Cell Reports MedicinePub Date : 2025-06-17Epub Date: 2025-06-10DOI: 10.1016/j.xcrm.2025.102188
Josephine Yates, Camille Mathey-Andrews, Jihye Park, Amanda Garza, Andréanne Gagné, Samantha Hoffman, Kevin Bi, Breanna Titchen, Connor Hennessey, Joshua Remland, Matthew Carnes, Erin Shannon, Sabrina Camp, Siddhi Balamurali, Shweta Kiran Cavale, Zhixin Li, Akhouri Kishore Raghawan, Agnieszka Kraft, Genevieve Boland, Andrew J Aguirre, Nilay S Sethi, Valentina Boeva, Eliezer M Van Allen
{"title":"Cell states and neighborhoods in distinct clinical stages of primary and metastatic esophageal adenocarcinoma.","authors":"Josephine Yates, Camille Mathey-Andrews, Jihye Park, Amanda Garza, Andréanne Gagné, Samantha Hoffman, Kevin Bi, Breanna Titchen, Connor Hennessey, Joshua Remland, Matthew Carnes, Erin Shannon, Sabrina Camp, Siddhi Balamurali, Shweta Kiran Cavale, Zhixin Li, Akhouri Kishore Raghawan, Agnieszka Kraft, Genevieve Boland, Andrew J Aguirre, Nilay S Sethi, Valentina Boeva, Eliezer M Van Allen","doi":"10.1016/j.xcrm.2025.102188","DOIUrl":"10.1016/j.xcrm.2025.102188","url":null,"abstract":"<p><p>Esophageal adenocarcinoma (EAC) is a highly lethal cancer of the upper gastrointestinal tract with rising incidence in western populations. To decipher EAC disease progression and therapeutic response, we perform multiomic analyses of a cohort of primary and metastatic EAC tumors, incorporating single-nuclei transcriptomic and chromatin accessibility sequencing along with spatial profiling. We recover tumor microenvironmental features previously described to associate with therapy response. We subsequently identify five malignant cell programs, including undifferentiated, intermediate, differentiated, epithelial-to-mesenchymal transition, and cycling programs, which are associated with differential epigenetic plasticity and clinical outcomes, and for which we infer candidate transcription factor regulons. Furthermore, we reveal diverse spatial localizations of malignant cells expressing their associated transcriptional programs and predict their significant interactions with microenvironmental cell types. We validate our findings in three external single-cell RNA sequencing (RNA-seq) and three bulk RNA-seq studies. Altogether, our findings advance the understanding of EAC heterogeneity, disease progression, and therapeutic response.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"102188"},"PeriodicalIF":11.7,"publicationDate":"2025-06-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144274284","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":"Probiotic-mediated tumor microenvironment reprogramming with protease-sensitive interleukin-15 and photothermal therapy.","authors":"Huifang Wang, Liuhai Zheng, Chuanbin Yang, Lin Jia, Runhua Zhou, Hongda Liu, Yafang Dong, Xiaolong Xu, Guangwei Shi, Jialu Yang, Yang Li, Haitao Yuan, Jinpeng Cen, Guiming Zhang, Le Yu, Tianqi Guo, Haibo Jiang, Yawei Liu, Xijun Wang, Zhijie Li, Jigang Wang","doi":"10.1016/j.xcrm.2025.102191","DOIUrl":"https://doi.org/10.1016/j.xcrm.2025.102191","url":null,"abstract":"<p><p>T cell inadequacy or exhaustion often causes the failure of immune checkpoint blockade (ICB)-based immunotherapy. Interleukin-15 (IL-15) has been used to prime the tumor microenvironment (TME) to boost the efficiency of immunotherapy. However, its clinical application is hindered by systemic toxicity and low intratumoral concentrations. Here, we engineer the probiotic Escherichia coli Nissle 1917 to deliver IL-15 and croconium dye, enabling the TME-responsive release of IL-15 and amplifying the antitumor effect through photothermal therapy. This promotes the recruitment of antigen-presenting cells and T cells and the expansion of T/natural killer cells induced by IL-15. Consequently, it halts the tumor growth and induces systemic memory T cell production. This approach combined with ICBs generates prominent synergistic effects across various immune-hot and immune-cold tumors. This study provides a strategy for targeted delivery of cytokines, demonstrating its high potential for TME reprogramming when combined with immunogenic cell death inducers.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":"6 6","pages":"102191"},"PeriodicalIF":11.7,"publicationDate":"2025-06-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144324518","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}
