Korshunov, Damian Stichel, Annika K. Wefers, Ann-Christin Hau, Henning Boldt, Patrick N. Harter, Zied Abdullaev, Jamal Benhamida, Daniel Teichmann, Arend Koch, Felix Sahm","doi":"10.1016/j.ccell.2025.11.002","DOIUrl":"https://doi.org/10.1016/j.ccell.2025.11.002","url":null,"abstract":"DNA methylation-based classification is now central to contemporary neuro-oncology, as highlighted by the World Health Organization (WHO) classification of central nervous system (CNS) tumors. We present the Heidelberg CNS Tumor Methylation Classifier version 12.8 (v12.8), trained on 7,495 methylation profiles, which expands recognized entities from 91 classes in version 11 (v11) to 184 subclasses. This expansion is a result of newly identified tumor types discovered through our large online repository and global collaborations, underscoring CNS tumor heterogeneity. The random forest-based classifier achieves 95% subclass-level accuracy, with its well-calibrated probabilistic scores providing a reliable measure of confidence for each classification. Its hierarchical output structure enables interpretation across subclass, class, family, and superfamily levels, thereby supporting clinical decisions at multiple granularities. Comparative analyses demonstrate that v12.8 surpasses previous versions and conventional WHO-based approaches. These advances highlight the improved precision and practical utility of the updated classifier in personalized neuro-oncology.","PeriodicalId":9670,"journal":{"name":"Cancer Cell","volume":"31 1","pages":""},"PeriodicalIF":50.3,"publicationDate":"2025-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145664473","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}
Pub Date : 2025-11-20DOI: 10.1016/j.ccell.2025.10.013
Toshiro Hara, Cong Ma
Glioblastoma features extensive gene expression heterogeneity and high lethality, yet the mechanisms underlying this heterogeneity and its link to clinical outcomes remain elusive. In this issue of Cancer Cell, Migliozzi et al. spatially profile glioblastoma specimens to uncover cellular mechanisms that govern the extent of the heterogeneity in malignant cells.
{"title":"Spatial patterns of glioblastoma","authors":"Toshiro Hara, Cong Ma","doi":"10.1016/j.ccell.2025.10.013","DOIUrl":"https://doi.org/10.1016/j.ccell.2025.10.013","url":null,"abstract":"Glioblastoma features extensive gene expression heterogeneity and high lethality, yet the mechanisms underlying this heterogeneity and its link to clinical outcomes remain elusive. In this issue of <em>Cancer Cell</em>, Migliozzi et al. spatially profile glioblastoma specimens to uncover cellular mechanisms that govern the extent of the heterogeneity in malignant cells.","PeriodicalId":9670,"journal":{"name":"Cancer Cell","volume":"41 1","pages":""},"PeriodicalIF":50.3,"publicationDate":"2025-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145554859","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}
Pub Date : 2025-11-13DOI: 10.1016/j.ccell.2025.10.011
Jiaqi Zhou, Xing Kang, Yang Zhang, Haiyun Gan
Extrachromosomal circular DNA (ecDNA), enriched with enhancers, drives oncogenic transcription and tumor progression, but the mechanisms remain elusive. In this issue of Cancer Cell, Wei et al. uncover MED1-driven ecDNA super-enhancers as regulatory hubs and show that disrupting ecDNA-containing condensates selectively impairs transcription and induces apoptosis in a cancer-type-specific manner.
