Cancer Cell最新文献_第8页

Radiotherapy promotes cuproptosis and synergizes with cuproptosis inducers to overcome tumor radioresistance 放疗促进铜体增生，并与铜体增生诱导剂协同克服肿瘤放射耐药

IF 50.3 1区医学

Cancer Cell Pub Date : 2025-04-10 DOI: 10.1016/j.ccell.2025.03.031

Guang Lei, Mingchuang Sun, Jun Cheng, Rui Ye, Zhengze Lu, Amber Horbath, David Huo, Shengrong Wu, Anagha Alapati, Sadhna Aggarwal, Zhihao Xu, Chao Mao, Yuelong Yan, Jun Yao, Qidong Li, Xiong Chen, Hyemin Lee, Li Zhuang, Dadi Jiang, Apar Pataer, Boyi Gan

{"title":"Radiotherapy promotes cuproptosis and synergizes with cuproptosis inducers to overcome tumor radioresistance","authors":"Guang Lei, Mingchuang Sun, Jun Cheng, Rui Ye, Zhengze Lu, Amber Horbath, David Huo, Shengrong Wu, Anagha Alapati, Sadhna Aggarwal, Zhihao Xu, Chao Mao, Yuelong Yan, Jun Yao, Qidong Li, Xiong Chen, Hyemin Lee, Li Zhuang, Dadi Jiang, Apar Pataer, Boyi Gan","doi":"10.1016/j.ccell.2025.03.031","DOIUrl":"https://doi.org/10.1016/j.ccell.2025.03.031","url":null,"abstract":"Cuproptosis is a recently identified form of copper-dependent cell death. Here, we reveal that radiotherapy (RT) induces cuproptosis in cancer cells, independent of apoptosis and ferroptosis, and depletes lipoylated proteins and iron-sulfur (Fe-S) cluster proteins—both hallmarks of cuproptosis—in patient tumors. Mechanistically, RT elevates mitochondrial copper levels by upregulating copper transporter 1 (CTR1) and depleting mitochondrial glutathione, a copper chelator, thereby triggering cuproptosis. Integrated analyses of RNA sequencing (RNA-seq) from radioresistant esophageal cancer cells and single-cell RNA-seq from esophageal tumors of patients unresponsive to RT link radioresistance to the downregulation of BTB and CNC homology 1 (BACH1). This downregulation de-represses the expression of copper-sequestering metallothionein (MT) 1E/X, thereby mitigating cuproptosis and contributing to radioresistance. Copper ionophore treatment sensitizes radioresistant cancer cells and cell line- and patient-derived xenografts to RT by potentiating cuproptosis. Our findings unveil a link between RT and cuproptosis and inform a therapeutic strategy to overcome tumor radioresistance by targeting cuproptosis.","PeriodicalId":9670,"journal":{"name":"Cancer Cell","volume":"107 1","pages":""},"PeriodicalIF":50.3,"publicationDate":"2025-04-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143814001","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}

引用次数: 0

Neoadjuvant toripalimab plus nimotuzumab combined with taxol-based chemotherapy in locally advanced penile squamous cell carcinoma 局部晚期阴茎鳞状细胞癌的新辅助托利帕利单抗加尼莫妥珠单抗联合紫杉醇化疗

IF 50.3 1区医学

Cancer Cell Pub Date : 2025-04-10 DOI: 10.1016/j.ccell.2025.03.023

Xin An, Sheng Jie Guo, Ru Yan, Ting Xue, Long Bin Xiong, Hua Li Ma, Cong Xue, Ying Chun Zhang, Ji Bin Li, Mei Ting Chen, Zai Shang Li, Ting Yu Liu, Zhi Ling Zhang, Pei Dong, Yong Hong Li, Kai Yao, Zhi Quan Hu, Xiao Feng Chen, Jie Xin Luo, Yong Hong Lei, Hui Han