Cell Reports MedicinePub Date : 2025-06-17Epub Date: 2025-05-16DOI: 10.1016/j.xcrm.2025.102139
Michaela Dvorakova, Taryn Bosquez-Berger, Jenna Billingsley, Natalia Murataeva, Taylor Woodward, Emma Leishman, Anaëlle Zimmowitch, Anne Gibson, Jim Wager-Miller, Ruyi Cai, Shangxuan Cai, Tim Ware, Ku-Lung Hsu, Yulong Li, Heather Bradshaw, Ken Mackie, Alex Straiker
{"title":"Acetaminophen inhibits diacylglycerol lipase synthesis of 2-arachidonoyl glycerol: Implications for nociception.","authors":"Michaela Dvorakova, Taryn Bosquez-Berger, Jenna Billingsley, Natalia Murataeva, Taylor Woodward, Emma Leishman, Anaëlle Zimmowitch, Anne Gibson, Jim Wager-Miller, Ruyi Cai, Shangxuan Cai, Tim Ware, Ku-Lung Hsu, Yulong Li, Heather Bradshaw, Ken Mackie, Alex Straiker","doi":"10.1016/j.xcrm.2025.102139","DOIUrl":"10.1016/j.xcrm.2025.102139","url":null,"abstract":"<p><p>Acetaminophen (paracetamol) is a common analgesic, but its mechanism of action remains unknown. Despite causing around 500 deaths annually in the US, safer alternatives have not been developed. Because endocannabinoids may have a role in acetaminophen action, we examine interactions between the two. We report that acetaminophen inhibits the activity of diacylglycerol lipase α (DAGLα), but not DAGLβ, decreasing the production of the endocannabinoid 2-arachidonoyl glycerol. This gives rise to the counterintuitive hypothesis that decreasing endocannabinoid production by DAGLα inhibition may be antinociceptive in certain settings. Supporting this hypothesis, we find that diacylglycerol lipase (DAGL) inhibition by RHC80267 is antinociceptive in wild-type but not CB1 knockout mice in the hot-plate test. We propose (1) that activation of DAGLα may exacerbate some forms of nociception and (2) a mechanism for the antinociceptive actions of acetaminophen, whereby acetaminophen inhibits a DAGLα/CB1-based circuit that plays a permissive role in at least one form of nociception.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"102139"},"PeriodicalIF":11.7,"publicationDate":"2025-06-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144093041","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}
Cell Reports MedicinePub Date : 2025-06-17Epub Date: 2025-06-02DOI: 10.1016/j.xcrm.2025.102156
Ruben Rodriguez, Anne Hergarden, Shyam Krishnan, Marikris Morales, Davina Lam, Ted Tracy, Teresa Tang, Avalon Patton, Craig Lee, Asmita Pant, Daniel A Erlanson, Johan Enquist, Derek Bone, Ray Fucini, Damian Bialonczyk, Stig K Hansen, Jian Luo, Manu V Chakravarthy
{"title":"Biased agonism of GLP-1R and GIPR enhances glucose lowering and weight loss, with dual GLP-1R/GIPR biased agonism yielding greater efficacy.","authors":"Ruben Rodriguez, Anne Hergarden, Shyam Krishnan, Marikris Morales, Davina Lam, Ted Tracy, Teresa Tang, Avalon Patton, Craig Lee, Asmita Pant, Daniel A Erlanson, Johan Enquist, Derek Bone, Ray Fucini, Damian Bialonczyk, Stig K Hansen, Jian Luo, Manu V Chakravarthy","doi":"10.1016/j.xcrm.2025.102156","DOIUrl":"10.1016/j.xcrm.2025.102156","url":null,"abstract":"<p><p>Glucagon-like peptide-1 receptor (GLP-1R) and glucose-dependent insulinotropic polypeptide receptor (GIPR) agonists have recently been shown to play a significant role in the treatment of diabetes and obesity. Better understanding of their signaling and mechanism of action could further improve their therapeutic effects. In the current study, we investigate the impact of biased cyclic AMP (cAMP) signaling of GLP-1R and GIPR, individually, as well as the combined effects of a unimolecular dually biased GLP-1R/GIPR agonist, CT-859, on glucose, food consumption, and body weight regulation. Our data demonstrate that biased agonism of either GLP-1R or GIPR leads to better glycemic regulation, greater food intake suppression, and weight loss. In addition, concerted biased activation of both GLP-1R and GIPR results in substantially higher efficacy. Activation of GLP-1R and GIPR with a combination of individually biased agonists or via a dually biased unimolecular approach with CT-859 may provide significant therapeutic advantages for the treatment of diabetes and obesity.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"102156"},"PeriodicalIF":11.7,"publicationDate":"2025-06-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144215047","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}
