Cancer discovery最新文献

{"title":"Targeting Acute Myeloid Leukemia Stem Cells through Perturbation of Mitochondrial Calcium.","authors":"Anagha Inguva Sheth, Mark J Althoff, Hunter Tolison, Krysta Engel, Maria L Amaya, Anna E Krug, Tracy N Young, Mohammad Minhajuddin, Shanshan Pei, Sweta B Patel, Amanda Winters, Regan Miller, Ian T Shelton, Jonathan St-Germain, Tianyi Ling, Courtney L Jones, Brian Raught, Austin E Gillen, Monica Ransom, Sarah Staggs, Clayton A Smith, Daniel A Pollyea, Brett M Stevens, Craig T Jordan","doi":"10.1158/2159-8290.CD-23-1145","DOIUrl":"10.1158/2159-8290.CD-23-1145","url":null,"abstract":"<p><p>Acute myeloid leukemia stem cells (LSCs) are uniquely reliant on oxidative phosphorylation (OXPHOS) for survival. Moreover, maintenance of OXPHOS is dependent on BCL-2, creating a therapeutic opportunity to target LSCs using the BCL-2 inhibitor venetoclax. Although venetoclax-based regimens have shown promising clinical activity, the emergence of drug resistance is prevalent. Thus, in the present study, we investigated how mitochondrial properties may influence venetoclax responsiveness. Our data show that utilization of mitochondrial calcium is fundamentally different between drug-responsive and nonresponsive LSCs. By comparison, venetoclax-resistant LSCs demonstrate an active metabolic (i.e., OXPHOS) status with relatively high levels of calcium. Consequently, we tested genetic and pharmacological approaches to target the mitochondrial calcium uniporter. We demonstrate that inhibition of calcium uptake reduces OXPHOS and leads to eradication of venetoclax-resistant LSCs. These findings demonstrate a central role for calcium signaling in LSCs and provide an avenue for clinical management of venetoclax resistance. Significance: We identify increased utilization of mitochondrial calcium as a distinct metabolic requirement of venetoclax-resistant LSCs and demonstrate the potential of targeting mitochondrial calcium uptake as a therapeutic strategy.</p>","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":" ","pages":"1922-1939"},"PeriodicalIF":29.7,"publicationDate":"2024-10-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11452272/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141086786","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Biologic and Clinical Analysis of Childhood Gamma Delta T-ALL Identifies LMO2/STAG2 Rearrangements as Extremely High Risk.","authors":"Shunsuke Kimura, Chun Shik Park, Lindsey E Montefiori, Ilaria Iacobucci, Petri Pölönen, Qingsong Gao, Elizabeth D Arnold, Andishe Attarbaschi, Anthony Brown, Barbara Buldini, Kenneth J Caldwell, Yunchao Chang, Chelsey Chen, Cheng Cheng, Zhongshan Cheng, John Choi, Valentino Conter, Kristine R Crews, Hester A de Groot-Kruseman, Takao Deguchi, Mariko Eguchi, Hannah E Muhle, Sarah Elitzur, Gabriele Escherich, Burgess B Freeman, Zhaohui Gu, Katie Han, Keizo Horibe, Toshihiko Imamura, Sima Jeha, Motohiro Kato, Kean H Chiew, Tanya Khan, Michal Kicinski, Stefan Köhrer, Steven M Kornblau, Rishi S Kotecha, Chi-Kong Li, Yen-Chun Liu, Franco Locatelli, Selina M Luger, Elisabeth M Paietta, Atsushi Manabe, Hanne V Marquart, Riccardo Masetti, Mellissa Maybury, Pauline Mazilier, Jules P P Meijerink, Sharnise Mitchell, Takako Miyamura, Andrew S Moore, Koichi Oshima, Katarzyna Pawinska-Wasikowska, Rob Pieters, Mollie S Prater, Shondra M Pruett-Miller, Ching-Hon Pui, Chunxu Qu, Michaela Reiterova, Noemi Reyes, Kathryn G Roberts, Jacob M Rowe, Atsushi Sato, Kjeld Schmiegelow, Martin Schrappe, Shuhong Shen, Szymon Skoczeń, Orietta Spinelli, Jan Stary, Michael Svaton, Masatoshi Takagi, Junko Takita, Yanjing Tang, David T Teachey, Paul G Thomas, Daisuke Tomizawa, Jan Trka, Elena Varotto, Tiffaney L Vincent, Jun J Yang, Allen E J Yeoh, Yinmei Zhou, Martin Zimmermann, Hiroto Inaba, Charles G Mullighan","doi":"10.1158/2159-8290.CD-23-1452","DOIUrl":"10.1158/2159-8290.CD-23-1452","url":null,"abstract":"<p><p>Acute lymphoblastic leukemia expressing the gamma delta T-cell receptor (γδ T-ALL) is a poorly understood disease. We studied 200 children with γδ T-ALL from 13 clinical study groups to