Cancer CellPub Date : 2025-03-10DOI: 10.1016/j.ccell.2025.02.021
Jiasheng Wang, Xin Lin
{"title":"An innovative ALA-CART platform exhibits high efficacy against cancers","authors":"Jiasheng Wang, Xin Lin","doi":"10.1016/j.ccell.2025.02.021","DOIUrl":"https://doi.org/10.1016/j.ccell.2025.02.021","url":null,"abstract":"The therapeutic efficacy of chimeric antigen receptor (CAR) T cells is compromised in antigen-low tumors due to poor sensitivity and insufficient persistence. In this issue of <em>Cancer Cell</em>, Pham-Danis et al. design the ALA-CART platform to improve CAR T cell sensitivity, persistence, differentiation, and cytotoxic function by enhancing LAT phosphorylation after low antigen stimulation.","PeriodicalId":9670,"journal":{"name":"Cancer Cell","volume":"53 1","pages":""},"PeriodicalIF":50.3,"publicationDate":"2025-03-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143582435","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 : 2025-03-10DOI: 10.1016/j.ccell.2025.02.008
Catherine Pham-Danis, Amanda J. Novak, Etienne Danis, Samantha M. McClellan, Lillie Leach, Michael C. Yarnell, Christopher C. Ebmeier, Sarah K. Tasian, M. Eric Kohler
{"title":"Restoration of LAT activity improves CAR T cell sensitivity and persistence in response to antigen-low acute lymphoblastic leukemia","authors":"Catherine Pham-Danis, Amanda J. Novak, Etienne Danis, Samantha M. McClellan, Lillie Leach, Michael C. Yarnell, Christopher C. Ebmeier, Sarah K. Tasian, M. Eric Kohler","doi":"10.1016/j.ccell.2025.02.008","DOIUrl":"https://doi.org/10.1016/j.ccell.2025.02.008","url":null,"abstract":"Chimeric antigen receptor (CAR) T cells induce responses in patients with relapsed/refractory leukemia; however, long-term efficacy is frequently limited by relapse. The inability to target antigen-low cells is an intrinsic vulnerability of second-generation CAR T cells and underlies most relapses following CD22BBz CAR T cell therapy. Here, we interrogate CD22BBz CAR signaling in response to low antigen and find inefficient phosphorylation of the linker for activation of T cells (LAT) limiting downstream signaling. To overcome this, we designed the adjunctive LAT-activating CAR T cell (ALA-CART) platform, pairing a second-generation CAR with a LAT-CAR incorporating the intracellular domain of LAT. ALA-CART cells demonstrate reduced differentiation during manufacturing and increased LAT phosphorylation, MAPK signaling, and AP-1 activity. ALA-CART cells show improved cytotoxicity, proliferation, persistence, and efficacy against antigen-low leukemias that were refractory to clinically active CD22BBz CAR T cells. Restoration of LAT signaling through the ALA-CART platform represents a promising strategy for overcoming multiple mechanisms of CAR T cell failure.","PeriodicalId":9670,"journal":{"name":"Cancer Cell","volume":"59 1","pages":""},"PeriodicalIF":50.3,"publicationDate":"2025-03-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143582536","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 : 2025-03-10DOI: 10.1016/j.ccell.2025.02.012
Mathieu Desaunay, Poulikos I. Poulikakos
{"title":"Overcoming melanoma therapy resistance with RAF-MEK and FAK inhibition","authors":"Mathieu Desaunay, Poulikos I. Poulikakos","doi":"10.1016/j.ccell.2025.02.012","DOIUrl":"https://doi.org/10.1016/j.ccell.2025.02.012","url":null,"abstract":"Cutaneous melanoma, frequently driven by BRAF (V600X) mutations, often develops resistance to mitogen-activated protein kinase (MAPK)-targeted therapies and immune checkpoint inhibitors. In this issue of <em>Cancer Cell</em>, Lubrano et al. identify RhoA-FAK-AKT signaling as a resistance mechanism and demonstrate that combining RAF-MEK glue with a FAK inhibitor enhances tumor regression and immune response.","PeriodicalId":9670,"journal":{"name":"Cancer Cell","volume":"53 1","pages":""},"PeriodicalIF":50.3,"publicationDate":"2025-03-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143582608","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 : 2025-03-10DOI: 10.1016/j.ccell.2025.02.016
