CellPub Date : 2025-05-19DOI: 10.1016/j.cell.2025.04.041
Asael Roichman, Qianying Zuo, Sunghoon Hwang, Wenyun Lu, Ricardo A. Cordova, Michael R. MacArthur, Jacob A. Boyer, Sarah J. Mitchell, Jesse Powers, Sophia A. Koval, Craig J. Hunter, Jamie Rijmers, Rolf-Peter Ryseck, Jenna E. AbuSalim, Seema Chatterjee, Won Dong Lee, Xincheng Xu, Xi Xing, Zihong Chen, Xianfeng Zeng, Joshua D. Rabinowitz
{"title":"Microbiome metabolism of dietary phytochemicals controls the anticancer activity of PI3K inhibitors","authors":"Asael Roichman, Qianying Zuo, Sunghoon Hwang, Wenyun Lu, Ricardo A. Cordova, Michael R. MacArthur, Jacob A. Boyer, Sarah J. Mitchell, Jesse Powers, Sophia A. Koval, Craig J. Hunter, Jamie Rijmers, Rolf-Peter Ryseck, Jenna E. AbuSalim, Seema Chatterjee, Won Dong Lee, Xincheng Xu, Xi Xing, Zihong Chen, Xianfeng Zeng, Joshua D. Rabinowitz","doi":"10.1016/j.cell.2025.04.041","DOIUrl":"https://doi.org/10.1016/j.cell.2025.04.041","url":null,"abstract":"Phosphatidylinositol 3-kinase (PI3K) signaling is both the effector pathway of insulin and among the most frequently activated pathways in human cancer. In murine cancer models, the efficacy of PI3K inhibitors is dramatically enhanced by a ketogenic diet, with a proposed mechanism involving dietary suppression of insulin. Here, we confirm profound diet-PI3K anticancer synergy but show that it is, surprisingly, unrelated to diet macronutrient composition. Instead, the diet-PI3K interaction involves microbiome metabolism of ingested phytochemicals. Specifically, murine ketogenic diet lacks the complex spectrum of phytochemicals found in standard chow, including the soy phytochemicals soyasaponins. We find that soyasaponins are converted by the microbiome into inducers of hepatic cytochrome P450 enzymes, and thereby lower PI3K inhibitor blood levels and anticancer activity. A high-carbohydrate, low-phytochemical diet synergizes with PI3K inhibition to treat cancer in mice, as do antibiotics that curtail the gut microbiome. Thus, diet impacts anticancer drug activity through phytochemical-microbiome-liver interactions.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"121 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2025-05-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144088142","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
CellPub Date : 2025-05-19DOI: 10.1016/j.cell.2025.04.038
Ran Guo, Ouyang Chen, Yang Zhou, Sangsu Bang, Sharat Chandra, Yize Li, Gang Chen, Rou-Gang Xie, Wei He, Jing Xu, Richard Zhou, Shaoyong Song, Kelsey L. Person, Madelyn N. Moore, Abigail R. Alwin, Ivan Spasojevic, Michael R. Jackson, Steven H. Olson, Marc G. Caron, Lauren M. Slosky, Ru-Rong Ji
{"title":"Arrestin-biased allosteric modulator of neurotensin receptor 1 alleviates acute and chronic pain","authors":"Ran Guo, Ouyang Chen, Yang Zhou, Sangsu Bang, Sharat Chandra, Yize Li, Gang Chen, Rou-Gang Xie, Wei He, Jing Xu, Richard Zhou, Shaoyong Song, Kelsey L. Person, Madelyn N. Moore, Abigail R. Alwin, Ivan Spasojevic, Michael R. Jackson, Steven H. Olson, Marc G. Caron, Lauren M. Slosky, Ru-Rong Ji","doi":"10.1016/j.cell.2025.04.038","DOIUrl":"https://doi.org/10.1016/j.cell.2025.04.038","url":null,"abstract":"G-protein-biased agonists have been shown to enhance opioid analgesia by circumventing β-arrestin-2 (βarr2) signaling. We previously reported that SBI-553, a neurotensin receptor 1 (NTSR1)-positive allosteric modulator biased toward βarr2 signaling, attenuates psychostimulant effects in mice. Here, we demonstrate that its analog, SBI-810, exhibits potent antinociceptive properties in rodent models of postoperative pain, inflammatory pain, and neuropathic pain via systemic and local administration. SBI-810’s analgesic effects require NTSR1 and βarr2 but not NTSR2 or βarr1. Mechanistically, SBI-810 suppresses excitatory synaptic transmission, inhibits NMDA receptor and extracellular-regulated signal kinase (ERK) signaling in spinal cord nociceptive neurons, reduces Nav1.7 surface expression and action potential firing in primary sensory neurons, and dampens C-fiber responses. Behaviorally, it reduces opioid-induced conditioned place preference, alleviates constipation, and mitigates chronic opioid withdrawal symptoms. These findings highlight NTSR1-biased allosteric modulators as a promising, non-addictive therapeutic strategy for acute and chronic pain management, acting through both peripheral and central mechanisms.