CellPub Date : 2024-11-14DOI: 10.1016/j.cell.2024.10.035
Harry F. Noller
{"title":"The ribosome comes to life","authors":"Harry F. Noller","doi":"10.1016/j.cell.2024.10.035","DOIUrl":"https://doi.org/10.1016/j.cell.2024.10.035","url":null,"abstract":"The ribosome, together with its tRNA substrates, links genotype to phenotype by translating the genetic information carried by mRNA into protein. During the past half-century, the structure and mechanisms of action of the ribosome have emerged from mystery and confusion. It is now evident that the ribosome is an ancient RNA-based molecular machine of staggering structural complexity and that it is fundamentally similar in all living organisms. The three central functions of protein synthesis—decoding, catalysis of peptide bond formation, and translocation of mRNA and tRNA—are based on elegant mechanisms that evolved from the properties of RNA, the founding macromolecule of life. Moreover, all three of these functions (and even life itself) seem to proceed in defiance of entropy. Protein synthesis thus appears to exploit both the energy of GTP hydrolysis and peptide bond formation to constrain the directionality and accuracy of events taking place on the ribosome.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"10 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2024-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142610562","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 : 2024-11-13DOI: 10.1016/j.cell.2024.10.022
Suguru Nishijima, Evelina Stankevic, Oliver Aasmets, Thomas S.B. Schmidt, Naoyoshi Nagata, Marisa Isabell Keller, Pamela Ferretti, Helene Bæk Juel, Anthony Fullam, Shahriyar Mahdi Robbani, Christian Schudoma, Johanne Kragh Hansen, Louise Aas Holm, Mads Israelsen, Robert Schierwagen, Nikolaj Torp, Anja Telzerow, Rajna Hercog, Stefanie Kandels, Diënty H.M. Hazenbrink, Maja Thiele
{"title":"Fecal microbial load is a major determinant of gut microbiome variation and a confounder for disease associations","authors":"Suguru Nishijima, Evelina Stankevic, Oliver Aasmets, Thomas S.B. Schmidt, Naoyoshi Nagata, Marisa Isabell Keller, Pamela Ferretti, Helene Bæk Juel, Anthony Fullam, Shahriyar Mahdi Robbani, Christian Schudoma, Johanne Kragh Hansen, Louise Aas Holm, Mads Israelsen, Robert Schierwagen, Nikolaj Torp, Anja Telzerow, Rajna Hercog, Stefanie Kandels, Diënty H.M. Hazenbrink, Maja Thiele","doi":"10.1016/j.cell.2024.10.022","DOIUrl":"https://doi.org/10.1016/j.cell.2024.10.022","url":null,"abstract":"The microbiota in individual habitats differ in both relative composition and absolute abundance. While sequencing approaches determine the relative abundances of taxa and genes, they do not provide information on their absolute abundances. Here, we developed a machine-learning approach to predict fecal microbial loads (microbial cells per gram) solely from relative abundance data. Applying our prediction model to a large-scale metagenomic dataset (<em>n</em> = 34,539), we demonstrated that microbial load is the major determinant of gut microbiome variation and is associated with numerous host factors, including age, diet, and medication. We further found that for several diseases, changes in microbial load, rather than the disease condition itself, more strongly explained alterations in patients’ gut microbiome. Adjusting for this effect substantially reduced the statistical significance of the majority of disease-associated species. Our analysis reveals that the fecal microbial load is a major confounder in microbiome studies, highlighting its importance for understanding microbiome variation in health and disease.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"19 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2024-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142600990","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 : 2024-11-12DOI: 10.1016/j.cell.2024.10.032
Maria Dolores Moya-Garzon, Mengjie Wang, Veronica L. Li, Xuchao Lyu, Wei Wei, Alan Sheng-Hwa Tung, Steffen H. Raun, Meng Zhao, Laetitia Coassolo, Hashim Islam, Barbara Oliveira, Yuqin Dai, Jan Spaas, Antonio Delgado-Gonzalez, Kenyi Donoso, Aurora Alvarez-Buylla, Francisco Franco-Montalban, Anudari Letian, Catherine P. Ward, Lichao Liu, Jonathan Z. Long