understand the clinical and genetic features of this disease. We found age and genetic drivers were significantly associated with outcome. γδ T-ALL diagnosed in children under 3 years of age was extremely high-risk and enriched for genetic alterations that result in both LMO2 activation and STAG2 inactivation. Mechanistically, using patient samples and isogenic cell lines, we show that inactivation of STAG2 profoundly perturbs chromatin organization by altering enhancer-promoter looping, resulting in deregulation of gene expression associated with T-cell differentiation. High-throughput drug screening identified a vulnerability in DNA repair pathways arising from STAG2 inactivation, which can be targeted by poly(ADP-ribose) polymerase inhibition. These data provide a diagnostic framework for classification and risk stratification of pediatric γδ T-ALL. Significance: Patients with acute lymphoblastic leukemia expressing the gamma delta T-cell receptor under 3 years old or measurable residual disease ≥1% at end of induction showed dismal outcomes and should be classified as having high-risk disease. The STAG2/LMO2 subtype was enriched in this very young age group. STAG2 inactivation may perturb chromatin conformation and cell differentiation and confer vulnerability to poly(ADP-ribose) polymerase inhibition.</p>","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":" ","pages":"1838-1859"},"PeriodicalIF":29.7,"publicationDate":"2024-10-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11452281/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141445688","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A New Era of Data-Driven Cancer Research and Care: Opportunities and Challenges.","authors":"Felicia Gomez, Arpad M Danos, Guilherme Del Fiol, Anant Madabhushi, Pallavi Tiwari, Joshua F McMichael, Spyridon Bakas, Jiang Bian, Christos Davatzikos, Elana J Fertig, Jayashree Kalpathy-Cramer, Johanna Kenney, Guergana K Savova, Meliha Yetisgen, Eliezer M Van Allen, Jeremy L Warner, Fred Prior, Malachi Griffith, Obi L Griffith","doi":"10.1158/2159-8290.CD-24-1130","DOIUrl":"10.1158/2159-8290.CD-24-1130","url":null,"abstract":"<p><p>People diagnosed with cancer and their formal and informal caregivers are increasingly faced with a deluge of complex information, thanks to rapid advancements in the type and volume of diagnostic, prognostic, and treatment data. This commentary discusses the opportunities and challenges that the society faces as we integrate large volumes of data into regular cancer care.</p>","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":"14 10","pages":"1774-1778"},"PeriodicalIF":29.7,"publicationDate":"2024-10-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11463721/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142370978","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Epigenetic Hallmarks of Cancer.","authors":"Manel Esteller, Mark A Dawson, Cigall Kadoch, Feyruz V Rassool, Peter A Jones, Stephen B Baylin","doi":"10.1158/2159-8290.CD-24-0296","DOIUrl":"https://doi.org/10.1158/2159-8290.CD-24-0296","url":null,"abstract":"<p><p>Cancer is a complex disease in which several molecular and cellular pathways converge to foster the tumoral phenotype. Notably, in the latest iteration of the cancer hallmarks, \"nonmutational epigenetic reprogramming\" was newly added. However, epigenetics, much like genetics, is a broad scientific area that deserves further attention due to its multiple roles in cancer initiation, progression, and adaptive nature. Herein, we present a detailed examination of the epigenetic hallmarks affected in human cancer, elucidating the pathways and genes involved, and dissecting the disrupted landscapes for DNA methylation, histone modifications, and chromatin architecture that define the disease. Significance: Cancer is a disease characterized by constant evolution, spanning from its initial premalignant stages to the advanced invasive and disseminated stages. It is a pathology that is able to adapt and survive amidst hostile cellular microenvironments and diverse treatments implemented by medical professionals. The more fixed setup of the genetic structure cannot fully provide transformed cells with the tools to survive but the rapid and plastic nature of epigenetic changes is ready for the task. This review summarizes the epigenetic hallmarks that define the ecological success of cancer cells in our bodies.