CellPub Date : 2025-04-15DOI: 10.1016/j.cell.2025.03.028
Raquel Martin-Arevalillo, Bruno Guillotin, Jonas Schön, Alice Hugues, Marie-France Gerentes, Kun Tang, Jérémy Lucas, Emmanuel Thévenon, Marianne Dreuillet, Graeme Vissers, Mohammed Mohammed Ateequr, Carlos S. Galvan-Ampudia, Guillaume Cerutti, Jonathan Legrand, Coralie Cance, Annick Dubois, François Parcy, Kenneth D. Birnbaum, Matias D. Zurbriggen, Renaud Dumas, Teva Vernoux
{"title":"Synthetic deconvolution of an auxin-dependent transcriptional code","authors":"Raquel Martin-Arevalillo, Bruno Guillotin, Jonas Schön, Alice Hugues, Marie-France Gerentes, Kun Tang, Jérémy Lucas, Emmanuel Thévenon, Marianne Dreuillet, Graeme Vissers, Mohammed Mohammed Ateequr, Carlos S. Galvan-Ampudia, Guillaume Cerutti, Jonathan Legrand, Coralie Cance, Annick Dubois, François Parcy, Kenneth D. Birnbaum, Matias D. Zurbriggen, Renaud Dumas, Teva Vernoux","doi":"10.1016/j.cell.2025.03.028","DOIUrl":"https://doi.org/10.1016/j.cell.2025.03.028","url":null,"abstract":"How developmental signals program gene expression in space and time is still poorly understood. Here, we addressed this question for the plant master regulator, auxin. Transcriptional responses to auxin rely on a large multigenic transcription factor family, the auxin response factors (ARFs). We deconvoluted the complexity of ARF-regulated transcription using auxin-inducible synthetic promoters built from <em>cis</em>-element pair configurations differentially bound by ARFs. We demonstrate using cellular systems that ARF transcriptional properties are not only intrinsic but also depend on the <em>cis</em>-element pair configurations they bind to, thus identifying a bi-layer ARF/<em>cis</em>-element transcriptional code. Auxin-inducible synthetic promoters were expressed differentially <em>in planta</em> showing at single-cell resolution how this bi-layer code patterns transcriptional responses to auxin. Combining <em>cis</em>-element pair configurations in synthetic promoters created distinct patterns, demonstrating the combinatorial power of the auxin bi-layer code in generating diverse gene expression patterns that are not simply a direct translation of auxin distribution.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"17 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2025-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143832392","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 : 2025-04-15DOI: 10.1016/j.cell.2025.02.029
Wen-Bing Jin, Leyi Xiao, Mingeum Jeong, Seong-Ji Han, Wen Zhang, Hiroshi Yano, Huiqing Shi, Mohammad Arifuzzaman, Mengze Lyu, Daoming Wang, Yuelin Angelina Tang, Shanshan Qiao, Xiaoyu Yang, He S. Yang, Jingyuan Fu, Gregory F. Sonnenberg, Nicholas Collins, David Artis, Chun-Jun Guo
{"title":"Microbiota-derived bile acids antagonize the host androgen receptor and drive anti-tumor immunity","authors":"Wen-Bing Jin, Leyi Xiao, Mingeum Jeong, Seong-Ji Han, Wen Zhang, Hiroshi Yano, Huiqing Shi, Mohammad Arifuzzaman, Mengze Lyu, Daoming Wang, Yuelin Angelina Tang, Shanshan Qiao, Xiaoyu Yang, He S. Yang, Jingyuan Fu, Gregory F. Sonnenberg, Nicholas Collins, David Artis, Chun-Jun Guo","doi":"10.1016/j.cell.2025.02.029","DOIUrl":"https://doi.org/10.1016/j.cell.2025.02.029","url":null,"abstract":"Microbiota-derived bile acids (BAs) are associated with host biology/disease, yet their causal effects remain largely undefined. Herein, we speculate that characterizing previously undefined microbiota-derived BAs would uncover previously unknown BA-sensing receptors and their biological functions. We integrated BA metabolomics and microbial genetics to functionally profile >200 putative microbiota BA metabolic genes. We identified 56 less-characterized BAs, many of which are detected in humans/mammals. Notably, a subset of these BAs are potent antagonists of the human androgen receptor (hAR). They inhibit AR-related gene expression and are human-relevant. As a proof-of-principle, we demonstrate that one of these BAs suppresses tumor progression and potentiates the efficacy of anti-PD-1 treatment in an AR-dependent manner. Our findings show that an approach combining bioinformatics, BA metabolomics, and microbial genetics can expand our knowledge of the microbiota metabolic potential and reveal an unexpected microbiota BA-AR interaction and its role in regulating host biology.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"15 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2025-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143832396","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 : 2025-04-15DOI: 10.1016/j.cell.2025.03.031