Caleb Stokes, Leanne S Whitmore, Dante Moreno, Karan Malhotra, Jennifer Tisoncik-Go, Emily Tran, Nick Wren, Ian A Glass, Jessica E Young, Michael Gale
{"title":"The human neural cell atlas of Zika virus infection in developing brain tissue.","authors":"Caleb Stokes, Leanne S Whitmore, Dante Moreno, Karan Malhotra, Jennifer Tisoncik-Go, Emily Tran, Nick Wren, Ian A Glass, Jessica E Young, Michael Gale","doi":"10.1016/j.xcrm.2025.102189","DOIUrl":"10.1016/j.xcrm.2025.102189","url":null,"abstract":"<p><p>Zika virus (ZIKV) infection during pregnancy can lead to fetal brain infection and developmental anomalies collectively known as congenital Zika syndrome (CZS). To define the molecular features underlying CZS in a relevant human cell model, we evaluate ZIKV infection in primary human fetal brain explants and human induced pluripotent stem cell-derived mixed neural cultures at single-cell resolution. We identify astrocytes as important innate immune sentinel cells detecting ZIKV and producing interferon-beta (IFN-β). In contrast, neural stem cells display impaired innate immunity and support high levels of viral replication. ZIKV infection of neurons suppresses differentiation and synaptic signaling gene networks and programs a molecular switch from neurogenesis to astrogliogenesis. We identify a universal ZIKV-driven cellular stress response linked to intrinsic apoptosis and regulated by IFN-β. These findings reveal innate immune signaling intersecting with ZIKV-driven perturbations in cellular function to influence CZS outcomes including neuron developmental dysfunction and apoptotic cell death.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":"6 6","pages":"102189"},"PeriodicalIF":11.7,"publicationDate":"2025-06-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144324520","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}
Cell Reports MedicinePub Date : 2025-06-17Epub Date: 2025-05-29DOI: 10.1016/j.xcrm.2025.102152
Alan Fappi, Bruce W Patterson, Kendal H Burks, Nicholas O Davidson, Tomas Vaisar, Jenny E Kanter, Karin E Bornfeldt, Edward A Fisher, Ira J Goldberg, Nathan O Stitziel, Bettina Mittendorfer
{"title":"Effect of complete, lifelong ANGPTL3 deficiency on triglyceride-rich lipoprotein kinetics.","authors":"Alan Fappi, Bruce W Patterson, Kendal H Burks, Nicholas O Davidson, Tomas Vaisar, Jenny E Kanter, Karin E Bornfeldt, Edward A Fisher, Ira J Goldberg, Nathan O Stitziel, Bettina Mittendorfer","doi":"10.1016/j.xcrm.2025.102152","DOIUrl":"10.1016/j.xcrm.2025.102152","url":null,"abstract":"<p><p>Angiopoietin-like 3 (ANGPTL3) inhibits lipases that hydrolyze triglycerides (TGs) in TG-rich lipoproteins (TRLs). We evaluated TRL-TGs, TRL particle (apolipoprotein B), palmitate, and glucose kinetics during a mixed-meal test that included intravenous and oral tracer administrations in people with extremely rare compound heterozygous ANGTPL3 loss-of-function mutations (ANGPTL3<sup>-/-</sup> group, n = 3) and matched control participants (n = 7). Multi-organ (liver, muscle, and adipose tissue) insulin sensitivity was evaluated with a two-step hyperinsulinemic-euglycemic clamp procedure and glucose and palmitate tracer infusions. We find that plasma TG and TRL particle concentrations are more than 10-fold lower in the ANGPTL3<sup>-/-</sup> than in the control group due to both markedly reduced liver-derived TRL particle and TG secretion rates combined with increased plasma clearance of both liver- and gut-derived TRLs. Palmitate and glucose kinetics during the meal test are not different between the groups. We conclude that the biological function of ANGPTL3 reaches beyond inhibiting intravascular lipase activity.