</p>","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":"14 10","pages":"1783-1809"},"PeriodicalIF":29.7,"publicationDate":"2024-10-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142370982","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":"Transforming Cancer Research through Informatics.","authors":"Juli D Klemm, Dinah S Singer, Jill P Mesirov","doi":"10.1158/2159-8290.CD-24-0604","DOIUrl":"10.1158/2159-8290.CD-24-0604","url":null,"abstract":"<p><p>For more than three decades, concurrent advances in laboratory technologies and computer science have driven the rise of cancer informatics. Today, software tools for cancer research are indispensable to the entire cancer research enterprise.</p>","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":"14 10","pages":"1779-1782"},"PeriodicalIF":29.7,"publicationDate":"2024-10-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11463720/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142370983","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Iron Chelation Therapy Elicits Innate Immune Control of Metastatic Ovarian Cancer.","authors":"Tito A Sandoval, Camilla Salvagno, Chang-Suk Chae, Deepika Awasthi, Paolo Giovanelli, Matias Marin Falco, Sung-Min Hwang, Eli Teran-Cabanillas, Lasse Suominen, Takahiro Yamazaki, Hui-Hsuan Kuo, Jenna E Moyer, M Laura Martin, Jyothi Manohar, Kihwan Kim, Maria A Sierra, Yusibeska Ramos, Chen Tan, Alexander Emmanuelli, Minkyung Song, Diana K Morales, Dmitriy Zamarin, Melissa K Frey, Evelyn Cantillo, Eloise Chapman-Davis, Kevin Holcomb, Christopher E Mason, Lorenzo Galluzzi, Zhen Ni Zhou, Anna Vähärautio, Suzanne M Cloonan, Juan R Cubillos-Ruiz","doi":"10.1158/2159-8290.CD-23-1451","DOIUrl":"10.1158/2159-8290.CD-23-1451","url":null,"abstract":"<p><p>Iron accumulation in tumors contributes to disease progression and chemoresistance. Although targeting this process can influence various hallmarks of cancer, the immunomodulatory effects of iron chelation in the tumor microenvironment are unknown. Here, we report that treatment with deferiprone, an FDA-approved iron chelator, unleashes innate immune responses that restrain ovarian cancer. Deferiprone reprogrammed ovarian cancer cells toward an immunostimulatory state characterized by the production of type-I IFN and overexpression of molecules that activate NK cells. Mechanistically, these effects were driven by innate sensing of mitochondrial DNA in the cytosol and concomitant activation of nuclear DNA damage responses triggered upon iron chelation. Deferiprone synergized with chemotherapy and prolonged the survival of mice with ovarian cancer by bolstering type-I IFN responses that drove NK cell-dependent control of metastatic disease. Hence, iron chelation may represent an alternative immunotherapeutic strategy for malignancies that are refractory to current T-cell-centric modalities. Significance: This study uncovers that targeting dysregulated iron accumulation in ovarian tumors represents a major therapeutic opportunity. Iron chelation therapy using an FDA-approved agent causes immunogenic stress responses in ovarian cancer cells that delay metastatic disease progression and enhance the effects of first-line chemotherapy. See related commentary by Bell and Zou, p. 1771.