Shady Saad, Tomek Swigut, Saman Tabatabaee, Pranav Lalgudi, Daniel F. Jarosz, Joanna Wysocka
{"title":"DNA binding and mitotic phosphorylation protect polyglutamine proteins from assembly formation","authors":"Shady Saad, Tomek Swigut, Saman Tabatabaee, Pranav Lalgudi, Daniel F. Jarosz, Joanna Wysocka","doi":"10.1016/j.cell.2025.03.031","DOIUrl":"https://doi.org/10.1016/j.cell.2025.03.031","url":null,"abstract":"Polyglutamine (polyQ) expansion is associated with pathogenic protein aggregation in neurodegenerative disorders. However, long polyQ tracts are also found in many transcription factors (TFs), such as FOXP2, a TF implicated in human speech. Here, we explore how FOXP2 and other glutamine-rich TFs avoid unscheduled assembly. Throughout interphase, DNA binding, irrespective of sequence specificity, has a solubilizing effect. During mitosis, multiple phosphorylation events promote FOXP2’s eviction from chromatin and supplant the solubilizing function of DNA. Further, human-specific amino acid substitutions linked to the evolution of speech map to a mitotic phospho-patch, the “EVO patch,” and reduce the propensity of the human FOXP2 to assemble. Fusing the pathogenic form of Huntingtin to either a DNA-binding domain, a phosphomimetic variant of this EVO patch, or a negatively charged peptide is sufficient to diminish assembly formation, suggesting that hijacking mechanisms governing solubility of glutamine-rich TFs may offer new strategies for treatment of polyQ expansion diseases.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"116 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2025-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143832393","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 : 2025-04-15DOI: 10.1016/j.cell.2025.03.032
Yanyu Zhu, Ashwin Balaji, Mengting Han, Leonid Andronov, Anish R. Roy, Zheng Wei, Crystal Chen, Leanne Miles, Sa Cai, Zhengxi Gu, Ariana Tse, Betty Chentzu Yu, Takeshi Uenaka, Xueqiu Lin, Andrew J. Spakowitz, W.E. Moerner, Lei S. Qi
{"title":"High-resolution dynamic imaging of chromatin DNA communication using Oligo-LiveFISH","authors":"Yanyu Zhu, Ashwin Balaji, Mengting Han, Leonid Andronov, Anish R. Roy, Zheng Wei, Crystal Chen, Leanne Miles, Sa Cai, Zhengxi Gu, Ariana Tse, Betty Chentzu Yu, Takeshi Uenaka, Xueqiu Lin, Andrew J. Spakowitz, W.E. Moerner, Lei S. Qi","doi":"10.1016/j.cell.2025.03.032","DOIUrl":"https://doi.org/10.1016/j.cell.2025.03.032","url":null,"abstract":"Three-dimensional (3D) genome dynamics are crucial for cellular functions and disease. However, real-time, live-cell DNA visualization remains challenging, as existing methods are often confined to repetitive regions, suffer from low resolution, or require complex genome engineering. Here, we present Oligo-LiveFISH, a high-resolution, reagent-based platform for dynamically tracking non-repetitive genomic loci in diverse cell types, including primary cells. Oligo-LiveFISH utilizes fluorescent guide RNA (gRNA) oligo pools generated by computational design, <em>in vitro</em> transcription, and chemical labeling, delivered as ribonucleoproteins. Utilizing machine learning, we characterized the impact of gRNA design and chromatin features on imaging efficiency. Multi-color Oligo-LiveFISH achieved 20-nm spatial resolution and 50-ms temporal resolution in 3D, capturing real-time enhancer and promoter dynamics. Our measurements and dynamic modeling revealed two distinct modes of chromatin communication, and active transcription slows enhancer-promoter dynamics at endogenous genes like <em>FOS</em>. Oligo-LiveFISH offers a versatile platform for studying 3D genome dynamics and their links to cellular processes and disease.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"40 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2025-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143832391","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 : 2025-04-15DOI: 10.1016/j.cell.2025.03.027