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"30 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2025-05-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144088140","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
CellPub Date : 2025-05-16DOI: 10.1016/j.cell.2025.04.030
Eitan Erez Zahavi, Indrek Koppel, Riki Kawaguchi, Juan A. Oses-Prieto, Adam Briner, Aboozar Monavarfeshani, Irene Dalla Costa, Erna van Niekerk, Jinyoung Lee, Samaneh Matoo, Shane Hegarty, Ryan J. Donahue, Pabitra K. Sahoo, Shifra Ben-Dor, Ester Feldmesser, Julia Ryvkin, Dena Leshkowitz, Rotem Ben-Tov Perry, Yuyan Cheng, Eli Farber, Mike Fainzilber
{"title":"Repeat-element RNAs integrate a neuronal growth circuit","authors":"Eitan Erez Zahavi, Indrek Koppel, Riki Kawaguchi, Juan A. Oses-Prieto, Adam Briner, Aboozar Monavarfeshani, Irene Dalla Costa, Erna van Niekerk, Jinyoung Lee, Samaneh Matoo, Shane Hegarty, Ryan J. Donahue, Pabitra K. Sahoo, Shifra Ben-Dor, Ester Feldmesser, Julia Ryvkin, Dena Leshkowitz, Rotem Ben-Tov Perry, Yuyan Cheng, Eli Farber, Mike Fainzilber","doi":"10.1016/j.cell.2025.04.030","DOIUrl":"https://doi.org/10.1016/j.cell.2025.04.030","url":null,"abstract":"Neuronal growth and regeneration are regulated by local translation of mRNAs in axons. We examined RNA polyadenylation changes upon sensory neuron injury and found upregulation of a subset of polyadenylated B2-SINE repeat elements, hereby termed GI-SINEs (growth-inducing B2-SINEs). GI-SINEs are induced from ATF3 and other AP-1 promoter-associated extragenic loci in injured sensory neurons but are not upregulated in lesioned retinal ganglion neurons. Exogenous GI-SINE expression elicited axonal growth in injured sensory, retinal, and corticospinal tract neurons. GI-SINEs interact with ribosomal proteins and nucleolin, an axon-growth-regulating RNA-binding protein, to regulate translation in neuronal cytoplasm. Finally, antisense oligos against GI-SINEs perturb sensory neuron outgrowth and nucleolin-ribosome interactions. Thus, a specific subfamily of transposable elements is integral to a physiological circuit linking AP-1 transcription with localized RNA translation.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"35 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2025-05-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144065977","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
CellPub Date : 2025-05-15DOI: 10.1016/j.cell.2025.04.026
Tom S. Weber, Christine Biben, Denise C. Miles, Stefan P. Glaser, Sara Tomei, Cheng-Yu Lin, Andrew Kueh, Martin Pal, Stephen Zhang, Patrick P.L. Tam, Samir Taoudi, Shalin H. Naik
{"title":"LoxCode in vivo barcoding reveals epiblast clonal fate bias to fetal organs","authors":"Tom S. Weber, Christine Biben, Denise C. Miles, Stefan P. Glaser, Sara Tomei, Cheng-Yu Lin, Andrew Kueh, Martin Pal, Stephen Zhang, Patrick P.L. Tam, Samir Taoudi, Shalin H. Naik","doi":"10.1016/j.cell.2025.04.026","DOIUrl":"https://doi.org/10.1016/j.cell.2025.04.026","url":null,"abstract":"Much remains to be learned about the clonal fate of mammalian epiblast cells. Here, we develop high-diversity Cre recombinase-driven LoxCode barcoding for <em>in vivo</em> clonal lineage tracing for bulk tissue and single-cell readout. Embryonic day (E) 5.5 pre-gastrulation embryos were barcoded <em>in utero</em>, and epiblast clones were assessed for their contribution to a wide range of tissues in E12.5 embryos. Some epiblast clones contributed broadly across germ layers, while many were biased toward either blood, ectoderm, mesenchyme, or limbs, across tissue compartments and body axes. Using a stochastic agent-based model of embryogenesis and LoxCode barcoding, we inferred and experimentally validated cell fate biases across tissues in line with shared and segregating differentiation trajectories. Single-cell readout revealed numerous instances of asymmetry in epiblast contribution, including left-versus-right and kidney-versus-gonad fate. LoxCode barcoding enables clonal fate analysis for the study of development and broader questions of clonality in murine biology.