Ting Liu, Leif W. Ellisen
{"title":"Exploring the “chemo” in chemoimmunotherapy for triple-negative breast cancer","authors":"Ting Liu, Leif W. Ellisen","doi":"10.1016/j.ccell.2025.02.016","DOIUrl":"https://doi.org/10.1016/j.ccell.2025.02.016","url":null,"abstract":"In this issue of <em>Cancer Cell</em>, Zhang et al. use single-cell RNA sequencing to compare immune cell dynamics in triple-negative breast cancers treated with the PD-L1 inhibitor atezolizumab plus paclitaxel or nab-paclitaxel. They identify distinct T cell activation patterns and highlight mast cells’ role in immune activation exclusively in the nab-paclitaxel combination.","PeriodicalId":9670,"journal":{"name":"Cancer Cell","volume":"19 1","pages":""},"PeriodicalIF":50.3,"publicationDate":"2025-03-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143582432","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":"Single-cell multi-stage spatial evolutional map of esophageal carcinogenesis","authors":"Jiang Chang, Junting Lu, Qingyi Liu, Tao Xiang, Shaosen Zhang, Yonglin Yi, Dongxu Li, Tianyuan Liu, Zeyuan Liu, Xinjie Chen, Zhenghao Dong, Cainan Li, HanZhang Yi, Siqi Yu, Luwei Huang, Fangfei Qu, Mengdi Wang, Dehe Wang, Hao Dong, Guoyu Cheng, Chen Wu","doi":"10.1016/j.ccell.2025.02.009","DOIUrl":"https://doi.org/10.1016/j.ccell.2025.02.009","url":null,"abstract":"Cancer development involves the co-evolution of cancer cells and their surrounding microenvironment, yet the dynamics of this interaction within the physical architecture remains poorly understood. Here, we present a spatial transcriptomic map at single-cell resolution, encompassing 127 multi-stage fields of view from 43 patients, to chart the evolutionary trajectories of human esophageal squamous cell carcinoma (ESCC). By analyzing 6.4 million cells, we reveal that ESCC progression is driven by a proliferative epithelial cell subpopulation that acquires dedifferentiated and invasive characteristics. At the late precancerous stage, these cells disrupt the epithelial-stromal interface and recruit normal fibroblasts via JAG1-NOTCH1 signaling, transforming them into cancer-associated fibroblasts (CAFs). This interaction leads to the formation of a “CAF-Epi” (CAF and epithelial cell) niche at the tumor edge that shields the tumor from immune surveillance. The CAF-Epi niche formation is a key indicator of progression in ESCC and other squamous cell carcinomas and patient outcomes.","PeriodicalId":9670,"journal":{"name":"Cancer Cell","volume":"62 1","pages":""},"PeriodicalIF":50.3,"publicationDate":"2025-03-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143582533","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 : 2025-03-06DOI: 10.1016/j.ccell.2025.02.002
W.K. Jacky Lam, Guannan Kang, Charles M.L. Chan, Vicky C.T. Lee, Mary-Jane L. Ma, Qing Zhou, Peiyong Jiang, Irene O.L. Tse, Ann D. King, Kenneth C.W. Wong, Edwin P. Hui, Brigette B.Y. Ma, Anthony T.C. Chan, K.C. Allen Chan, Y.M. Dennis Lo
{"title":"Fragmentomics profiling and quantification of plasma Epstein-Barr virus DNA enhance prediction of future nasopharyngeal carcinoma","authors":"W.K. Jacky Lam, Guannan Kang, Charles M.L. Chan, Vicky C.T. Lee, Mary-Jane L. Ma, Qing Zhou, Peiyong Jiang, Irene O.L. Tse, Ann D. King, Kenneth C.W. Wong, Edwin P. Hui, Brigette B.Y. Ma, Anthony T.C. Chan, K.C. Allen Chan, Y.M. Dennis Lo","doi":"10.1016/j.ccell.2025.02.002","DOIUrl":"https://doi.org/10.1016/j.ccell.2025.02.002","url":null,"abstract":"Fragmentomics analysis of plasma autosomal DNA has shown promise in cancer diagnostics. Here we evaluated the clinical utility of plasma Epstein-Barr virus (EBV) DNA fragmentomics analysis for nasopharyngeal carcinoma (NPC) screening. Among our prospective cohort of approximately 20,000 subjects that underwent two rounds of screening, we analyzed the first-round blood samples of subjects who tested positive for EBV DNA via polymerase chain