Krista G. Freeman, Sudipta Mondal, Lourriel S. Macale, Jennifer Podgorski, Simon J. White, Benjamin H. Silva, Valery Ortiz, Alexis Huet, Ronelito J. Perez, Joemark T. Narsico, Meng-Chiao Ho, Deborah Jacobs-Sera, Todd L. Lowary, James F. Conway, Donghyun Park, Graham F. Hatfull
{"title":"Structure and infection dynamics of mycobacteriophage Bxb1","authors":"Krista G. Freeman, Sudipta Mondal, Lourriel S. Macale, Jennifer Podgorski, Simon J. White, Benjamin H. Silva, Valery Ortiz, Alexis Huet, Ronelito J. Perez, Joemark T. Narsico, Meng-Chiao Ho, Deborah Jacobs-Sera, Todd L. Lowary, James F. Conway, Donghyun Park, Graham F. Hatfull","doi":"10.1016/j.cell.2025.03.027","DOIUrl":"https://doi.org/10.1016/j.cell.2025.03.027","url":null,"abstract":"Mycobacteriophage Bxb1 is a well-characterized virus of <em>Mycobacterium smegmatis</em> with double-stranded DNA and a long, flexible tail. Mycobacteriophages show considerable potential as therapies for <em>Mycobacterium</em> infections, but little is known about the structural details of these phages or how they bind to and traverse the complex <em>Mycobacterium</em> cell wall. Here, we report the complete structure and atomic model of phage Bxb1, including the arrangement of immunodominant domains of both the capsid and tail tube subunits, as well as the assembly of the protein subunits in the tail-tip complex. The structure contains protein assemblies with 3-, 5-, 6-, and 12-fold symmetries, which interact to satisfy several symmetry mismatches. Cryoelectron tomography of phage particles bound to <em>M. smegmatis</em> reveals the structural transitions that occur for free phage particles to bind to the cell surface and navigate through the cell wall to enable DNA transfer into the cytoplasm.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"7 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2025-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143832394","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 : 2025-04-14DOI: 10.1016/j.cell.2025.03.019
Jia-Shu Yang, Andrew J. Morris, Koki Kamizaki, Jianzhong Chen, Jillian Stark, William M. Oldham, Toshitaka Nakamura, Eikan Mishima, Joseph Loscalzo, Yasuhiro Minami, Marcus Conrad, Whitney S. Henry, Victor W. Hsu
{"title":"ALDH7A1 protects against ferroptosis by generating membrane NADH and regulating FSP1","authors":"Jia-Shu Yang, Andrew J. Morris, Koki Kamizaki, Jianzhong Chen, Jillian Stark, William M. Oldham, Toshitaka Nakamura, Eikan Mishima, Joseph Loscalzo, Yasuhiro Minami, Marcus Conrad, Whitney S. Henry, Victor W. Hsu","doi":"10.1016/j.cell.2025.03.019","DOIUrl":"https://doi.org/10.1016/j.cell.2025.03.019","url":null,"abstract":"Ferroptosis is a form of cell death due to iron-induced lipid peroxidation. Ferroptosis suppressor protein 1 (FSP1) protects against this death by generating antioxidants, which requires nicotinamide adenine dinucleotide, reduced form (NADH) as a cofactor. We initially uncover that NADH exists at significant levels on cellular membranes and then find that this form of NADH is generated by aldehyde dehydrogenase 7A1 (ALDH7A1) to support FSP1 activity. ALDH7A1 activity also acts directly to decrease lipid peroxidation by consuming reactive aldehydes. Furthermore, ALDH7A1 promotes the membrane recruitment of FSP1, which is instigated by ferroptotic stress activating AMP-activated protein kinase (AMPK) to promote the membrane localization of ALDH7A1 that stabilizes FSP1 on membranes. These findings advance a fundamental understanding of NADH by revealing a previously unappreciated pool on cellular membranes, with the elucidation of its function providing a major understanding of how FSP1 acts and how an aldehyde dehydrogenase protects against ferroptosis.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"1 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2025-04-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143827206","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 : 2025-04-14DOI: 10.1016/j.cell.2025.03.026
Fernanda Martins Rodrigues, Nadezhda V. Terekhanova, Kathleen J. Imbach, Karl R. Clauser, Myvizhi Esai Selvan, Isabel Mendizabal, Yifat Geffen, Yo Akiyama, Myranda Maynard, Tomer M. Yaron, Yize Li, Song Cao, Erik P. Storrs, Olivia S. Gonda, Adrian Gaite-Reguero, Akshay Govindan, Emily A. Kawaler, Matthew A. Wyczalkowski, Robert J. Klein, Berk Turhan, Yige Wu