</p>","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":" ","pages":"1901-1921"},"PeriodicalIF":29.7,"publicationDate":"2024-10-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11452292/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141787262","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Perivascular NOTCH3+ Stem Cells Drive Meningioma Tumorigenesis and Resistance to Radiotherapy.","authors":"Abrar Choudhury, Martha A Cady, Calixto-Hope G Lucas, Hinda Najem, Joanna J Phillips, Brisa Palikuqi, Naomi Zakimi, Tara Joseph, Janeth O Birrueta, William C Chen, Nancy A Oberheim Bush, Shawn L Hervey-Jumper, Ophir D Klein, Christine M Toedebusch, Craig M Horbinski, Stephen T Magill, Aparna Bhaduri, Arie Perry, Peter J Dickinson, Amy B Heimberger, Alan Ashworth, Elizabeth E Crouch, David R Raleigh","doi":"10.1158/2159-8290.CD-23-1459","DOIUrl":"10.1158/2159-8290.CD-23-1459","url":null,"abstract":"<p><p>Meningiomas are the most common primary intracranial tumors. Treatments for patients with meningiomas are limited to surgery and radiotherapy, and systemic therapies remain ineffective or experimental. Resistance to radiotherapy is common in high-grade meningiomas and the cell types and signaling mechanisms that drive meningioma tumorigenesis and resistance to radiotherapy are incompletely understood. Here, we report that NOTCH3 drives meningioma tumorigenesis and resistance to radiotherapy and find that perivascular NOTCH3+ stem cells are conserved across meningiomas from humans, dogs, and mice. Integrating single-cell transcriptomics with lineage tracing and imaging approaches in genetically engineered mouse models and xenografts, we show NOTCH3 drives tumor-initiating capacity, cell proliferation, angiogenesis, and resistance to radiotherapy to increase meningioma growth and reduce survival. To translate these findings to patients, we show that an antibody stabilizing the extracellular negative regulatory region of NOTCH3 blocks meningioma tumorigenesis and sensitizes meningiomas to radiotherapy, reducing tumor growth and improving survival. Significance: There are no effective systemic therapies to treat meningiomas, and meningioma stem cells are poorly understood. Here, we report perivascular NOTCH3+ stem cells to drive meningioma tumorigenesis and resistance to radiotherapy. Our results identify a conserved mechanism and a therapeutic vulnerability to treat meningiomas that are resistant to standard interventions.</p>","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":" ","pages":"1823-1837"},"PeriodicalIF":29.7,"publicationDate":"2024-10-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11452293/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140920963","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cancer Genomes Sometimes Take the Longest Evolutionary Road.","authors":"Alison M Taylor","doi":"10.1158/2159-8290.CD-24-1017","DOIUrl":"https://doi.org/10.1158/2159-8290.CD-24-1017","url":null,"abstract":"<p><p>Baker and colleagues developed a new algorithm called \"Gain Route Identification and Timing In Cancer\" (GRITIC) to uncover the path of chromosomal evolution in a tumor, particularly in the context of whole-genome duplication. Their approach found that tumors with genome doubling frequently take an indirect path from one copy number state to another. In addition, the timing of genome doubling within a tumor's evolution impacts its consequences on downstream chromosomal instability. See related article by Baker et al., p. 1810.</p>","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":"14 10","pages":"1766-1767"},"PeriodicalIF":29.7,"publicationDate":"2024-10-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142370980","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":"Clonal Lineage Tracing with Somatic Delivery of Recordable Barcodes Reveals Migration Histories of Metastatic Prostate Cancer.","authors":"Ryan N Serio, Armin Scheben, Billy Lu, Domenic V Gargiulo, Lucrezia Patruno, Caroline L Buckholtz, Ryan J Chaffee, Megan C Jibilian, Steven G Persaud, Stephen J Staklinski, Rebecca Hassett, Lise M Brault, Daniele Ramazzotti, Christopher E Barbieri, Adam C Siepel, Dawid G Nowak","doi":"10.1158/2159-8290.CD-23-1332","DOIUrl":"10.1158/2159-8290.CD-23-1332","url":null,"abstract":"<p><p>The patterns by which primary tumors spread to metastatic sites remain poorly understood. Here, we define patterns of metastatic seeding in prostate cancer using a novel injection-based mouse model-EvoCaP (Evolution in Cancer of the Prostate), featuring aggressive metastatic cancer to bone, liver, lungs, and lymph nodes. To define migration histories between primary