reaction (PCR) (<em>n</em> = 558). We found that those who subsequently developed NPC in the second round exhibited a distinctive mononucleosomal size pattern, an NPC-associated end motif (specifically, a depletion of CC-motif) and aberrations in methylation identified through fragmentomics-based methylation analysis (FRAGMA). Subjects with these aberrant fragmentomics features and higher quantity of EBV DNA had a relative risk of 87.1 times greater for developing NPC in the second round compared to subjects tested negative for EBV DNA on PCR. These results demonstrate plasma DNA fragmentomics could predict future cancer risk.","PeriodicalId":9670,"journal":{"name":"Cancer Cell","volume":"26 1","pages":""},"PeriodicalIF":50.3,"publicationDate":"2025-03-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143569571","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 : 2025-03-06DOI: 10.1016/j.ccell.2025.02.025
Lindsay M. LaFave, Vinay K. Kartha, Sai Ma, Kevin Meli, Isabella Del Priore, Caleb Lareau, Santiago Naranjo, Peter M.K. Westcott, Fabiana M. Duarte, Venkat Sankar, Zachary Chiang, Alison Brack, Travis Law, Haley Hauck, Annalisa Okimoto, Aviv Regev, Jason D. Buenrostro, Tyler Jacks
{"title":"Epigenomic State Transitions Characterize Tumor Progression in Mouse Lung Adenocarcinoma","authors":"Lindsay M. LaFave, Vinay K. Kartha, Sai Ma, Kevin Meli, Isabella Del Priore, Caleb Lareau, Santiago Naranjo, Peter M.K. Westcott, Fabiana M. Duarte, Venkat Sankar, Zachary Chiang, Alison Brack, Travis Law, Haley Hauck, Annalisa Okimoto, Aviv Regev, Jason D. Buenrostro, Tyler Jacks","doi":"10.1016/j.ccell.2025.02.025","DOIUrl":"https://doi.org/10.1016/j.ccell.2025.02.025","url":null,"abstract":"(Cancer Cell <em>38</em>, 212–228; August 10, 2020)","PeriodicalId":9670,"journal":{"name":"Cancer Cell","volume":"14 1","pages":""},"PeriodicalIF":50.3,"publicationDate":"2025-03-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143569569","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 : 2025-03-06DOI: 10.1016/j.ccell.2025.02.017
Sara Lamorte, Rene Quevedo, Robbie Jin, Luke Neufeld, Zhe Qi Liu, M. Teresa Ciudad, Sabelo Lukhele, Jessica Bruce, Shreya Mishra, Xin Zhang, Zaid Kamil Saeed, Hal Berman, Dana J. Philpott, Stephen E. Girardin, Shane Harding, David H. Munn, Tak W. Mak, Mikael C.I. Karlsson, David G. Brooks, Tracy L. McGaha
{"title":"Lymph node macrophages drive immune tolerance and resistance to cancer therapy by induction of the immune-regulatory cytokine IL-33","authors":"Sara Lamorte, Rene Quevedo, Robbie Jin, Luke Neufeld, Zhe Qi Liu, M. Teresa Ciudad, Sabelo Lukhele, Jessica Bruce, Shreya Mishra, Xin Zhang, Zaid Kamil Saeed, Hal Berman, Dana J. Philpott, Stephen E. Girardin, Shane Harding, David H. Munn, Tak W. Mak, Mikael C.I. Karlsson, David G. Brooks, Tracy L. McGaha","doi":"10.1016/j.ccell.2025.02.017","DOIUrl":"https://doi.org/10.1016/j.ccell.2025.02.017","url":null,"abstract":"Apoptotic cells are immunosuppressive, creating a barrier in cancer treatment. Thus, we investigated immune responses to dying tumor cells after therapy in the tumor draining lymph node (TDLN). A key population responsible for clearing tumor material in the TDLN was medullary sinus macrophages (MSMs). Tumor debris phagocytosis by MSMs induces the cytokine IL-33, and blocking the IL-33 receptor (ST2) or deletion of <em>Il33</em> in MSMs enhances therapy responses. Mechanistically, IL-33 activates T regulatory cells in TDLNs that migrate to the tumor to suppress CD8<sup>+</sup> T cells. Therapeutically combining ST2 blockade, targeted kinase inhibitors, and anti-PD-1 immunotherapy increases CD8<sup>+</sup> T cell activity promoting tumor regression. Importantly, we observe similar activity in human macrophages, and IL-33 expression in sentinel lymph nodes correlates with disease stage and survival in melanoma. Thus, our data identifies an IL-33-dependent immune response to therapy that attenuates therapy-induced anti-tumor