{"title":"MED1-driven ecDNA super-enhancers in cancer","authors":"Jiaqi Zhou, Xing Kang, Yang Zhang, Haiyun Gan","doi":"10.1016/j.ccell.2025.10.011","DOIUrl":"https://doi.org/10.1016/j.ccell.2025.10.011","url":null,"abstract":"Extrachromosomal circular DNA (ecDNA), enriched with enhancers, drives oncogenic transcription and tumor progression, but the mechanisms remain elusive. In this issue of <em>Cancer Cell</em>, Wei et al. uncover MED1-driven ecDNA super-enhancers as regulatory hubs and show that disrupting ecDNA-containing condensates selectively impairs transcription and induces apoptosis in a cancer-type-specific manner.","PeriodicalId":9670,"journal":{"name":"Cancer Cell","volume":"17 1","pages":""},"PeriodicalIF":50.3,"publicationDate":"2025-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145499118","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}
While dual KRAS and epidermal growth factor receptor (EGFR) inhibition shows promise in treating KRAS-mutant colorectal cancer (CRC), resistance remains a major challenge. Using genetically engineered mouse models, patient-derived organoids and xenografts, as well as clinical specimens, we discover that colorectal tumors surviving combined KRAS and EGFR inhibition acquire a Paneth-like cell state—a secretory lineage typically confined to the intestinal crypt. Lineage tracing reveals that CRC cells evade dual therapy by transitioning into a Paneth-like state. Through integrated transcriptomic analysis and CRISPR genetic screening, we identify SMAD1 as a key regulator of this lineage plasticity, promoting resistance by directly activating FGFR3. Genetic or pharmacological inhibition of FGFR3 prevents the Paneth-like transition, restores drug sensitivity, and synergizes with KRAS-EGFR inhibition across multiple preclinical models. These findings reveal that the SMAD1-FGFR3 axis triggers Paneth-like plasticity to drive KRAS-EGFR dual therapy resistance in CRC and highlight FGFR3 blockade as a promising strategy to overcome plasticity-driven drug tolerance.
{"title":"Paneth-like transition drives resistance to dual targeting of KRAS and EGFR in colorectal cancer","authors":"Yuetong Zhang, Jiaying Chen, Yong She, Zhaoyuan Fang, Yaxin Zhang, Danyun Ruan, Wenjun Guo, Jianping Liao, Weiping Zhou, Jianpei Lao, Weicheng Fang, Xingyan Pan, Wenfei Kang, Zifeng Wang, Yuanzhong Wu, Rong Deng, Lin Tian, Liqin Wang, Huilin Huang, Jian Zheng, Yijun Gao","doi":"10.1016/j.ccell.2025.10.010","DOIUrl":"https://doi.org/10.1016/j.ccell.2025.10.010","url":null,"abstract":"While dual KRAS and epidermal growth factor receptor (EGFR) inhibition shows promise in treating <em>KRAS</em>-mutant colorectal cancer (CRC), resistance remains a major challenge. Using genetically engineered mouse models, patient-derived organoids and xenografts, as well as clinical specimens, we discover that colorectal tumors surviving combined KRAS and EGFR inhibition acquire a Paneth-like cell state—a secretory lineage typically confined to the intestinal crypt. Lineage tracing reveals that CRC cells evade dual therapy by transitioning into a Paneth-like state. Through integrated transcriptomic analysis and CRISPR genetic screening, we identify SMAD1 as a key regulator of this lineage plasticity, promoting resistance by directly activating FGFR3. Genetic or pharmacological inhibition of FGFR3 prevents the Paneth-like transition, restores drug sensitivity, and synergizes with KRAS-EGFR inhibition across multiple preclinical models. These findings reveal that the SMAD1-FGFR3 axis triggers Paneth-like plasticity to drive KRAS-EGFR dual therapy resistance in CRC and highlight FGFR3 blockade as a promising strategy to overcome plasticity-driven drug tolerance.","PeriodicalId":9670,"journal":{"name":"Cancer Cell","volume":"170 1","pages":""},"PeriodicalIF":50.3,"publicationDate":"2025-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145498667","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}
Pub Date : 2025-11-13DOI: 10.1016/j.ccell.2025.10.009
David M. Nash, Lauren V. Terry, Mark A. Febbraio
Exercise holds significant potential as an adjunct therapy in cancer, extending beyond quality-of-life improvements to influencing tumor progression, treatment response, and survival. Its clinical integration remains limited by variability in models, heterogenous interventions, and the absence of predictive biomarkers. As the field progresses, identifying molecular effectors of exercise, in addition to emphasizing practical clinical translation, is essential. This commentary highlights the anti-tumor effects of exercise and evaluates how exercise can advance from supportive care to a targeted, evidence-based component of cancer treatment.
