CellPub Date : 2025-07-10DOI: 10.1016/j.cell.2025.06.019
Eryn Blass, Derin B. Keskin, Chloe R. Tu, Cleo Forman, Allison Vanasse, Haley E. Sax, Bohoon Shim, Vipheaviny Chea, Nawoo Kim, Isabel Carulli, Jackson Southard, Haoxiang Lyu, Wesley Lu, Micah Rickles-Young, Alexander B. Afeyan, Oriol Olive, Ambica Mehndiratta, Haley Greenslade, Keerthi Shetty, Joanna Baginska, Patrick A. Ott
{"title":"A multi-adjuvant personal neoantigen vaccine generates potent immunity in melanoma","authors":"Eryn Blass, Derin B. Keskin, Chloe R. Tu, Cleo Forman, Allison Vanasse, Haley E. Sax, Bohoon Shim, Vipheaviny Chea, Nawoo Kim, Isabel Carulli, Jackson Southard, Haoxiang Lyu, Wesley Lu, Micah Rickles-Young, Alexander B. Afeyan, Oriol Olive, Ambica Mehndiratta, Haley Greenslade, Keerthi Shetty, Joanna Baginska, Patrick A. Ott","doi":"10.1016/j.cell.2025.06.019","DOIUrl":"https://doi.org/10.1016/j.cell.2025.06.019","url":null,"abstract":"Personalized neoantigen-targeting vaccines have demonstrated great promise; however, improved immunogenicity is still needed. Since antigen availability and effective T cell priming are critical for maximal immunogenicity, we tested a synthetic long peptide vaccine formulated with Montanide, poly-ICLC, and locally administered ipilimumab in addition to systemic nivolumab in 10 patients with melanoma. These personalized vaccines generated <em>de novo ex vivo</em> T cell responses against the majority of immunizing neoepitopes in all 9 fully vaccinated patients and <em>ex vivo</em> CD8+ T cell responses in 6 of 9. Vaccination induced hundreds of circulating and intratumoral T cell receptor (TCR) clonotypes that were distinct from those arising after PD-1 inhibition. By linking the vaccine neoantigen specificity of T cell clonotypes with single-cell phenotypes in tumors, we demonstrate remodeling of the intratumoral T cell repertoire following vaccination. These observations show that multi-pronged immune adjuvanticity can boost T cell responses to neoantigen-targeting vaccines.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"697 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2025-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144594755","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 : 2025-07-10DOI: 10.1016/j.cell.2025.06.009
Michael A. Skinnider, Gregoire Courtine, Jocelyne Bloch, Jordan W. Squair
{"title":"A clinical road map for single-cell omics","authors":"Michael A. Skinnider, Gregoire Courtine, Jocelyne Bloch, Jordan W. Squair","doi":"10.1016/j.cell.2025.06.009","DOIUrl":"https://doi.org/10.1016/j.cell.2025.06.009","url":null,"abstract":"In a matter of years, single-cell omics has matured from a pioneering technique employed by just a handful of specialized laboratories to become a ubiquitous feature of biological research and a key driver of scientific discovery. The widespread adoption and development of single-cell omic assays has sparked mounting enthusiasm that these technologies are poised to also enhance the precision of diagnosis, the monitoring of disease progression, and the personalization of therapeutic strategies. Despite initial forays into clinical settings, however, single-cell technologies are not yet routinely used to inform medical or surgical decision-making. Here, we identify and categorize key experimental, computational, and conceptual barriers that currently hinder the clinical deployment of single-cell omics. We focus on the potential for single-cell transcriptomics to guide clinical decision-making through the development of combinatorial biomarkers that simultaneously quantify multiple cell-type-specific pathophysiological processes. We articulate a framework to identify patient subpopulations that stand to benefit from such biomarkers, and we outline the experimental and computational requirements to derive reproducible and actionable clinical readouts from single-cell omics.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"11 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2025-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144594801","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 : 2025-07-09DOI: 10.1016/j.cell.2025.06.018