{"title":"Neoadjuvant toripalimab plus nimotuzumab combined with taxol-based chemotherapy in locally advanced penile squamous cell carcinoma","authors":"Xin An, Sheng Jie Guo, Ru Yan, Ting Xue, Long Bin Xiong, Hua Li Ma, Cong Xue, Ying Chun Zhang, Ji Bin Li, Mei Ting Chen, Zai Shang Li, Ting Yu Liu, Zhi Ling Zhang, Pei Dong, Yong Hong Li, Kai Yao, Zhi Quan Hu, Xiao Feng Chen, Jie Xin Luo, Yong Hong Lei, Hui Han","doi":"10.1016/j.ccell.2025.03.023","DOIUrl":"https://doi.org/10.1016/j.ccell.2025.03.023","url":null,"abstract":"The conventional neoadjuvant chemotherapy regimen for locally advanced penile squamous cell carcinoma (La-PSCC) has shown moderate response rates and survival benefits. This single-arm, phase II trial (NCT04475016<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>) evaluated a neoadjuvant regimen of four cycles of toripalimab (anti-PD-1 antibody), nimotuzumab (anti-EGFR antibody), and taxol-based chemotherapy (TNT), followed by consolidative surgery. The primary endpoint was the pathological complete response (pCR) rate. Among 29 enrolled patients, 24 (82.8%) underwent consolidative surgery, with 14 (48.3%, 95% confidence interval [CI], 29.4–67.5%) achieving pCR. The objective response rate (ORR) was 82.8% (95% CI, 64.2–94.2). Median follow-up was 39.97 months, with two-year overall survival (OS) and progression-free survival (PFS) rates of 72.4% and 65.5%. Grade 3–4 treatment-related adverse events (TRAEs) occurred in 12 (41.4%) patients, with no treatment-related deaths. Biomarker analysis identified PD-L1 expression, TP53 mutation status, and CD8+ T cell density as potential predictive markers. Therefore, neoadjuvant TNT shows promising anti-tumor activity and acceptable toxicity.","PeriodicalId":9670,"journal":{"name":"Cancer Cell","volume":"60 1","pages":""},"PeriodicalIF":50.3,"publicationDate":"2025-04-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143814004","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}

引用次数: 0

ZEB2 is a master switch controlling the tumor-associated macrophage program ZEB2是控制肿瘤相关巨噬细胞程序的主开关

IF 50.3 1区医学

Cancer Cell Pub Date : 2025-04-10 DOI: 10.1016/j.ccell.2025.03.021

Fadi Sheban, Truong San Phan, Ken Xie, Florian Ingelfinger, Chamutal Gur, Yuval Shapir Itai, Ronnie Blecher-Gonen, Chunsong Yu, Roberto Avellino, Paulina Chalan, Kiara Freitag, Ido Yofe, Vladimir Yutkin, Pierre Boyeau, Can Ergen, Justin Hong, Kfir Mazuz, Yuxiao Liu, Kangming Chen, Rony Dahan, Ido Amit

{"title":"ZEB2 is a master switch controlling the tumor-associated macrophage program","authors":"Fadi Sheban, Truong San Phan, Ken Xie, Florian Ingelfinger, Chamutal Gur, Yuval Shapir Itai, Ronnie Blecher-Gonen, Chunsong Yu, Roberto Avellino, Paulina Chalan, Kiara Freitag, Ido Yofe, Vladimir Yutkin, Pierre Boyeau, Can Ergen, Justin Hong, Kfir Mazuz, Yuxiao Liu, Kangming Chen, Rony Dahan, Ido Amit","doi":"10.1016/j.ccell.2025.03.021","DOIUrl":"https://doi.org/10.1016/j.ccell.2025.03.021","url":null,"abstract":"Tumor-associated macrophages (TAMs) are key mediators of tumor immune evasion. However, their regulatory circuits and checkpoints are partially understood. Here, we generated a TAM regulatory network by integrating human tumors single-cell RNA sequencing (scRNA-seq) data with a dedicated CRISPR screen. Using a deep generative model, we constructed a gene perturbation network linking individual candidates with prototypical TAM functions. We identified Zeb2 as the master regulator of TAM programs, orchestrating suppression of type-I interferon response and antigen presentation alongside activation of immune suppression programs. Genetic ablation of ZEB2 reprograms TAM function and identity on the chromatin, RNA, and protein levels. In macrophage-rich human tumors, ZEB2 expression is associated with poor prognosis. Selective Zeb2 in vivo targeting reprograms TAMs and mobilizes systemic T cell responses, achieving robust tumor clearance. Overall, our study generates a detailed roadmap of TAM gene circuits and identifies ZEB2 as a master switch with therapeutic potential.","PeriodicalId":9670,"journal":{"name":"Cancer Cell","volume":"183 1","pages":""},"PeriodicalIF":50.3,"publicationDate":"2025-04-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143814007","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}