{"title":"Exercising through cancer: Physical activity as medicine for cancer care","authors":"David M. Nash, Lauren V. Terry, Mark A. Febbraio","doi":"10.1016/j.ccell.2025.10.009","DOIUrl":"https://doi.org/10.1016/j.ccell.2025.10.009","url":null,"abstract":"Exercise holds significant potential as an adjunct therapy in cancer, extending beyond quality-of-life improvements to influencing tumor progression, treatment response, and survival. Its clinical integration remains limited by variability in models, heterogenous interventions, and the absence of predictive biomarkers. As the field progresses, identifying molecular effectors of exercise, in addition to emphasizing practical clinical translation, is essential. This commentary highlights the anti-tumor effects of exercise and evaluates how exercise can advance from supportive care to a targeted, evidence-based component of cancer treatment.","PeriodicalId":9670,"journal":{"name":"Cancer Cell","volume":"143 1","pages":""},"PeriodicalIF":50.3,"publicationDate":"2025-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145499119","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}
Glioblastoma (GBM), the most aggressive primary brain tumor, is shaped by its integration into neural networks. While glutamatergic input is linked to tumor progression, the broader architecture and function of neuron-glioma connectomes remain unclear. Using monosynaptic rabies tracing, we map brain-wide neural input to patient-derived xenografts and reveal a consistent organizational logic: local inputs are primarily glutamatergic, while long-range connections exhibit diverse neurotransmitter profiles, with basal forebrain cholinergic projections emerging as a conserved input across sites. Functionally, presynaptic acetylcholine release promotes GBM progression through muscarinic receptor CHRM3 in a circuit-specific manner. Mechanistically, glutamatergic and cholinergic signals converge to enhance glioma calcium transients but diverge in temporal transcriptional control, with their dual blockade producing additive anti-tumor effects. Therapeutically, the anticholinergic drug scopolamine attenuates glioma growth, whereas the acetylcholinesterase inhibitor donepezil exacerbates disease. These findings reveal the complexity of neuron-glioma connectivity, highlighting long-range neuromodulatory pathways as promising therapeutic targets in GBM.
{"title":"Long-range cholinergic input promotes glioblastoma progression.","authors":"Yang Yang, Chuanyan Yang, Xuezhu Chen, Yibin Jiang, Xuejiao Lei, Kang Ma, Yulian Quan, Tianran Li, Chenfu Guo, Yijing Meng, Lin Kang, Xinyu Zhang, Long Jin, Jiafeng Huang, Ning Mu, Zexuan Yan, Qinghua Ma, Shuai Wang, Yanxia Wang, Yong-Ning Shang, Cong Chen, Yu Shi, Shukun Hu, Likun Yang, Chuan Lan, Rong Hu, Ying Zhang, Xia Li, Yunqing Li, Chong Liu, Yu-Hai Wang, Fei Li, Hua Feng, Xiu-Wu Bian, Tunan Chen","doi":"10.1016/j.ccell.2025.07.024","DOIUrl":"10.1016/j.ccell.2025.07.024","url":null,"abstract":"<p><p>Glioblastoma (GBM), the most aggressive primary brain tumor, is shaped by its integration into neural networks. While glutamatergic input is linked to tumor progression, the broader architecture and function of neuron-glioma connectomes remain unclear. Using monosynaptic rabies tracing, we map brain-wide neural input to patient-derived xenografts and reveal a consistent organizational logic: local inputs are primarily glutamatergic, while long-range connections exhibit diverse neurotransmitter profiles, with basal forebrain cholinergic projections emerging as a conserved input across sites. Functionally, presynaptic acetylcholine release promotes GBM progression through muscarinic receptor CHRM3 in a circuit-specific manner. Mechanistically, glutamatergic and cholinergic signals converge to enhance glioma calcium transients but diverge in temporal transcriptional control, with their dual blockade producing additive anti-tumor effects. Therapeutically, the anticholinergic drug scopolamine attenuates glioma growth, whereas the acetylcholinesterase inhibitor donepezil exacerbates disease. These findings reveal the complexity of neuron-glioma connectivity, highlighting long-range neuromodulatory pathways as promising therapeutic targets in GBM.</p>","PeriodicalId":9670,"journal":{"name":"Cancer Cell","volume":" ","pages":"2089-2105.e10"},"PeriodicalIF":44.5,"publicationDate":"2025-11-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144882291","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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