{"title":"A β-hydroxybutyrate shunt pathway generates anti-obesity ketone metabolites","authors":"Maria Dolores Moya-Garzon, Mengjie Wang, Veronica L. Li, Xuchao Lyu, Wei Wei, Alan Sheng-Hwa Tung, Steffen H. Raun, Meng Zhao, Laetitia Coassolo, Hashim Islam, Barbara Oliveira, Yuqin Dai, Jan Spaas, Antonio Delgado-Gonzalez, Kenyi Donoso, Aurora Alvarez-Buylla, Francisco Franco-Montalban, Anudari Letian, Catherine P. Ward, Lichao Liu, Jonathan Z. Long","doi":"10.1016/j.cell.2024.10.032","DOIUrl":"https://doi.org/10.1016/j.cell.2024.10.032","url":null,"abstract":"β-Hydroxybutyrate (BHB) is an abundant ketone body. To date, all known pathways of BHB metabolism involve the interconversion of BHB and primary energy intermediates. Here, we identify a previously undescribed BHB secondary metabolic pathway via CNDP2-dependent enzymatic conjugation of BHB and free amino acids. This BHB shunt pathway generates a family of anti-obesity ketone metabolites, the BHB-amino acids. Genetic ablation of CNDP2 in mice eliminates tissue amino acid BHB-ylation activity and reduces BHB-amino acid levels. The most abundant BHB-amino acid, BHB-Phe, is a ketosis-inducible congener of Lac-Phe that activates hypothalamic and brainstem neurons and suppresses feeding. Conversely, CNDP2-KO mice exhibit increased food intake and body weight following exogenous ketone ester supplementation or a ketogenic diet. CNDP2-dependent amino acid BHB-ylation and BHB-amino acid metabolites are also conserved in humans. Therefore, enzymatic amino acid BHB-ylation defines a ketone shunt pathway and bioactive ketone metabolites linked to energy balance.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"95 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2024-11-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142599611","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 Zea genus-specific micropeptide controls kernel dehydration in maize","authors":"Yanhui Yu, Wenqiang Li, Yuanfang Liu, Yanjun Liu, Qinzhi Zhang, Yidan Ouyang, Wenya Ding, Yu Xue, Yilin Zou, Junjun Yan, Anqiang Jia, Jiali Yan, Xinfei Hao, Yujie Gou, Zhaowei Zhai, Longyu Liu, Yang Zheng, Bao Zhang, Jieting Xu, Ning Yang, Jianbing Yan","doi":"10.1016/j.cell.2024.10.030","DOIUrl":"https://doi.org/10.1016/j.cell.2024.10.030","url":null,"abstract":"Kernel dehydration rate (KDR) is a crucial production trait that affects mechanized harvesting and kernel quality in maize; however, the underlying mechanisms remain unclear. Here, we identified a quantitative trait locus (QTL), <em>qKDR1</em>, as a non-coding sequence that regulates the expression of <em>qKDR1 REGULATED PEPTIDE GENE</em> (<em>RPG</em>). <em>RPG</em> encodes a 31 amino acid micropeptide, microRPG1, which controls KDR by precisely modulating the expression of two genes, <em>ZmETHYLENE-INSENSITIVE3-like 1</em> and <em>3</em>, in the ethylene signaling pathway in the kernels after filling. microRPG1 is a <em>Zea</em> genus-specific micropeptide and originated <em>de novo</em> from a non-coding sequence. Knockouts of microRPG1 result in faster KDR in maize. By contrast, overexpression or exogenous application of the micropeptide shows the opposite effect both in maize and <em>Arabidopsis</em>. Our findings reveal the molecular mechanism of microRPG1 in kernel dehydration and provide an important tool for future crop breeding.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"51 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2024-11-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142599612","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 : 2024-11-12DOI: 10.1016/j.cell.2024.10.023
Tian Lu, Mengdi Wang, Wei Zhou, Qi Ni, Yuanlei Yue, Wei Wang, Yingchao Shi, Zeyuan Liu, Changlin Li, Bei Hong, Xin Zhou, Suijuan Zhong, Kaikai Wang, Bo Zeng, Jun Zhang, Wei Wang, Xu Zhang, Qian Wu, Xiaoqun Wang