引用次数: 0

Spatial transcriptomics reveals tryptophan metabolism restricting maturation of intratumoral tertiary lymphoid structures 空间转录组学揭示了色氨酸代谢限制肿瘤内三级淋巴样结构的成熟

IF 50.3 1区医学

Cancer Cell Pub Date : 2025-04-03 DOI: 10.1016/j.ccell.2025.03.011

Zhonghui Tang, Yinqi Bai, Qi Fang, Yuchen Yuan, Qianwen Zeng, Shuling Chen, Tianyi Xu, Jianyu Chen, Li Tan, Chunqing Wang, Qian Li, Jinpei Lin, Zhuoxuan Yang, Xia Wu, Guowei Shi, Ji Wang, Changjun Yin, Jianping Guo, Shiping Liu, Sui Peng, Ming Kuang

{"title":"Spatial transcriptomics reveals tryptophan metabolism restricting maturation of intratumoral tertiary lymphoid structures","authors":"Zhonghui Tang, Yinqi Bai, Qi Fang, Yuchen Yuan, Qianwen Zeng, Shuling Chen, Tianyi Xu, Jianyu Chen, Li Tan, Chunqing Wang, Qian Li, Jinpei Lin, Zhuoxuan Yang, Xia Wu, Guowei Shi, Ji Wang, Changjun Yin, Jianping Guo, Shiping Liu, Sui Peng, Ming Kuang","doi":"10.1016/j.ccell.2025.03.011","DOIUrl":"https://doi.org/10.1016/j.ccell.2025.03.011","url":null,"abstract":"Tertiary lymphoid structures (TLSs) are ectopic lymphoid aggregates found in numerous cancers, often linked to enhanced immunotherapy responses and better clinical outcomes. However, the factors driving TLS maturation are not fully understood. Using near single-cell spatial transcriptomic mapping, we comprehensively profile TLSs under various maturation stages and their microenvironment in hepatocellular carcinoma (HCC). Based on their developmental trajectories, we classify immature TLSs into two groups: conforming and deviating TLSs. Our findings indicate that conforming TLSs, similar to mature TLSs, possess a niche function for immunotherapy responses, while deviating TLSs do not. We discover that the tryptophan-enriched metabolic microenvironment shaped by malignant cells contributes to the deviation of TLS maturation. Inhibiting tryptophan metabolism promotes intratumoral TLS maturation and enhances tumor control, synergizing with anti-PD-1 treatments. Therefore, promoting TLS maturation represents a potential strategy to improve antitumor responses and immunotherapy outcomes.","PeriodicalId":9670,"journal":{"name":"Cancer Cell","volume":"10 1","pages":""},"PeriodicalIF":50.3,"publicationDate":"2025-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143766921","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}

引用次数: 0

Proteogenomic characterization of non-functional pancreatic neuroendocrine tumors unravels clinically relevant subgroups 非功能性胰腺神经内分泌肿瘤的蛋白质基因组学特征揭示了临床相关亚群

IF 50.3 1区医学

Cancer Cell Pub Date : 2025-04-03 DOI: 10.1016/j.ccell.2025.03.016

Shunrong Ji, Lihua Cao, Jing Gao, Yang Du, Zeng Ye, Xin Lou, Fen Liu, Yehan Zhang, Junfeng Xu, Xiaohan Shi, Huan Wang, Penghao Li, Yikai Li, Hongxu Chen, Zhicheng Yang, Suizhi Gao, Wuhu Zhang, Dan Huang, Shujuan Ni, Miaoyan Wei, Xianjun Yu