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"27 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2025-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143979917","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
CellPub Date : 2025-05-15DOI: 10.1016/j.cell.2025.03.023
Mohamed S. Sarhan, Giacomo Antonello, Hansi Weissensteiner, Claudia Mengoni, Deborah Mascalzoni, Levi Waldron, Nicola Segata, Christian Fuchsberger
{"title":"Human mitochondrial DNA in public metagenomes: Opportunity or privacy threat?","authors":"Mohamed S. Sarhan, Giacomo Antonello, Hansi Weissensteiner, Claudia Mengoni, Deborah Mascalzoni, Levi Waldron, Nicola Segata, Christian Fuchsberger","doi":"10.1016/j.cell.2025.03.023","DOIUrl":"https://doi.org/10.1016/j.cell.2025.03.023","url":null,"abstract":"Human DNA is unavoidably present in metagenomic analyses of human microbiomes. While current protocols remove human DNA before submission to public repositories, mitochondrial DNA (mtDNA) has been overlooked and frequently persists. We discuss the privacy risks and research opportunities associated with mtDNA, urging consideration by the scientific, ethics, and legal communities.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"123 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2025-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143979941","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
CellPub Date : 2025-05-15DOI: 10.1016/j.cell.2025.04.025
Borzo Gharibi, Oliver C.K. Inge, Irene Rodriguez-Hernandez, Paul C. Driscoll, Christelle Dubois, Ming Jiang, Michael Howell, J. Mark Skehel, James I. Macrae, Silvia D.M. Santos
{"title":"Post-gastrulation amnioids as a stem cell-derived model of human extra-embryonic development","authors":"Borzo Gharibi, Oliver C.K. Inge, Irene Rodriguez-Hernandez, Paul C. Driscoll, Christelle Dubois, Ming Jiang, Michael Howell, J. Mark Skehel, James I. Macrae, Silvia D.M. Santos","doi":"10.1016/j.cell.2025.04.025","DOIUrl":"https://doi.org/10.1016/j.cell.2025.04.025","url":null,"abstract":"The amnion, an extra-embryonic tissue in mammalian embryos, is thought to provide crucial signaling, structural, and nutritional support during pregnancy. Despite its pivotal importance, studying human amnion formation and function has been hampered by the lack of accurate <em>in vitro</em> models. Here, we present an embryonic stem cell-derived 3D model of the post-gastrulation amnion, post-gastrulation amnioids (PGAs), that faithfully recapitulates extra-embryonic development up to 4 weeks post-fertilization, closely mimicking the functional traits of the human amniotic sac. PGAs self-organize, forming the amnion and the yolk sac, and are surrounded by the extra-embryonic mesoderm. Using PGAs, we show that GATA3 is required and sufficient for amniogenesis and that an autoregulatory feedback loop governs amnion formation, whereby extra-embryonic signals promote amnion specification. The reproducibility and scalability of the PGA system, with its precise cellular, structural, and functional integrity, opens avenues for investigating embryo-amnion interactions beyond gastrulation and offers an ideal platform for large-scale pharmacological and clinical studies.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"13 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2025-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143979942","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
CellPub Date : 2025-05-15DOI: 10.1016/j.cell.2025.04.024