{"title":"Decoding transcriptional identity in developing human sensory neurons and organoid modeling","authors":"Tian Lu, Mengdi Wang, Wei Zhou, Qi Ni, Yuanlei Yue, Wei Wang, Yingchao Shi, Zeyuan Liu, Changlin Li, Bei Hong, Xin Zhou, Suijuan Zhong, Kaikai Wang, Bo Zeng, Jun Zhang, Wei Wang, Xu Zhang, Qian Wu, Xiaoqun Wang","doi":"10.1016/j.cell.2024.10.023","DOIUrl":"https://doi.org/10.1016/j.cell.2024.10.023","url":null,"abstract":"Dorsal root ganglia (DRGs) play a crucial role in processing sensory information, making it essential to understand their development. Here, we construct a single-cell spatiotemporal transcriptomic atlas of human embryonic DRG. This atlas reveals the diversity of cell types and highlights the extrinsic signaling cascades and intrinsic regulatory hierarchies that guide cell fate decisions, including neuronal/glial lineage restriction, sensory neuron differentiation and specification, and the formation of neuron-satellite glial cell (SGC) units. Additionally, we identify a human-enriched <em>NTRK3</em><sup>+</sup>/<em>DCC</em><sup>+</sup> nociceptor subtype, which is involved in multimodal nociceptive processing. Mimicking the programmed activation of signaling pathways <em>in vivo</em>, we successfully establish functional human DRG organoids and underscore the critical roles of transcriptional regulators in the fate commitment of unspecialized sensory neurons (uSNs). Overall, our research elucidates the multilevel signaling pathways and transcription factor (TF) regulatory hierarchies that underpin the diversity of somatosensory neurons, emphasizing the phenotypic distinctions in human nociceptor subtypes.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"41 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2024-11-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142599610","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 : 2024-11-11DOI: 10.1016/j.cell.2024.10.027
Jing L. Guo, Dylan Braun, Gabriel A. Fitzgerald, Yun-Ting Hsieh, Lionel Rougé, Alexandra Litvinchuk, Micah Steffek, Nicholas E. Propson, Catherine M. Heffner, Claire Discenza, Suk Ji Han, Anil Rana, Lukas L. Skuja, Bi Qi Lin, Elizabeth W. Sun, Sonnet S. Davis, Srijana Balasundar, Isabel Becerra, Jason C. Dugas, Connie Ha, Gilbert Di Paolo
{"title":"Decreased lipidated ApoE-receptor interactions confer protection against pathogenicity of ApoE and its lipid cargoes in lysosomes","authors":"Jing L. Guo, Dylan Braun, Gabriel A. Fitzgerald, Yun-Ting Hsieh, Lionel Rougé, Alexandra Litvinchuk, Micah Steffek, Nicholas E. Propson, Catherine M. Heffner, Claire Discenza, Suk Ji Han, Anil Rana, Lukas L. Skuja, Bi Qi Lin, Elizabeth W. Sun, Sonnet S. Davis, Srijana Balasundar, Isabel Becerra, Jason C. Dugas, Connie Ha, Gilbert Di Paolo","doi":"10.1016/j.cell.2024.10.027","DOIUrl":"https://doi.org/10.1016/j.cell.2024.10.027","url":null,"abstract":"While apolipoprotein E (<em>APOE</em>) is the strongest genetic modifier for late-onset Alzheimer’s disease (LOAD), the molecular mechanisms underlying isoform-dependent risk and the relevance of ApoE-associated lipids remain elusive. Here, we report that impaired low-density lipoprotein (LDL) receptor (LDLR) binding of lipidated ApoE2 (lipApoE2) avoids LDLR recycling defects observed with lipApoE3/E4 and decreases the uptake of cholesteryl esters (CEs), which are lipids linked to neurodegeneration. In human neurons, the addition of ApoE carrying polyunsaturated fatty acids (PUFAs)-CE revealed an allelic series (ApoE4 > ApoE3 > ApoE2) associated with lipofuscinosis, an age-related lysosomal pathology resulting from lipid peroxidation. Lipofuscin increased lysosomal accumulation of tau fibrils and was elevated in the <em>APOE4</em> mouse brain with exacerbation by tau pathology. Intrahippocampal injection of PUFA-CE-lipApoE4 was sufficient to induce lipofuscinosis in wild-type mice. Finally, the protective Christchurch mutation also reduced LDLR binding and phenocopied ApoE2. Collectively, our data strongly suggest decreased lipApoE-LDLR interactions minimize LOAD risk by reducing the deleterious effects of endolysosomal targeting of ApoE and associated pathogenic lipids.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"35 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2024-11-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142599615","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 : 2024-11-11DOI: 10.1016/j.cell.2024.10.028