immunity.","PeriodicalId":9670,"journal":{"name":"Cancer Cell","volume":"85 1","pages":""},"PeriodicalIF":50.3,"publicationDate":"2025-03-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143569568","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":"Hypoxia inducible factor-1α drives cancer resistance to cuproptosis","authors":"Zhou Yang, Wei Su, Xiyi Wei, Yitong Pan, Mengying Xing, Lili Niu, Baijie Feng, Weiyu Kong, Xiaohan Ren, Feng Huang, Jingwan Zhou, Wei Zhao, Yingyi Qiu, Tian Liao, Qi Chen, Shuang Qu, Yunjun Wang, Qing Guan, Duanshu Li, Ke Zen, Bing Yao","doi":"10.1016/j.ccell.2025.02.015","DOIUrl":"https://doi.org/10.1016/j.ccell.2025.02.015","url":null,"abstract":"Cuproptosis represents a new type of cell death that intricately associated with copper homeostasis and protein lipoylation. The cuproptosis suppression has been characterized in the hypoxic tumor microenvironment (TME). Here we reveal that hypoxia inducible factor-1α (HIF-1α) is a driver of cuproptosis resistance in solid tumor. We found that HIF-1α activates pyruvate dehydrogenase kinase 1 and 3 (PDK1/3), resulting in decreased expression of dihydrolipoamide S-acetyltransferase (DLAT) (target of copper), and promotes the accumulation of metallothionein, which sequesters mitochondrial copper, leading to resistance to cuproptosis under hypoxic conditions. Furthermore, we discovered that high levels of copper reduce ubiquitination and increase the stability of HIF-1α protein without affecting its mRNA levels. Inhibition of HIF-1α increases the susceptibility of cancer to cuproptosis <em>in vivo</em>. This study unveils the multifaceted role of HIF-1α in cuproptosis and demonstrates the molecular mechanism of hypoxia-promoted carcinogenesis.","PeriodicalId":9670,"journal":{"name":"Cancer Cell","volume":"17 1","pages":""},"PeriodicalIF":50.3,"publicationDate":"2025-03-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143569570","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":"Nivolumab combined with induction chemotherapy and radiotherapy in nasopharyngeal carcinoma: A multicenter phase 2 PLATINUM trial","authors":"Cheng Xu, Guan-Qun Zhou, Wen-Fei Li, De-Sheng Hu, Xiao-Zhong Chen, Shao-Jun Lin, Feng Jin, Xin-Qiong Huang, Gang Peng, Jing Huang, Yuan Wu, Chang-Juan Tao, Ji-Bin Li, Ai-Hua Lin, Hong-Yun Zhao, Shu-Bin Hong, Hui-Ling Huang, Ling-Long Tang, Ying-Lin Peng, Ke-Fu Shi, Jun Ma","doi":"10.1016/j.ccell.2025.01.014","DOIUrl":"https://doi.org/10.1016/j.ccell.2025.01.014","url":null,"abstract":"Severe toxicities caused by concurrent cisplatin are a critical problem in nasopharyngeal carcinoma (NPC) treatment. In this phase 2 multicenter PLATINUM trial (<span><span>NCT03984357</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>), we recruited 152 NPC patients who received 12-cycle nivolumab plus induction chemotherapy and radiotherapy without concurrent cisplatin. After a median follow-up of 43 months, the 3-year failure-free survival (FFS) was 88.5% (95% confidence interval [CI], 83.4%–93.8%) and the 3-year overall survival was 97.9%. An early clearance of Epstein-Barr virus (EBV) DNA after induction-phase treatment was associated with FFS benefit. Sixty (40.2%) and eight (5.2%) patients had acute and late grade 3–4 adverse events (AEs), respectively. Most patients had good tolerance to AE-associated frequency (68.0%–96.7%), severity (56.0%–98.6%), and interference (58.0%–98.0%); 86.7%–100.0% of quality-of-life domains showed either no clinically meaningful deterioration or a rapid recovery. Nivolumab plus induction chemotherapy and radiotherapy demonstrated efficacious anti-tumor activity, low toxicity, and favorable tolerability and quality-of-life for NPC patients.","PeriodicalId":9670,"journal":{"name":"Cancer Cell","volume":"2 1","pages":""},"PeriodicalIF":50.3,"publicationDate":"2025-02-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143506858","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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