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"102152"},"PeriodicalIF":11.7,"publicationDate":"2025-06-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144186614","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":"Ultrabright ratiometric Raman-guided epilepsy surgery by intraoperatively visualizing proinflammatory microglia.","authors":"Cong Wang, Zhi Li, Xiao Zhu, Wanbing Sun, Yue Ding, Wenjia Duan, Difei Wang, Yiqing Jiang, Ming Chen, Yuncan Chen, Jiayi Hu, Zheping Cai, Jing Zhao, Junfeng Wang, Zhen Fan, Faming Zheng, Xingyu Zhou, Fang Xie, Jianping Zhang, Yihui Guan, Kui Yan, Zuhai Lei, Qinyue Wang, Luting Wang, Xiao Xiao, Hairong Zheng, Liang Chen, Cong Li, Ying Mao","doi":"10.1016/j.xcrm.2025.102155","DOIUrl":"10.1016/j.xcrm.2025.102155","url":null,"abstract":"<p><p>Resective surgery is an effective approach for long-term seizure control in drug-resistant focal epilepsy when the epileptic focus (EF) can be accurately delineated and removed. However, intraoperative mapping of EF with electrocorticography is laborious, time-consuming, and highly vulnerable to the effects of anesthesia. Here, we demonstrated that activated microglia can be reliable biomarkers for EF localization. Leveraging a newly developed ratiometric Raman nanosensor, ultraHOCls, we successfully visualize proinflammatory microglia in live epileptic mice, allowing for precise EF delineation without the interference of anesthesia. Compared to electrocorticography-guided surgery, ultraHOCl-guided surgery results in a substantial 61% reduction in total seizure burden in epileptic mouse models. Notably, ultraHOCls sprayed on freshly excised human brain tissues can effectively discriminate epileptic regions from non-epileptic tissues with high sensitivity (94.89%) and specificity (93.3%). This work provides an alternative strategy for delineating the EF intraoperatively, potentially revolutionizing surgery outcomes in epilepsy patients.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"102155"},"PeriodicalIF":11.7,"publicationDate":"2025-06-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144191584","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}
Cell Reports MedicinePub Date : 2025-06-17Epub Date: 2025-06-02DOI: 10.1016/j.xcrm.2025.102147
Nabil Smichi, Biswajit Khatua, Sergiy Kostenko, Cristiane de Oliveira, Bara El Kurdi, Kalpit Himmatbhai Devani, Shubham Trivedi, Megan Summers, Bryce McFayden, Sarah Navina, Krutika Patel, Sarah Jahangir, Marek Belohlavek, Vijay P Singh
{"title":"Visceral fat lipolysis by pancreatic lipases worsens heart failure.","authors":"Nabil Smichi, Biswajit Khatua, Sergiy Kostenko, Cristiane de Oliveira, Bara El Kurdi, Kalpit Himmatbhai Devani, Shubham Trivedi, Megan Summers, Bryce McFayden, Sarah Navina, Krutika Patel, Sarah Jahangir, Marek Belohlavek, Vijay P Singh","doi":"10.1016/j.xcrm.2025.102147","DOIUrl":"10.1016/j.xcrm.2025.102147","url":null,"abstract":"<p><p>Heart failure can be worse when associated with obesity, elevated serum pancreatic enzymes, elevated non-esterified fatty acids (NEFAs), or acute pancreatitis (AP). To understand this, here we study doxorubicin-induced heart failure, experimental AP, or pancreatic lipase-induced visceral fat necrosis in lean, genetically obese (ob/ob), or dual ob/ob pancreatic triglyceride lipase (PNLIP)-knockout mice. NEFA generation and resulting cardiac injury are measured. We note that ob/ob mice develop fat necrosis containing PNLIP and phospholipase A<sub>2</sub>. This generates excess NEFAs that worsen cardiac injury, cause hypotension, and reduce survival. All these are prevented by PNLIP deletion or pharmacologic inhibition. Live imaging shows that phospholipase A<sub>2</sub> damages adipocyte membranes, resulting in PNLIP entry and leakage of adipocyte lipases. PNLIP hydrolyzes adipose triglyceride, generates NEFAs, and causes lipid droplet loss and adipocyte necrosis. Therefore, pancreatic injury can worsen antecedent heart failure by leaked PNLIP, causing excessive visceral adipose lipolysis. Inhibition of such lipolysis may improve heart failure outcomes.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"102147"},"PeriodicalIF":11.7,"publicationDate":"2025-06-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144215050","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}