Muhammad Abdelbasset, Wilfried A.A. Saron, Dongliang Ma, Abhay P.S. Rathore, Tatsuya Kozaki, Chengwei Zhong, Chinmay Kumar Mantri, Yingrou Tan, Chi-Ching Tung, Hong Liang Tey, Justin Jang Hann Chu, Jinmiao Chen, Lai Guan Ng, Hongyan Wang, Florent Ginhoux, Ashley L. St. John
{"title":"Differential contributions of fetal mononuclear phagocytes to Zika virus neuroinvasion versus neuroprotection during congenital infection","authors":"Muhammad Abdelbasset, Wilfried A.A. Saron, Dongliang Ma, Abhay P.S. Rathore, Tatsuya Kozaki, Chengwei Zhong, Chinmay Kumar Mantri, Yingrou Tan, Chi-Ching Tung, Hong Liang Tey, Justin Jang Hann Chu, Jinmiao Chen, Lai Guan Ng, Hongyan Wang, Florent Ginhoux, Ashley L. St. John","doi":"10.1016/j.cell.2024.10.028","DOIUrl":"https://doi.org/10.1016/j.cell.2024.10.028","url":null,"abstract":"Fetal immune cell functions during congenital infections are poorly understood. Zika virus (ZIKV) can vertically transmit from mother to fetus, causing nervous system infection and congenital ZIKV syndrome (CZS). We identified differential functional roles for fetal monocyte/macrophage cell types and microglia in ZIKV dissemination versus clearance using mouse models. Trafficking of ZIKV-infected primitive macrophages from the yolk sac allowed initial fetal virus inoculation, while recruited monocytes promoted non-productive neuroinflammation. Conversely, brain-resident differentiated microglia were protective, limiting infection and neuronal death. Single-cell RNA sequencing identified transcriptional profiles linked to the protective versus detrimental contributions of mononuclear phagocyte subsets. In human brain organoids, microglia also promoted neuroprotective transcriptional changes and infection clearance. Thus, microglia are protective before birth, contrasting with the disease-enhancing roles of primitive macrophages and monocytes. Differential modulation of myeloid cell phenotypes by genetically divergent ZIKVs underscores the potential of immune cells to regulate diverse outcomes during fetal infections.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"45 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2024-11-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142599613","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 : 2024-11-11DOI: 10.1016/j.cell.2024.10.021
Wen-Wei Liang, Simon Müller, Sydney K. Hart, Hans-Hermann Wessels, Alejandro Méndez-Mancilla, Akash Sookdeo, Olivia Choi, Christina M. Caragine, Alba Corman, Lu Lu, Olena Kolumba, Breanna Williams, Neville E. Sanjana
{"title":"Transcriptome-scale RNA-targeting CRISPR screens reveal essential lncRNAs in human cells","authors":"Wen-Wei Liang, Simon Müller, Sydney K. Hart, Hans-Hermann Wessels, Alejandro Méndez-Mancilla, Akash Sookdeo, Olivia Choi, Christina M. Caragine, Alba Corman, Lu Lu, Olena Kolumba, Breanna Williams, Neville E. Sanjana","doi":"10.1016/j.cell.2024.10.021","DOIUrl":"https://doi.org/10.1016/j.cell.2024.10.021","url":null,"abstract":"Mammalian genomes host a diverse array of RNA that includes protein-coding and noncoding transcripts. However, the functional roles of most long noncoding RNAs (lncRNAs) remain elusive. Using RNA-targeting CRISPR-Cas13 screens, we probed how the loss of ∼6,200 lncRNAs impacts cell fitness across five human cell lines and identified 778 lncRNAs with context-specific or broad essentiality. We confirm their essentiality with individual perturbations and find that the majority of essential lncRNAs operate independently of their nearest protein-coding genes. Using transcriptome profiling in single cells, we discover that the loss of essential lncRNAs impairs cell-cycle progression and drives apoptosis. Many essential lncRNAs demonstrate dynamic expression across tissues during development. Using ∼9,000 primary tumors, we pinpoint those lncRNAs whose expression in tumors correlates with survival, yielding new biomarkers and potential therapeutic targets. This transcriptome-wide survey of functional lncRNAs advances our understanding of noncoding transcripts and demonstrates the potential of transcriptome-scale noncoding screens with Cas13.