Cell Chemical Biology最新文献_第3页

RENBP inhibition amplifies metabolic glycan labeling efficiency of antigen-presenting cells in vitro and in vivo 在体外和体内，RENBP抑制增强了抗原呈递细胞的代谢聚糖标记效率

IF 7.2 1区生物学

Cell Chemical Biology Pub Date : 2025-08-21 DOI: 10.1016/j.chembiol.2025.07.001

Yusheng Liu , Jiadiao Zhou , Yueji Wang , Daniel Nguyen , Dhyanesh Baskaran , Yuan Liu , Hua Wang

{"title":"RENBP inhibition amplifies metabolic glycan labeling efficiency of antigen-presenting cells in vitro and in vivo","authors":"Yusheng Liu , Jiadiao Zhou , Yueji Wang , Daniel Nguyen , Dhyanesh Baskaran , Yuan Liu , Hua Wang","doi":"10.1016/j.chembiol.2025.07.001","DOIUrl":"10.1016/j.chembiol.2025.07.001","url":null,"abstract":"<div><div>Metabolic glycoengineering of unnatural sugars provides a powerful tool to introduce unique chemical tags onto cell membrane for subsequent conjugation of cargos. However, the metabolic glycan labeling efficiency of antigen-presenting cells (APCs), the key mediators of adaptive immunity, is often low. Here, we report that APCs upregulate GlcNAc 2-epimerase (RENBP) and that RENBP inhibition leads to improved labeling efficiency of tetraacetyl-<em>N</em>-azidoacetylmannosamine (AAM) in APCs, including dendritic cells (1.2-fold), macrophages (1.3-fold), and B cells (1.4-fold) <em>in vitro</em>. RENBP inhibition can preferentially enhance AAM labeling efficiency in APCs than in non-APCs and selectively enhance the labeling efficiency of AAM over azido-galactosamine. We further demonstrate that RENBP inhibitors can improve AAM-mediated labeling of B cells and other APCs <em>in vivo</em>, with the largest enhancement for B cells (>3-fold) for 7 days. Our study uncovers a facile approach to improving metabolic glycan labeling of APCs, enabling the development of APC-targeted immunotherapies.</div></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"32 8","pages":"Pages 983-993.e5"},"PeriodicalIF":7.2,"publicationDate":"2025-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144792345","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}

引用次数: 0

An adjuvant database for preclinical evaluation of vaccines and immunotherapeutics 用于疫苗和免疫疗法临床前评估的佐剂数据库

IF 7.2 1区生物学

Cell Chemical Biology Pub Date : 2025-08-21 DOI: 10.1016/j.chembiol.2025.07.005

Yayoi Natsume-Kitatani , Kouji Kobiyama , Yoshinobu Igarashi , Taiki Aoshi , Noriyuki Nakatsu , Lokesh P. Tripathi , Junichi Ito , Johan Nyström-Persson , Yuji Kosugi , Rodolfo S. Allendes Osorio , Chioko Nagao , Burcu Temizoz , Etsushi Kuroda , Daron M. Standley , Hiroshi Kiyono , Kenji Nakanishi , Satoshi Uematsu , Isao Hamaguchi , Yasuhiro Yasutomi , Jun Kunisawa , Ken J. Ishii