{"title":"Proteogenomic characterization of non-functional pancreatic neuroendocrine tumors unravels clinically relevant subgroups","authors":"Shunrong Ji, Lihua Cao, Jing Gao, Yang Du, Zeng Ye, Xin Lou, Fen Liu, Yehan Zhang, Junfeng Xu, Xiaohan Shi, Huan Wang, Penghao Li, Yikai Li, Hongxu Chen, Zhicheng Yang, Suizhi Gao, Wuhu Zhang, Dan Huang, Shujuan Ni, Miaoyan Wei, Xianjun Yu","doi":"10.1016/j.ccell.2025.03.016","DOIUrl":"https://doi.org/10.1016/j.ccell.2025.03.016","url":null,"abstract":"The majority of neuroendocrine neoplasms in pancreas are non-functional pancreatic neuroendocrine tumors (NF-PanNETs), which exhibit a high occurrence of distant metastases with limited therapeutic options. Here, we perform a comprehensive molecular characterization of 108 NF-PanNETs through integrative analysis of genomic, transcriptomic, proteomic, and phosphoproteomic profiles. Proteogenomic analysis provides functional insights into the genomic driver alterations of NF-PanNETs, revealing a potential mediator of MEN1 alterations using Men1-conditional knockout mice. Machine-learning-based modeling uncovers a three-protein signature as an independent prognostic factor, which is validated by an independent external cohort. Proteomic and phosphoproteomic-based stratification identifies four subtypes with distinct molecular characteristics, immune microenvironments, and clinicopathological features. Drug screening using patient-derived tumor organoids identifies cyclin-dependent kinase (CDK) 5 and Calcium Voltage-Gated Channel Subunit Alpha1 D (CACNA1D) as ubiquitous and subtype-specific targets, respectively, with in vivo validation using xenograft models. Together, our proteogenomic analyses illustrate a comprehensive molecular landscape of NF-PanNETs, revealing biological insights and therapeutic vulnerabilities.","PeriodicalId":9670,"journal":{"name":"Cancer Cell","volume":"133 1","pages":""},"PeriodicalIF":50.3,"publicationDate":"2025-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143766926","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}

引用次数: 0

The Terry Fox Research Institute Marathon of Hope Cancer Centres Network: A pan-Canadian precision oncology initiative 泰瑞福克斯研究所马拉松希望癌症中心网络：一个泛加拿大精确肿瘤学倡议

IF 50.3 1区医学

Cancer Cell Pub Date : 2025-04-03 DOI: 10.1016/j.ccell.2025.03.014

引用次数: 0

Translation dysregulation in cancer as a source for targetable antigens 翻译失调在癌症中作为靶向抗原的来源

IF 50.3 1区医学

Cancer Cell Pub Date : 2025-03-27 DOI: 10.1016/j.ccell.2025.03.003

Chen Weller, Osnat Bartok, Christopher S. McGinnis, Heyilimu Palashati, Tian-Gen Chang, Dmitry Malko, Merav D. Shmueli, Asuteka Nagao, Deborah Hayoun, Ayaka Murayama, Yuriko Sakaguchi, Panagiotis Poulis, Aseel Khatib, Bracha Erlanger Avigdor, Sagi Gordon, Sapir Cohen Shvefel, Marie J. Zemanek, Morten M. Nielsen, Sigalit Boura-Halfon, Shira Sagie, Yardena Samuels

{"title":"Translation dysregulation in cancer as a source for targetable antigens","authors":"Chen Weller, Osnat Bartok, Christopher S. McGinnis, Heyilimu Palashati, Tian-Gen Chang, Dmitry Malko, Merav D. Shmueli, Asuteka Nagao, Deborah Hayoun, Ayaka Murayama, Yuriko Sakaguchi, Panagiotis Poulis, Aseel Khatib, Bracha Erlanger Avigdor, Sagi Gordon, Sapir Cohen Shvefel, Marie J. Zemanek, Morten M. Nielsen, Sigalit Boura-Halfon, Shira Sagie, Yardena Samuels","doi":"10.1016/j.ccell.2025.03.003","DOIUrl":"https://doi.org/10.1016/j.ccell.2025.03.003","url":null,"abstract":"Aberrant peptides presented by major histocompatibility complex (MHC) molecules are targets for tumor eradication, as these peptides can be recognized as foreign by T cells. Protein synthesis in malignant cells is dysregulated, which may result in the generation and presentation of aberrant peptides that can be exploited for T cell-based therapies. To investigate the role of translational dysregulation in immunological tumor control, we disrupt translation fidelity by deleting tRNA wybutosine (yW)-synthesizing protein 2 (TYW2) in tumor cells and characterize the downstream impact on translation fidelity and immunogenicity using immunopeptidomics, genomics, and functional assays. These analyses reveal that TYW2 knockout (KO) cells generate immunogenic out-of-frame peptides. Furthermore, Tyw2 loss increases tumor immunogenicity and leads to anti-programmed cell death 1 (PD-1) checkpoint blockade sensitivity in vivo. Importantly, reduced TYW2 expression is associated with increased response to checkpoint blockade in patients. Together, we demonstrate that defects in translation fidelity drive tumor immunogenicity and may be leveraged for cancer immunotherapy.","PeriodicalId":9670,"journal":{"name":"Cancer Cell","volume":"3 1","pages":""},"PeriodicalIF":50.3,"publicationDate":"2025-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143713596","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}