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"19 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2024-11-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142599875","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":"Spatiotemporal modeling of molecular holograms","authors":"Xiaojie Qiu, Daniel Y. Zhu, Yifan Lu, Jiajun Yao, Zehua Jing, Kyung Hoi Min, Mengnan Cheng, Hailin Pan, Lulu Zuo, Samuel King, Qi Fang, Huiwen Zheng, Mingyue Wang, Shuai Wang, Qingquan Zhang, Sichao Yu, Sha Liao, Chao Liu, Xinchao Wu, Yiwei Lai, Yinqi Bai","doi":"10.1016/j.cell.2024.10.011","DOIUrl":"https://doi.org/10.1016/j.cell.2024.10.011","url":null,"abstract":"Quantifying spatiotemporal dynamics during embryogenesis is crucial for understanding congenital diseases. We developed Spateo (<span><span>https://github.com/aristoteo/spateo-release</span><svg aria-label=\"Opens in new window\" focusable=\"false\" height=\"20\" viewbox=\"0 0 8 8\"><path d=\"M1.12949 2.1072V1H7V6.85795H5.89111V2.90281L0.784057 8L0 7.21635L5.11902 2.1072H1.12949Z\"></path></svg></span>), a 3D spatiotemporal modeling framework, and applied it to a 3D mouse embryogenesis atlas at E9.5 and E11.5, capturing eight million cells. Spateo enables scalable, partial, non-rigid alignment, multi-slice refinement, and mesh correction to create molecular holograms of whole embryos. It introduces digitization methods to uncover multi-level biology from subcellular to whole organ, identifying expression gradients along orthogonal axes of emergent 3D structures, e.g., secondary organizers such as midbrain-hindbrain boundary (MHB). Spateo further jointly models intercellular and intracellular interaction to dissect signaling landscapes in 3D structures, including the zona limitans intrathalamica (ZLI). Lastly, Spateo introduces “morphometric vector fields” of cell migration and integrates spatial differential geometry to unveil molecular programs underlying asymmetrical murine heart organogenesis and others, bridging macroscopic changes with molecular dynamics. Thus, Spateo enables the study of organ ecology at a molecular level in 3D space over time.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"23 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2024-11-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142599614","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":"Multimodal targeting chimeras enable integrated immunotherapy leveraging tumor-immune microenvironment","authors":"Feng Lin, Shenyi Yin, Zijian Zhang, Ying Yu, Haoming Fang, Zhen Liang, Rujie Zhu, Haitao Zhou, Jianjie Li, Kunxia Cao, Weiming Guo, Shan Qin, Yuxuan Zhang, Chenghao Lu, Han Li, Shibo Liu, Heng Zhang, Buqing Ye, Jian Lin, Yan Li, Peng R. Chen","doi":"10.1016/j.cell.2024.10.016","DOIUrl":"https://doi.org/10.1016/j.cell.2024.10.016","url":null,"abstract":"Although immunotherapy has revolutionized cancer treatment, its efficacy is affected by multiple factors, particularly those derived from the complexity and heterogeneity of the tumor-immune microenvironment (TIME). Strategies that simultaneously and synergistically engage multiple immune cells in TIME remain highly desirable but challenging. Herein, we report a multimodal and programmable platform that enables the integration of multiple therapeutic modules into single agents for tumor-targeted co-engagement of multiple immune cells within TIME. We developed the triple orthogonal linker (T-Linker) technology to integrate various therapeutic small molecules and biomolecules as multimodal targeting chimeras (Multi-TACs). The EGFR-CD3-PDL1 Multi-TAC facilitated T-dendritic cell co-engagement to target solid tumors with excellent efficacy, as demonstrated <em>in vitro</em>, in several humanized mouse models and in patient-derived tumor models. Furthermore, Multi-TACs were constructed to coordinate T cells with other immune cell types. The highly modular and programmable feature of our Multi-TACs may find broad applications in immunotherapy and beyond.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"34 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2024-11-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142580518","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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