{"title":"An adjuvant database for preclinical evaluation of vaccines and immunotherapeutics","authors":"Yayoi Natsume-Kitatani , Kouji Kobiyama , Yoshinobu Igarashi , Taiki Aoshi , Noriyuki Nakatsu , Lokesh P. Tripathi , Junichi Ito , Johan Nyström-Persson , Yuji Kosugi , Rodolfo S. Allendes Osorio , Chioko Nagao , Burcu Temizoz , Etsushi Kuroda , Daron M. Standley , Hiroshi Kiyono , Kenji Nakanishi , Satoshi Uematsu , Isao Hamaguchi , Yasuhiro Yasutomi , Jun Kunisawa , Ken J. Ishii","doi":"10.1016/j.chembiol.2025.07.005","DOIUrl":"10.1016/j.chembiol.2025.07.005","url":null,"abstract":"<div><div>Adjuvants are immunostimulators used to enhance vaccine efficacy against infectious diseases. However, current methods for evaluating their efficacy and safety are limited, hindering large-scale screening. To address this, we developed a prototype Adjuvant Database (ADB) containing transcriptome data, generated using the same protocols as the widely used Open TG-GATEs (OTG) toxicogenomics database, covering 25 adjuvants across multiple species, organs, time points, and doses. This enabled cross-database integration of ADB and OTG. Transcriptomic patterns successfully distinguished each adjuvant regardless of organs or species. Using both databases, we built machine learning models to predict adjuvanticity and hepatotoxicity. Notably, we identified colchicine’s adjuvant activity and FK565’s liver toxicity through data-driven analysis. Overall, ADB combined with OTG offers a framework for transcriptomics-based, data-driven screening of adjuvant candidates.</div></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"32 8","pages":"Pages 1075-1088.e3"},"PeriodicalIF":7.2,"publicationDate":"2025-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144813235","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}

引用次数: 0

Engineering affinity-matured variants of an anti-polysialic acid monoclonal antibody with superior cytotoxicity-mediating potency 具有优越细胞毒性介导效力的抗多唾液酸单克隆抗体的工程亲和成熟变体

IF 7.2 1区生物学

Cell Chemical Biology Pub Date : 2025-08-21 DOI: 10.1016/j.chembiol.2025.07.007

Weiyao Wang , Mehman Bunyatov , Deana Moffat , Natalia Lopez-Barbosa , Matthew P. DeLisa

{"title":"Engineering affinity-matured variants of an anti-polysialic acid monoclonal antibody with superior cytotoxicity-mediating potency","authors":"Weiyao Wang , Mehman Bunyatov , Deana Moffat , Natalia Lopez-Barbosa , Matthew P. DeLisa","doi":"10.1016/j.chembiol.2025.07.007","DOIUrl":"10.1016/j.chembiol.2025.07.007","url":null,"abstract":"<div><div>Monoclonal antibodies (mAbs) that specifically recognize cell surface glycans associated with cancer and infectious disease hold tremendous value for basic research and clinical applications. However, high-quality anti-glycan mAbs with sufficiently high affinity and specificity remain scarce, highlighting the need for strategies that enable optimization of antigen-binding properties. To this end, we engineered the affinity of a polysialic acid (polySia)-specific antibody called mAb735, which possesses only modest affinity. Using a combination of rational design and directed evolution, we isolated several affinity-matured IgG variants with ∼5- to 7-fold stronger affinity for polySia relative to mAb735. The higher affinity IgG variants opsonized polySia-positive cancer cells more avidly and triggered greater antibody-dependent cell-mediated cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC). Collectively, these results demonstrate the effective application of molecular evolution techniques to an important anti-glycan antibody, providing insights into its carbohydrate recognition and uncovering variants with greater therapeutic promise due to their enhanced affinity and potency.</div></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"32 8","pages":"Pages 1042-1057.e6"},"PeriodicalIF":7.2,"publicationDate":"2025-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144879272","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}

引用次数: 0

Inhibiting cancer metastasis with water-solubilized membrane receptor CXCR4QTY-Fc as a molecular trap 水溶性膜受体CXCR4QTY-Fc作为分子陷阱抑制肿瘤转移

IF 7.2 1区生物学

Cell Chemical Biology Pub Date : 2025-08-21 DOI: 10.1016/j.chembiol.2025.07.006

Changfa Sun , Shilei Hao , Lili Wang , Run Meng , Hui Wang , Wenfeng Li , Jia Deng , Qiudan Yin , Xiaoliang Chen , Tingxiu Xiang , Zuojin Liu , Haiming Zheng , Zhongli Luo , Kaiyong Cai , Bochu Wang , Shuguang Zhang , Rui Qing