{"title":"Precision proteogenomics reveals pan-cancer impact of germline variants","authors":"Fernanda Martins Rodrigues, Nadezhda V. Terekhanova, Kathleen J. Imbach, Karl R. Clauser, Myvizhi Esai Selvan, Isabel Mendizabal, Yifat Geffen, Yo Akiyama, Myranda Maynard, Tomer M. Yaron, Yize Li, Song Cao, Erik P. Storrs, Olivia S. Gonda, Adrian Gaite-Reguero, Akshay Govindan, Emily A. Kawaler, Matthew A. Wyczalkowski, Robert J. Klein, Berk Turhan, Yige Wu","doi":"10.1016/j.cell.2025.03.026","DOIUrl":"https://doi.org/10.1016/j.cell.2025.03.026","url":null,"abstract":"We investigate the impact of germline variants on cancer patients’ proteomes, encompassing 1,064 individuals across 10 cancer types. We introduced an approach, “precision peptidomics,” mapping 337,469 coding germline variants onto peptides from patients’ mass spectrometry data, revealing their potential impact on post-translational modifications, protein stability, allele-specific expression, and protein structure by leveraging the relevant protein databases. We identified rare pathogenic and common germline variants in cancer genes potentially affecting proteomic features, including variants altering protein abundance and structure and variants in kinases (<em>ERBB2</em> and <em>MAP2K2</em>) impacting phosphorylation. Precision peptidome analysis predicted destabilizing events in signal-regulatory protein alpha (SIRPA) and glial fibrillary acid protein (GFAP), relevant to immunomodulation and glioblastoma diagnostics, respectively. Genome-wide association studies identified quantitative trait loci for gene expression and protein levels, spanning millions of SNPs and thousands of proteins. Polygenic risk scores correlated with distal effects from risk variants. Our findings emphasize the contribution of germline genetics to cancer heterogeneity and high-throughput precision peptidomics.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"39 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2025-04-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143827204","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}
{"title":"A two-step self-pollination mechanism maximizes fertility in Brassicaceae","authors":"Pu Liu, Xin Quan, Zihan Song, Wenhao Li, Yuan Wang, Hongya Gu, Daoxin Xie, Weicai Yang, Thomas Dresselhaus, Sheng Zhong, Li-Jia Qu","doi":"10.1016/j.cell.2025.03.021","DOIUrl":"https://doi.org/10.1016/j.cell.2025.03.021","url":null,"abstract":"Self-pollination in self-compatible plant species often occurs prior to flower opening. By tracking the temporal progress of pollination in Arabidopsis, we observed that pollen predominantly targets the lateral region of the stigma in unopened flowers. Notably, approximately 7 h after flower opening, flowers close, thereby pressing anthers toward the central region of the stigma for a second self-pollination. This two-step self-pollination results in a doubling of pollen deposition, which significantly increases the ovule-targeting ratio and improves fertility under pollen-limiting conditions, as evident in the anther-dehiscence-defective mutant <em>myb108</em> and under environmental stress conditions. Analysis using gamete-interaction-defective mutants <em>hap2/gcs1</em> and <em>dmp8 dmp9</em> revealed that the timely separation of both pollination events promotes fertilization recovery efficiency. A similar two-step pollination was observed in two other self-pollinating but not in outcrossing Brassicaceae species. This mechanism represents a reproductive assurance strategy in predominantly self-pollinating annuals to maximize fertility under unfavorable conditions.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"19 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2025-04-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143827203","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 : 2025-04-14DOI: 10.1016/j.cell.2025.03.025
Apoorva Baluapuri, Nicole ChenCheng Zhao, Ryan J. Marina, Kai-Lieh Huang, Anastasia Kuzkina, Maria E. Amodeo, Chad B. Stein, Lucie Y. Ahn, Jordan S. Farr, Ashleigh E. Schaffer, Vikram Khurana, Eric J. Wagner, Karen Adelman