Catherine M. Phelps, Nathaniel B. Willis, Tingting Duan, Amanda H. Lee, Yue Zhang, Daphne M. Rodriguez J, Surya P. Pandey, Colin R. Laughlin, Aaron B.I. Rosen, Alex C. McPherson, Jake H. Shapira, Simran K. Randhawa, Lee Hedden, Tanner G. Richie, Hallie M. Wiechman, Mackenzie J. Bender, Ina Nemet, Patrick A. Zöhrer, Rachel A. Gottschalk, Kathryn H. Schmitz, Marlies Meisel
{"title":"Exercise-induced microbiota metabolite enhances CD8 T cell antitumor immunity promoting immunotherapy efficacy","authors":"Catherine M. Phelps, Nathaniel B. Willis, Tingting Duan, Amanda H. Lee, Yue Zhang, Daphne M. Rodriguez J, Surya P. Pandey, Colin R. Laughlin, Aaron B.I. Rosen, Alex C. McPherson, Jake H. Shapira, Simran K. Randhawa, Lee Hedden, Tanner G. Richie, Hallie M. Wiechman, Mackenzie J. Bender, Ina Nemet, Patrick A. Zöhrer, Rachel A. Gottschalk, Kathryn H. Schmitz, Marlies Meisel","doi":"10.1016/j.cell.2025.06.018","DOIUrl":"https://doi.org/10.1016/j.cell.2025.06.018","url":null,"abstract":"Exercise improves immune checkpoint inhibitor (ICI) efficacy in cancers such as melanoma; however, the mechanisms through which exercise mediates this antitumor effect remain obscure. Here, we identify that the gut microbiota plays a critical role in how exercise improves ICI efficacy in preclinical melanoma. Our study demonstrates that exercise stimulates microbial one-carbon metabolism, increasing levels of the metabolite formate, which subsequently enhances cytotoxic CD8 T cell (Tc1)-mediated ICI efficacy. We further establish that microbiota-derived formate is both sufficient and required to enhance Tc1 cell fate <em>in vitro</em> and promote tumor antigen-specific Tc1 immunity <em>in vivo</em>. Mechanistically, we identify the transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) as a crucial mediator of formate-driven Tc1 function enhancement <em>in vitro</em> and a key player in the exercise-mediated antitumor effect <em>in vivo</em>. Finally, we uncover human microbiota-derived formate as a potential biomarker of enhanced Tc1-mediated antitumor immunity, supporting its functional role in melanoma suppression.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"109 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2025-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144586956","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":"Modeling the vertebrate regulatory sequence landscape by UUATAC-seq and deep learning","authors":"Xiaoping Han, Hanyu Wu, Xueyi Wang, Daiyuan Liu, Yuting Fu, Lei Yang, Renying Wang, Peijing Zhang, Jingjing Wang, Lifeng Ma, Jizhong Mao, Lina Zhou, Siqi Wang, Xinlian Zhang, Mengmeng Jiang, Xinru Wang, Guoxia Wen, Danmei Jia, Guoji Guo","doi":"10.1016/j.cell.2025.06.020","DOIUrl":"https://doi.org/10.1016/j.cell.2025.06.020","url":null,"abstract":"The regulatory sequences of vertebrate genomes remain incompletely understood. To address this, we developed an ultra-throughput, ultra-sensitive single-nucleus assay for transposase-accessible chromatin using sequencing (UUATAC-seq) protocol that enables the construction of chromatin accessibility landscapes for one species in a 1-day experiment. Using UUATAC-seq, we mapped candidate <em>cis-</em>regulatory elements (cCREs) across five representative vertebrate species. Our analysis revealed that genome size differences across species influence the number but not the size of cCREs. We introduced Nvwa <em>cis</em>-regulatory element (NvwaCE), a mega-task deep-learning model designed to interpret <em>cis-</em>regulatory grammar and predict cCRE landscapes directly from genomic sequences with high precision. NvwaCE demonstrated that regulatory grammar is more conserved than nucleotide sequences and that this grammar organizes cCREs into distinct functional modules. Moreover, NvwaCE accurately predicted the effects of synthetic mutations on lineage-specific cCRE function, aligning with causal quantitative trait loci (QTLs) and genome editing results. Together, our study provides a valuable resource for decoding the vertebrate regulatory language.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"3 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2025-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144578499","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 : 2025-07-07DOI: 10.1016/j.cell.2025.06.017
Yiru Wang, Lixia Zhao, Yi Zhang, Xiuxia Gao, Yannan Wang, Wenping Shi, Roger D. Kornberg, Heqiao Zhang