引用次数: 0

A niche driven mechanism determines response and a mutation-independent therapeutic approach for myeloid malignancies 一个利基驱动的机制决定了骨髓恶性肿瘤的反应和一种不依赖突变的治疗方法

IF 50.3 1区医学

Cancer Cell Pub Date : 2025-03-27 DOI: 10.1016/j.ccell.2025.03.007

Ioanna Mosialou, Abdullah M. Ali, Rossella Labella, Brygida Bisikirska, Alvaro Cuesta-Dominguez, Paraskevi Vgenopoulou, Ismarc Reyes, Sanjana M. Rao, Anqi Wang, Na Luo, Marta Galan-Diez, Junfei Zhao, Brian J. Chernak, Jan Philipp Bewersdorf, Kazuya Fukasawa, Jiayu Su, Jason Higa, Rachel A. Adams, Adam L. Corper, Sergey Pampou, Stavroula Kousteni

{"title":"A niche driven mechanism determines response and a mutation-independent therapeutic approach for myeloid malignancies","authors":"Ioanna Mosialou, Abdullah M. Ali, Rossella Labella, Brygida Bisikirska, Alvaro Cuesta-Dominguez, Paraskevi Vgenopoulou, Ismarc Reyes, Sanjana M. Rao, Anqi Wang, Na Luo, Marta Galan-Diez, Junfei Zhao, Brian J. Chernak, Jan Philipp Bewersdorf, Kazuya Fukasawa, Jiayu Su, Jason Higa, Rachel A. Adams, Adam L. Corper, Sergey Pampou, Stavroula Kousteni","doi":"10.1016/j.ccell.2025.03.007","DOIUrl":"https://doi.org/10.1016/j.ccell.2025.03.007","url":null,"abstract":"Myeloid cancers such as myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) remain resistant to standard of care (SOC) and targeted therapies. In this study, we demonstrate that responsiveness to therapy is associated with activation of β-catenin-JAG1 in osteoblastic cells of patients treated with all-trans-retinoic acid (ATRA). ATRA suppresses β-catenin activity in patients and leukemic mice. Consequently, it inhibits the growth and survival of MDS/AML cells from patients with active β-catenin-JAG1 signaling and promotes their differentiation. This occurs independently of cytogenetics and mutational profile. ATRA also improves disease outcome in mice with no evidence of relapse and a superior safety profile to SOC. A human anti-JAG1 antibody improves efficacy in leukemic mice and patient-derived MDS/AML cells. β-catenin activation provides an explanation for the differential response to ATRA and a mechanistic biomarker for ATRA repurposing in myeloid malignancies, potentially evading relapse and extending across a broad range of cancers.","PeriodicalId":9670,"journal":{"name":"Cancer Cell","volume":"33 1","pages":""},"PeriodicalIF":50.3,"publicationDate":"2025-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143713602","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}

引用次数: 0

The discrete charm of oncolytic viruses: Toward the finish line 溶瘤病毒的独特魅力：冲向终点线

IF 50.3 1区医学

Cancer Cell Pub Date : 2025-03-27 DOI: 10.1016/j.ccell.2025.03.010

Pedro R. Lowenstein, Maria Luisa Varela, Maria G. Castro

引用次数: 0

All-trans retinoic acid beyond acute promyelocytic leukemia 全反式维甲酸治疗急性早幼粒细胞白血病

IF 50.3 1区医学

Cancer Cell Pub Date : 2025-03-27 DOI: 10.1016/j.ccell.2025.03.008

Usama-Ur Rehman, Michael Lübbert

引用次数: 0