{"title":"Inhibiting cancer metastasis with water-solubilized membrane receptor CXCR4QTY-Fc as a molecular trap","authors":"Changfa Sun , Shilei Hao , Lili Wang , Run Meng , Hui Wang , Wenfeng Li , Jia Deng , Qiudan Yin , Xiaoliang Chen , Tingxiu Xiang , Zuojin Liu , Haiming Zheng , Zhongli Luo , Kaiyong Cai , Bochu Wang , Shuguang Zhang , Rui Qing","doi":"10.1016/j.chembiol.2025.07.006","DOIUrl":"10.1016/j.chembiol.2025.07.006","url":null,"abstract":"<div><div>The CXCR4/CXCL12 axis is vital for tumor metastasis and immune evasion in various cancers. However, developing effective inhibitors is challenging due to complex intracellular interactions and limitations of soluble receptor drugs targeting single transmembrane proteins. Here, we engineered a water-soluble CXCR4<sup>QTY</sup>-Fc molecular trap by fusing a redesigned CXCR4 variant with the IgG1-Fc domain. CXCR4<sup>QTY</sup>-Fc effectively neutralizes CXCL12, inhibits CXCR4 downstream signaling, and suppresses migration and invasion of CXCR4-positive cancer cells <em>in vitro</em>, even with dipeptidyl peptidase 4 (DPP-4) inhibition. In mouse models of pancreatic, breast, and prostate cancer metastasis, CXCR4<sup>QTY</sup>-Fc significantly reduced tumor metastasis, outperforming the clinical CXCR4 antagonist AMD3100. Mechanistically, CXCR4<sup>QTY</sup>-Fc blocks endosomal CXCL12/CXCR4 signaling and reshapes the tumor microenvironment by downregulating CXCL12, thereby inhibiting tumor growth, metastasis, and angiogenesis. This biomimetic, non-immunogenic approach offers a promising strategy for broad-spectrum metastasis inhibition.</div></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"32 8","pages":"Pages 1058-1074.e6"},"PeriodicalIF":7.2,"publicationDate":"2025-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144879273","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}

引用次数: 0

Robust antitumor treatment driven by lock-and-key biorecognition of dynamic cyclic diselenide-guided chiral prodrug self-assembly 动态环二硒引导手性前药自组装的锁-键生物识别驱动的强大抗肿瘤治疗

IF 7.2 1区生物学

Cell Chemical Biology Pub Date : 2025-08-21 DOI: 10.1016/j.chembiol.2025.07.003

Yixin Sun , Baoyuan Zhang , Jiayao Wang , Xin Li , Zhonggui He , Chutong Tian , Bingjun Sun , Jin Sun

{"title":"Robust antitumor treatment driven by lock-and-key biorecognition of dynamic cyclic diselenide-guided chiral prodrug self-assembly","authors":"Yixin Sun , Baoyuan Zhang , Jiayao Wang , Xin Li , Zhonggui He , Chutong Tian , Bingjun Sun , Jin Sun","doi":"10.1016/j.chembiol.2025.07.003","DOIUrl":"10.1016/j.chembiol.2025.07.003","url":null,"abstract":"<div><div>Designing highly selective nanomedicines with precise recognition of biological interfaces for efficient cancer therapy represents a tremendous challenge. Inspired by the inherent chirality and enantioselectivity of organisms, we constructed dynamic chiral cyclic diselenide-conjugated paclitaxel prodrug nanoassemblies (CSEPNs) to simulate the chiral recognition process. The optimal chiral configuration with potent antitumor effects was screened by deconstructing the lock-and-key biorecognition of CSEPNs. Compared with R-(−)-CSEP, S-(+)-CSEP displayed steady chirality-dependent self-assembly due to the balance of intermolecular interaction and steric hindrance. With ring-tensioned backbone and superior chiral topology, S-(+)-CSEPNs exhibited ultra-high redox sensitivity and enhanced clathrin-mediated endocytosis. More importantly, S-(+)-CSEPNs presented the <em>in vivo</em> transport advantages of high tumor accumulation and low excretion rate. Finally, CSEPNs exerted robust synergistic tumor suppression through chemotherapy, tumor redox axis modulation, and tumor angiogenesis inhibition. These findings confirmed the dominant role of chiral lock-and-key biorecognition in determining the biological fate of the nanomedicines.</div></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"32 8","pages":"Pages 1013-1027.e5"},"PeriodicalIF":7.2,"publicationDate":"2025-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144813234","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}