{"title":"Integrator loss leads to dsRNA formation that triggers the integrated stress response","authors":"Apoorva Baluapuri, Nicole ChenCheng Zhao, Ryan J. Marina, Kai-Lieh Huang, Anastasia Kuzkina, Maria E. Amodeo, Chad B. Stein, Lucie Y. Ahn, Jordan S. Farr, Ashleigh E. Schaffer, Vikram Khurana, Eric J. Wagner, Karen Adelman","doi":"10.1016/j.cell.2025.03.025","DOIUrl":"https://doi.org/10.1016/j.cell.2025.03.025","url":null,"abstract":"Integrator (INT) is a metazoan-specific complex that targets promoter-proximally paused RNA polymerase II (RNAPII) for termination, preventing immature RNAPII from entering gene bodies and functionally attenuating transcription of stress-responsive genes. Mutations in INT subunits are associated with many human diseases, including cancer, ciliopathies, and neurodevelopmental disorders, but how reduced INT activity contributes to disease is unknown. Here, we demonstrate that the loss of INT-mediated termination in human cells triggers the integrated stress response (ISR). INT depletion causes upregulation of short genes such as the ISR transcription factor activating transcription factor 3 (ATF3). Further, immature RNAPII that escapes into genes upon INT depletion is prone to premature termination, generating incomplete pre-mRNAs with retained introns. Retroelements within retained introns form double-stranded RNA (dsRNA) that is recognized by protein kinase R (PKR), which drives ATF4 activation and prolonged ISR. Critically, patient cells with INT mutations exhibit dsRNA accumulation and ISR activation, thereby implicating chronic ISR in diseases caused by INT deficiency.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"34 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2025-04-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143827151","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 : 2025-04-11DOI: 10.1016/j.cell.2025.03.017
Taisuke Kondo, François X.P. Bourassa, Sooraj Achar, Justyn DuSold, Pablo F. Céspedes, Makoto Ando, Alka Dwivedi, Josquin Moraly, Christopher Chien, Saliha Majdoul, Adam L. Kenet, Madison Wahlsten, Audun Kvalvaag, Edward Jenkins, Sanghyun P. Kim, Catherine M. Ade, Zhiya Yu, Guillaume Gaud, Marco Davila, Paul Love, Naomi Taylor
{"title":"Engineering TCR-controlled fuzzy logic into CAR T cells enhances therapeutic specificity","authors":"Taisuke Kondo, François X.P. Bourassa, Sooraj Achar, Justyn DuSold, Pablo F. Céspedes, Makoto Ando, Alka Dwivedi, Josquin Moraly, Christopher Chien, Saliha Majdoul, Adam L. Kenet, Madison Wahlsten, Audun Kvalvaag, Edward Jenkins, Sanghyun P. Kim, Catherine M. Ade, Zhiya Yu, Guillaume Gaud, Marco Davila, Paul Love, Naomi Taylor","doi":"10.1016/j.cell.2025.03.017","DOIUrl":"https://doi.org/10.1016/j.cell.2025.03.017","url":null,"abstract":"Chimeric antigen receptor (CAR) T cell immunotherapy represents a breakthrough in the treatment of hematological malignancies, but poor specificity has limited its applicability to solid tumors. By contrast, natural T cells harboring T cell receptors (TCRs) can discriminate between neoantigen-expressing cancer cells and self-antigen-expressing healthy tissues but have limited potency against tumors. We used a high-throughput platform to systematically evaluate the impact of co-expressing a TCR and CAR on the same CAR T cell. While strong TCR-antigen interactions enhanced CAR activation, weak TCR-antigen interactions actively antagonized their activation. Mathematical modeling captured this TCR-CAR crosstalk in CAR T cells, allowing us to engineer dual TCR/CAR T cells targeting neoantigens (HHAT<sup>L8F</sup>/p53<sup>R175H</sup>) and human epithelial growth factor receptor 2 (HER2) ligands, respectively. These T cells exhibited superior anti-cancer activity and minimal toxicity against healthy tissue compared with conventional CAR T cells in a humanized solid tumor mouse model. Harnessing pre-existing inhibitory crosstalk between receptors, therefore, paves the way for the design of more precise cancer immunotherapies.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"108 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2025-04-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143819964","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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