Maria H. Festing, Kubra B. Akkaya-Colak, Maria M. Mihaylova
{"title":"Reaching for more: How reproduction transforms the maternal intestine","authors":"Maria H. Festing, Kubra B. Akkaya-Colak, Maria M. Mihaylova","doi":"10.1016/j.cell.2025.04.024","DOIUrl":"https://doi.org/10.1016/j.cell.2025.04.024","url":null,"abstract":"Several organs undergo changes during pregnancy to accommodate fetal growth, including the small intestine. However, the signals that trigger this intestinal remodeling are not well understood. In a recent study, Ameku et al. describe an anticipatory intestinal growth program that is partially irreversible and supported by SGLT3a-dependent increase of <em>Fgfbp1</em>-positive progenitor cells.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"1 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2025-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143980014","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
CellPub Date : 2025-05-15DOI: 10.1016/j.cell.2025.04.028
Zhisen Yang, Hong Wei, Yulin Gan, Huihui Liu, Yang Cao, Huihui An, Xiuzheng Que, Yongxiang Gao, Lizhe Zhu, Shutang Tan, Xin Liu, Linfeng Sun
{"title":"Structural insights into auxin influx mediated by the Arabidopsis AUX1","authors":"Zhisen Yang, Hong Wei, Yulin Gan, Huihui Liu, Yang Cao, Huihui An, Xiuzheng Que, Yongxiang Gao, Lizhe Zhu, Shutang Tan, Xin Liu, Linfeng Sun","doi":"10.1016/j.cell.2025.04.028","DOIUrl":"https://doi.org/10.1016/j.cell.2025.04.028","url":null,"abstract":"Auxin is crucial in orchestrating diverse aspects of plant growth and development and modulating responses to environmental signals. The asymmetric spatiotemporal distribution of auxin generates local gradient patterns, which are regulated by both cellular auxin influx and efflux. The AUXIN1/LIKE-AUX1 (AUX1/LAX) family transporters have been identified as major auxin influx carriers. Here, we characterize the auxin uptake mediated by AUX1 from <em>Arabidopsis thaliana</em>. Using cryoelectron microscopy (cryo-EM), we determine its structure in three states: the auxin-unbound, the auxin-bound, and the competitive inhibitor, 3-chloro-4-hydroxyphenylacetic acid (CHPAA)-bound state. All structures adopt an inward-facing conformation. In the auxin-bound structure, indole-3-acetic acid (IAA) is coordinated to AUX1 primarily through hydrogen bonds with its carboxyl group. The functional roles of key residues in IAA binding are validated by <em>in vitro</em> and <em>in planta</em> analyses. CHPAA binds to the same site as IAA. These findings advance our understanding of auxin transport in plants.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"28 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2025-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143979940","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
CellPub Date : 2025-05-15Epub Date: 2025-04-09DOI: 10.1016/j.cell.2025.03.015
Julian Geilenkeuser, Niklas Armbrust, Emily Steinmaßl, Samuel W Du, Sebastian Schmidt, Eva Maria Hildegard Binder, Yuchun Li, Niklas Wilhelm Warsing, Stephanie Victoria Wendel, Florian von der Linde, Elisa Marie Schiele, Xiya Niu, Luisa Stroppel, Oleksandr Berezin, Tobias Heinrich Santl, Tanja Orschmann, Keith Nelson, Christoph Gruber, Grazyna Palczewska, Carolline Rodrigues Menezes, Eleonora Risaliti, Zachary J Engfer, Naile Koleci, Andrea Schmidts, Arie Geerlof, Krzysztof Palczewski, Gil Gregor Westmeyer, Dong-Jiunn Jeffery Truong