引用次数: 0

Targeting the MYC oncogene with a selective bi-steric mTORC1 inhibitor elicits tumor regression in MYC-driven cancers 用选择性双位mTORC1抑制剂靶向MYC癌基因可诱导MYC驱动型癌症的肿瘤消退

IF 7.2 1区生物学

Cell Chemical Biology Pub Date : 2025-08-21 DOI: 10.1016/j.chembiol.2025.07.004

Wadie D. Mahauad-Fernandez , Yu Chi Yang , Ian Lai , Jangho Park , Lilian Yao , James W. Evans , Danielle F. Atibalentja , Xinyu Chen , Vishnupriya Kanakaveti , Zihui Zhao , G. Leslie Burnett , Bianca J. Lee , Nuntana Dinglasan , Nataliya Tovbis Shifrin , Ethan Ahler , Elsa Quintana , Adrian L. Gill , Jacqueline A.M. Smith , Mallika Singh , Dean W. Felsher

{"title":"Targeting the MYC oncogene with a selective bi-steric mTORC1 inhibitor elicits tumor regression in MYC-driven cancers","authors":"Wadie D. Mahauad-Fernandez , Yu Chi Yang , Ian Lai , Jangho Park , Lilian Yao , James W. Evans , Danielle F. Atibalentja , Xinyu Chen , Vishnupriya Kanakaveti , Zihui Zhao , G. Leslie Burnett , Bianca J. Lee , Nuntana Dinglasan , Nataliya Tovbis Shifrin , Ethan Ahler , Elsa Quintana , Adrian L. Gill , Jacqueline A.M. Smith , Mallika Singh , Dean W. Felsher","doi":"10.1016/j.chembiol.2025.07.004","DOIUrl":"10.1016/j.chembiol.2025.07.004","url":null,"abstract":"<div><div>The <em>MYC</em> oncogene is causally involved in the pathogenesis of most human cancers. The mTORC1 complex regulates MYC translation through 4EBP1 and S6K. However, agents that selectively target mTORC1 (without affecting mTORC2) have so far failed to reactivate 4EBP1 and, thus, cannot effectively suppress MYC <em>in vivo.</em> In contrast, nonselective inhibitors that block both mTOR complexes can activate 4EBP1, but often lack tolerability and induce immunosuppression. Here, we introduce bi-steric mTORC1-selective inhibitors, including the clinical candidate RMC-5552, which potently reactivate 4EBP1 and decrease MYC protein expression levels. Consequently, suppression of MYC signaling occurs, resulting in tumor growth inhibition through both direct effects on tumor cells and immune activation. RMC-5552 exhibits anti-tumor activity in human patient-derived xenografts models harboring genomic <em>MYC</em> amplifications and reduces MYC protein levels <em>in vivo</em>. Furthermore, bi-steric mTORC1-selective inhibitors enhance the efficacy of immune checkpoint blockade, leading to tumor regression.</div></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"32 8","pages":"Pages 994-1012.e11"},"PeriodicalIF":7.2,"publicationDate":"2025-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144819450","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}

引用次数: 0

Ribosomal RNA transcription regulates splicing through ribosomal protein RPL22 核糖体RNA转录通过核糖体蛋白RPL22调控剪接

IF 6.6 1区生物学

Cell Chemical Biology Pub Date : 2025-07-17 DOI: 10.1016/j.chembiol.2025.05.012

Wenjun Fan , Hester Liu , Gregory C. Stachelek , Asma Begum , Catherine E. Davis , Tony E. Dorado , Glen Ernst , William C. Reinhold , Busra Ozbek , Qizhi Zheng , Angelo M. De Marzo , N.V. Rajeshkumar , James C. Barrow , Marikki Laiho