{"title":"Structures of the measles virus polymerase complex with non-nucleoside inhibitors and mechanism of inhibition","authors":"Yiru Wang, Lixia Zhao, Yi Zhang, Xiuxia Gao, Yannan Wang, Wenping Shi, Roger D. Kornberg, Heqiao Zhang","doi":"10.1016/j.cell.2025.06.017","DOIUrl":"https://doi.org/10.1016/j.cell.2025.06.017","url":null,"abstract":"The measles virus (MeV), a highly contagious non-segmented negative-sense RNA virus in the <em>Paramyxoviridae</em> family, causes millions of infections annually, with no approved antivirals available. The viral polymerase complex, comprising the large (L) protein and the tetrameric phosphoprotein (P), is a key antiviral target. We determined the cryo-electron microscopy structures of the MeV polymerase complex alone and bound to two non-nucleoside inhibitors, ERDRP-0519 and AS-136A. Inhibitor binding induces a conformational change in the catalytic loop, allosterically locking the polymerase in an inactive “GDN-out” state. These findings led to the proposal that ERDRP-0519 would also be effective against Nipah virus (NiV), a highly pathogenic virus with no available antivirals. This proposal was confirmed by structure determination of the NiV polymerase complex and by inhibition of transcription.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"93 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2025-07-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144568949","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":"Advancing protein evolution with inverse folding models integrating structural and evolutionary constraints","authors":"Hongyuan Fei, Yunjia Li, Yijing Liu, Jingjing Wei, Aojie Chen, Caixia Gao","doi":"10.1016/j.cell.2025.06.014","DOIUrl":"https://doi.org/10.1016/j.cell.2025.06.014","url":null,"abstract":"Protein engineering enables artificial protein evolution through iterative sequence changes, but current methods often suffer from low success rates and limited cost effectiveness. Here, we present AI-informed constraints for protein engineering (AiCE), an approach that facilitates efficient protein evolution using generic protein inverse folding models, reducing dependence on human heuristics and task-specific models. By sampling sequences from inverse folding models and integrating structural and evolutionary constraints, AiCE identifies high-fitness single and multi-mutations. We applied AiCE to eight protein engineering tasks, including deaminases, a nuclear localization sequence, nucleases, and a reverse transcriptase, spanning proteins from tens to thousands of residues, with success rates of 11%–88%. We also developed base editors for precision medicine and agriculture, including enABE8e (5-bp window), enSdd6-CBE (1.3-fold improved fidelity), and enDdd1-DdCBE (up to 14.3-fold enhanced mitochondrial activity). These results demonstrate that AiCE is a versatile, user-friendly mutation-design method that outperforms conventional approaches in efficiency, scalability, and generalizability.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"685 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2025-07-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144568948","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 : 2025-07-01DOI: 10.1016/j.cell.2025.06.006
Laszlo Radnai, Erica J. Young, Carlos Kikuti, Katalin Toth, Minghai Zhou, Madalyn Hafenbreidel, Rebecca F. Stremel, Li Lin, Paolo Pasetto, Xiaomin Jin, Aagam Patel, Michael Conlon, Sherri B. Briggs, Leïla Heidsieck, H. Lee Sweeney, James Sellers, Teresa Krieger-Burke, William H. Martin, Jay Sisco, Steven Young, Courtney A. Miller
{"title":"Development of clinically viable non-muscle myosin II small molecule inhibitors","authors":"Laszlo Radnai, Erica J. Young, Carlos Kikuti, Katalin Toth, Minghai Zhou, Madalyn Hafenbreidel, Rebecca F. Stremel, Li Lin, Paolo Pasetto, Xiaomin Jin, Aagam Patel, Michael Conlon, Sherri B. Briggs, Leïla Heidsieck, H. Lee Sweeney, James Sellers, Teresa Krieger-Burke, William H. Martin, Jay Sisco, Steven Young, Courtney A. Miller","doi":"10.1016/j.cell.2025.06.006","DOIUrl":"https://doi.org/10.1016/j.cell.2025.06.006","url":null,"abstract":"Non-muscle myosin II (NMII), a molecular motor that regulates critical processes such as cytokinesis and neuronal plasticity, has substantial therapeutic potential. However, translating this