{"title":"Engineered nucleocytosolic vehicles for loading of programmable editors.","authors":"Julian Geilenkeuser, Niklas Armbrust, Emily Steinmaßl, Samuel W Du, Sebastian Schmidt, Eva Maria Hildegard Binder, Yuchun Li, Niklas Wilhelm Warsing, Stephanie Victoria Wendel, Florian von der Linde, Elisa Marie Schiele, Xiya Niu, Luisa Stroppel, Oleksandr Berezin, Tobias Heinrich Santl, Tanja Orschmann, Keith Nelson, Christoph Gruber, Grazyna Palczewska, Carolline Rodrigues Menezes, Eleonora Risaliti, Zachary J Engfer, Naile Koleci, Andrea Schmidts, Arie Geerlof, Krzysztof Palczewski, Gil Gregor Westmeyer, Dong-Jiunn Jeffery Truong","doi":"10.1016/j.cell.2025.03.015","DOIUrl":"10.1016/j.cell.2025.03.015","url":null,"abstract":"<p><p>Advanced gene editing methods have accelerated biomedical discovery and hold great therapeutic promise, but safe and efficient delivery of gene editors remains challenging. In this study, we present a virus-like particle (VLP) system featuring nucleocytosolic shuttling vehicles that retrieve pre-assembled Cas-effectors via aptamer-tagged guide RNAs. This approach ensures preferential loading of fully assembled editor ribonucleoproteins (RNPs) and enhances the efficacy of prime editing, base editing, trans-activators, and nuclease activity coupled to homology-directed repair in multiple immortalized, primary, stem cell, and stem-cell-derived cell types. We also achieve additional protection of inherently unstable prime editing guide RNAs (pegRNAs) by shielding the 3'-exposed end with Csy4/Cas6f, further enhancing editing performance. Furthermore, we identify a minimal set of packaging and budding modules that can serve as a platform for bottom-up engineering of enveloped delivery vehicles. Notably, our system demonstrates superior per-VLP editing efficiency in primary T lymphocytes and two mouse models of inherited retinal disease, highlighting its therapeutic potential.</p>","PeriodicalId":9656,"journal":{"name":"Cell","volume":" ","pages":"2637-2655.e31"},"PeriodicalIF":45.5,"publicationDate":"2025-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143965090","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
CellPub Date : 2025-05-12DOI: 10.1016/j.cell.2025.03.041
Anna C. Geraghty, Lehi Acosta-Alvarez, Maria C. Rotiroti, Selena Dutton, Michael R. O’Dea, Wonju Kim, Vrunda Trivedi, Rebecca Mancusi, Kiarash Shamardani, Karen Malacon, Pamelyn J. Woo, Naiara Martinez-Velez, Theresa Pham, Noemi N. Reche-Ley, Gabriel Otubu, Enrique H. Castenada, Kamsi Nwangwu, Haojun Xu, Sara B. Mulinyawe, Daniel B. Zamler, Michelle Monje
{"title":"Immunotherapy-related cognitive impairment after CAR T cell therapy in mice","authors":"Anna C. Geraghty, Lehi Acosta-Alvarez, Maria C. Rotiroti, Selena Dutton, Michael R. O’Dea, Wonju Kim, Vrunda Trivedi, Rebecca Mancusi, Kiarash Shamardani, Karen Malacon, Pamelyn J. Woo, Naiara Martinez-Velez, Theresa Pham, Noemi N. Reche-Ley, Gabriel Otubu, Enrique H. Castenada, Kamsi Nwangwu, Haojun Xu, Sara B. Mulinyawe, Daniel B. Zamler, Michelle Monje","doi":"10.1016/j.cell.2025.03.041","DOIUrl":"https://doi.org/10.1016/j.cell.2025.03.041","url":null,"abstract":"Immunotherapies have revolutionized cancer care for many tumor types, but their potential long-term cognitive impacts are incompletely understood. Here, we demonstrated in mouse models that chimeric antigen receptor (CAR) T cell therapy for both central nervous system (CNS) and non-CNS cancers impaired cognitive function and induced a persistent CNS immune response characterized by white matter microglial reactivity, microglial chemokine expression, and elevated cerebrospinal fluid (CSF) cytokines and chemokines. Consequently, oligodendroglial homeostasis and hippocampal neurogenesis were disrupted. Single-nucleus sequencing studies of human frontal lobe from patients with or without previous CAR T cell therapy for brainstem tumors confirmed reactive states of microglia and oligodendrocytes following treatment. In mice, transient microglial depletion or CCR3 chemokine receptor blockade rescued oligodendroglial deficits and cognitive performance in a behavioral test of attention and short-term memory function following CAR T cell therapy. Taken together, these findings illustrate targetable neural-immune mechanisms underlying immunotherapy-related cognitive impairment.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"119 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2025-05-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143933510","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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