{"title":"Ribosomal RNA transcription regulates splicing through ribosomal protein RPL22","authors":"Wenjun Fan , Hester Liu , Gregory C. Stachelek , Asma Begum , Catherine E. Davis , Tony E. Dorado , Glen Ernst , William C. Reinhold , Busra Ozbek , Qizhi Zheng , Angelo M. De Marzo , N.V. Rajeshkumar , James C. Barrow , Marikki Laiho","doi":"10.1016/j.chembiol.2025.05.012","DOIUrl":"10.1016/j.chembiol.2025.05.012","url":null,"abstract":"<div><div>Ribosome biosynthesis is a cancer vulnerability targeted by inhibiting RNA polymerase I (Pol I) transcription. We developed specific Pol I inhibitors that activate a ribotoxic stress pathway to uncover drivers of sensitivity. Integrating multi-omics and drug response data from a large cancer cell panel, we found that RPL22 frameshift mutations confer Pol I inhibitor sensitivity. Mechanistically, RPL22 interacts directly with 28S rRNA and mRNA splice junctions, acting as a splicing regulator. RPL22 deficiency, intensified by 28S rRNA sequestration, promotes splicing of its paralog RPL22L1 and the p53 negative regulator MDM4. Both chemical and genetic inhibition of rRNA synthesis broadly remodel mRNA splicing controlling hundreds of targets. Notably, RPL22-dependent alternative splicing is reversed by Pol I inhibition, revealing a non-canonical ribotoxic stress-initiated tumor suppressive pathway. This study uncovers a robust mechanism linking rRNA synthesis activity to splicing, coordinated by the ribosomal protein RPL22.</div></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"32 7","pages":"Pages 908-925.e9"},"PeriodicalIF":6.6,"publicationDate":"2025-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144311709","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}

引用次数: 0

Powering the powerhouse: Mitochondrial NADPH propels oxidative metabolism 动力：线粒体NADPH促进氧化代谢

IF 6.6 1区生物学

Cell Chemical Biology Pub Date : 2025-07-17 DOI: 10.1016/j.chembiol.2025.06.006

Riley J. Wedan , Sara M. Nowinski

引用次数: 0

RPL22 links ribosome biogenesis, RNA splicing, and sensitivity to RNA polymerase I inhibition RPL22连接核糖体生物发生，RNA剪接和对RNA聚合酶I抑制的敏感性

IF 6.6 1区生物学

Cell Chemical Biology Pub Date : 2025-07-17 DOI: 10.1016/j.chembiol.2025.06.001

Kenyon Weis , Omar Abdel-Wahab

引用次数: 0

Site-resolved assessment of targeted protein degradation 靶向蛋白降解的位点分辨评估

IF 6.6 1区生物学

Cell Chemical Biology Pub Date : 2025-07-17 DOI: 10.1016/j.chembiol.2025.06.002

Ricardo Moreno-Ballesteros , Thomas Pembridge , Gaurav Beniwal , Satpal Virdee

{"title":"Site-resolved assessment of targeted protein degradation","authors":"Ricardo Moreno-Ballesteros , Thomas Pembridge , Gaurav Beniwal , Satpal Virdee","doi":"10.1016/j.chembiol.2025.06.002","DOIUrl":"10.1016/j.chembiol.2025.06.002","url":null,"abstract":"<div><div>Induced proximity using small molecules, exemplified by targeted protein degradation (TPD), represents a highly promising therapeutic strategy with significant untapped potential. However, evaluating an induced proximity event that accurately reflects drug binding typically requires the challenging and costly development of specific ligands, which limits the advancement of medicines based on this modality. To overcome this bottleneck, we combine genetic code expansion with ultra-fast bioorthogonal chemistry to sensitize specific protein sites at single-residue resolution to a generic bioorthogonal proximity inducer (BPI) molecule. Mammalian cells expressing sensitized mutants of the ubiquitin E3 ligases VHL and CRBN exhibit neosubstrate degradation in the presence of a BPI equipped with a ligand targeting bromodomain and extraterminal (BET) proteins. Furthermore, we demonstrate E3-independent degradation through recruitment of an upstream E2 conjugating enzyme. We anticipate that this approach will have broad applicability, enabling comprehensive assessment of the scope of induced proximity.</div></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"32 7","pages":"Pages 969-981.e7"},"PeriodicalIF":6.6,"publicationDate":"2025-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144547594","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}

引用次数: 0