Juanita Suzanne Lopez, Simon Haefliger, Ruth Plummer, Paul M Clement, Thomas R Jeffry Evans, Heinz Läubli, Patrick Roth, Rebecca Kristeleit, Lucy Brazil, Ghazaleh Tabatabai, Antje Wick, Benjamin Wunderlich, Kirk Beebe, Joel Robert Eisner, Heidi Lane, Marc Engelhardt, Thomas Kaindl, Peter Hau, Thomas Hundsberger, Joachim Steinbach
{"title":"A phase 1/2a dose-finding study and biomarker assessment of oral lisavanbulin in patients with high-grade glioma or glioblastoma.","authors":"Juanita Suzanne Lopez, Simon Haefliger, Ruth Plummer, Paul M Clement, Thomas R Jeffry Evans, Heinz Läubli, Patrick Roth, Rebecca Kristeleit, Lucy Brazil, Ghazaleh Tabatabai, Antje Wick, Benjamin Wunderlich, Kirk Beebe, Joel Robert Eisner, Heidi Lane, Marc Engelhardt, Thomas Kaindl, Peter Hau, Thomas Hundsberger, Joachim Steinbach","doi":"10.1016/j.xcrm.2025.102165","DOIUrl":"https://doi.org/10.1016/j.xcrm.2025.102165","url":null,"abstract":"<p><p>Lisavanbulin is a prodrug of the microtubule-targeting agent avanbulin. Both avanbulin and lisavanbulin have demonstrated significant antitumor activity in several preclinical tumor models including glioblastoma. Previous human studies demonstrated that 48-h infusions of intravenous lisavanbulin were well tolerated with preliminary activity in recurrent glioblastoma. The current phase 1/2a study evaluates the safety and tolerability of once-daily oral lisavanbulin in patients with solid tumors or recurrent glioblastoma or high-grade glioma. Lisavanbulin is associated with profound, durable responses in a subset of patients with recurrent refractory grade 4 astrocytoma or glioblastoma. We present here the clinical and translational results from this trial, including a description of a response-predictive molecular signature that warrants further exploration in these tumor types of significant unmet need. The study is registered at ClinicalTrials.gov (NCT02490800).</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":"6 6","pages":"102165"},"PeriodicalIF":11.7,"publicationDate":"2025-06-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144324515","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}
Cell Reports MedicinePub Date : 2025-06-17Epub Date: 2025-05-26DOI: 10.1016/j.xcrm.2025.102148
Kai Shang, Deyu Huang, Jun Liu, Zebin Yu, Wei Bian, Jiangqing Chen, Yin Zhao, Lina Liu, Jie Jiang, Yajie Wang, Yanting Duan, Jingyu Ge, Shize Zhang, Chun Zhou, Yingli Han, Yongxian Hu, Weiyan Zheng, Jie Sun, He Huang, Shanshan Pei, Pengxu Qian, Jie Sun
{"title":"CD97-directed CAR-T cells with enhanced persistence eradicate acute myeloid leukemia in diverse xenograft models.","authors":"Kai Shang, Deyu Huang, Jun Liu, Zebin Yu, Wei Bian, Jiangqing Chen, Yin Zhao, Lina Liu, Jie Jiang, Yajie Wang, Yanting Duan, Jingyu Ge, Shize Zhang, Chun Zhou, Yingli Han, Yongxian Hu, Weiyan Zheng, Jie Sun, He Huang, Shanshan Pei, Pengxu Qian, Jie Sun","doi":"10.1016/j.xcrm.2025.102148","DOIUrl":"10.1016/j.xcrm.2025.102148","url":null,"abstract":"<p><p>Chimeric antigen receptor (CAR)-T therapy on acute myeloid leukemia (AML) is hindered by the absence of a suitable tumor-specific antigen. Here, we propose CD97 as a potential target for CAR-T therapy against AML based on its broader and higher expression on AML cells compared to normal hematopoietic stem and progenitor cells (HSPCs). To resolve the fratricide problem caused by CD97 expression on T cells, we knock out CD97 in CAR-T cells using CRISPR-Cas9. Our CD97<sup>KO</sup> CAR-T cells eliminate both AML cell lines and primary AML cells effectively while showing tolerable toxicity to HSPCs. Furthermore, we mutate the CD3ζ domain of the CAR and find that the optimized CD97 CAR-T cells exhibit persistent anti-tumor activity both in vitro and in multiple xenograft models. Mechanistically, transcriptional profiles reveal that the optimized CAR-T cells delay differentiation and resist exhaustion. Collectively, our study supports CD97 as a promising target for CAR-T therapy against AML.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"102148"},"PeriodicalIF":11.7,"publicationDate":"2025-06-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144157012","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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