and metastatic sites, we used our EvoTraceR pipeline to track distinct tumor clones containing recordable barcodes. We detected widespread intratumoral heterogeneity from the primary tumor in metastatic seeding, with few clonal populations instigating most migration. Metastasis-to-metastasis seeding was uncommon, as most cells remained confined within the tissue. Migration patterns in our model were congruent with human prostate cancer seeding topologies. Our findings support the view of metastatic prostate cancer as a systemic disease driven by waves of aggressive clones expanding their niche, infrequently overcoming constraints that otherwise keep them confined in the primary or metastatic site. Significance: Defining the kinetics of prostate cancer metastasis is critical for developing novel therapeutic strategies. This study uses CRISPR/Cas9-based barcoding technology to accurately define tumor clonal patterns and routes of migration in a novel somatically engineered mouse model (EvoCaP) that recapitulates human prostate cancer using an in-house developed analytical pipeline (EvoTraceR).</p>","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":" ","pages":"1990-2009"},"PeriodicalIF":29.7,"publicationDate":"2024-10-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141537637","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":"CD28 Costimulation Augments CAR Signaling in NK Cells via the LCK/CD3ζ/ZAP70 Signaling Axis.","authors":"Sunil Acharya, Rafet Basar, May Daher, Hind Rafei, Ping Li, Nadima Uprety, Emily Ensley, Mayra Shanley, Bijender Kumar, Pinaki P Banerjee, Luciana Melo Garcia, Paul Lin, Vakul Mohanty, Kun H Kim, Xianli Jiang, Yuchen Pan, Ye Li, Bin Liu, Ana K Nunez Cortes, Chenyu Zhang, Mohsen Fathi, Ali Rezvan, Melisa J Montalvo, Sophia L Cha, Francia Reyes-Silva, Rejeena Shrestha, Xingliang Guo, Kiran Kundu, Alexander Biederstädt, Luis Muniz-Feliciano, Gary M Deyter, Mecit Kaplan, Xin R Jiang, Enli Liu, Antrix Jain, Janos Roszik, Natalie W Fowlkes, Luisa M Solis Soto, Maria G Raso, Joseph D Khoury, Pei Lin, Francisco Vega, Navin Varadarajan, Ken Chen, David Marin, Elizabeth J Shpall, Katayoun Rezvani","doi":"10.1158/2159-8290.CD-24-0096","DOIUrl":"10.1158/2159-8290.CD-24-0096","url":null,"abstract":"<p><p>Multiple factors in the design of a chimeric antigen receptor (CAR) influence CAR T-cell activity, with costimulatory signals being a key component. Yet, the impact of costimulatory domains on the downstream signaling and subsequent functionality of CAR-engineered natural killer (NK) cells remains largely unexplored. Here, we evaluated the impact of various costimulatory domains on CAR-NK cell activity, using a CD70-targeting CAR. We found that CD28, a costimulatory molecule not inherently present in mature NK cells, significantly enhanced the antitumor efficacy and long-term cytotoxicity of CAR-NK cells both in vitro and in multiple xenograft models of hematologic and solid tumors. Mechanistically, we showed that CD28 linked to CD3ζ creates a platform that recruits critical kinases, such as lymphocyte-specific protein tyrosine kinase (LCK) and zeta-chain-associated protein kinase 70 (ZAP70), initiating a signaling cascade that enhances CAR-NK cell function. Our study provides insights into how CD28 costimulation enhances CAR-NK cell function and supports its incorporation in NK-based CARs for cancer immunotherapy. Significance: We demonstrated that incorporation of the T-cell-centric costimulatory molecule CD28, which is normally absent in mature natural killer (NK) cells, into the chimeric antigen receptor (CAR) construct recruits key kinases including lymphocyte-specific protein tyrosine kinase and zeta-chain-associated protein kinase 70 and results in enhanced CAR-NK cell persistence and sustained antitumor cytotoxicity.</p>","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":" ","pages":"1879-1900"},"PeriodicalIF":29.7,"publicationDate":"2024-10-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11452288/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141426394","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}