potential to <em>in vivo</em> use has been hampered by a lack of selective tools. The most prototypical non-selective inhibitor inactivates both NMII and cardiac muscle myosin II (CMII), a key regulator of heart function. Using rational drug design, we developed a series of NMII inhibitors that markedly improve tolerability by selectively targeting NMII over CMII, including MT-228 and clinical candidate MT-110. MT-228 and MT-110 have excellent properties, including high brain penetration and efficacy in preclinical models of methamphetamine use disorder (MUD), which has no current FDA-approved therapies. The structure of MT-228 bound to myosin II provides insight into its selectivity for NMII over CMII. The broad therapeutic windows of these NMII inhibitors provide valuable tools for the scientific community and a promising clinical candidate for the treatment of MUD.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"36 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144520832","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":"Recessive epistasis of a synonymous mutation confers cucumber domestication through epitranscriptomic regulation","authors":"Tongxu Xin, Zhen Zhang, Yueying Zhang, Xutong Li, Shenhao Wang, Guanqun Wang, Haoxuan Li, Bowen Wang, Mengzhuo Zhang, Wenjing Li, Haojie Tian, Zhonghua Zhang, Yu-Lan Xiao, Weixin Tang, Chuan He, Yiliang Ding, Sanwen Huang, Xueyong Yang","doi":"10.1016/j.cell.2025.06.007","DOIUrl":"https://doi.org/10.1016/j.cell.2025.06.007","url":null,"abstract":"Synonymous mutations, once known as “silent” mutations, are increasingly attracting the interest of biologists. Although they may affect transcriptional or post-transcriptional processes, their impact on biological traits remains under-investigated, particularly at the organismal level. Here, we identified two closely linked, epistatically interacting genes: <em>YTH1</em>, an RNA <em>N</em><sup>6</sup>-methyladenosine (m<sup>6</sup>A) reader, and <em>ACS2</em>, an <em>aminocyclopropane-1-carboxylic acid</em> (ACC) synthase, which contribute to cucumber fruit length domestication. The causative mutation in <em>ACS2</em> is a synonymous substitution at 1287C>T. In wild cucumber, <em>ACS2</em><sup><em>1287C</em></sup> results in m<sup>6</sup>A modification on nearby adenosine residues and the formation of loose RNA structural conformations. YTH1 recognizes the m<sup>6</sup>A modification, alters the folding equilibrium toward the weakest RNA structural conformation, and increases the <em>ACS2</em> protein level, resulting in shorter fruit. In cultivated cucumber, <em>ACS2</em><sup><em>1287T</em></sup> disrupts m<sup>6</sup>A methylation and forms compact RNA structural conformations, leading to attenuated protein production and fruit elongation. This study provides genetic evidence of synonymous variation shaping a biological trait through epitranscriptomic regulations.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"27 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144520775","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 : 2025-06-30DOI: 10.1016/j.cell.2025.06.004
Jasper Du, Hui Chen, Jia You, Wei Hu, Jia Liu, Qiao Lu, Yong Zhang, Jie Gao, Meng-ju Lin, Connor James Ryan Foster, Eric Rao, Michael Cammer, Weiwei Yin, Shohei Koide, Catherine Pei-ju Lu, Wei Chen, Jizhong Lou, Jun Wang
{"title":"Proximity between LAG-3 and the T cell receptor guides suppression of T cell activation and autoimmunity","authors":"Jasper Du, Hui Chen, Jia You, Wei Hu, Jia Liu, Qiao Lu, Yong Zhang, Jie Gao, Meng-ju Lin, Connor James Ryan Foster, Eric Rao, Michael Cammer, Weiwei Yin, Shohei Koide, Catherine Pei-ju Lu, Wei Chen, Jizhong Lou, Jun Wang","doi":"10.1016/j.cell.2025.06.004","DOIUrl":"https://doi.org/10.1016/j.cell.2025.06.004","url":null,"abstract":"Therapeutically targeting pathogenic T cells in autoimmune diseases has been challenging. Although LAG-3, an inhibitory checkpoint receptor specifically expressed on activated T cells, is known to bind to major histocompatibility complex class II (MHC class II), we demonstrate that MHC class II interaction alone is insufficient for optimal LAG-3 function. Instead, LAG-3’s spatial proximity to T cell receptor (TCR) but not CD4 co-receptor, facilitated by cognate peptide-MHC class II, is crucial in mediating CD4<sup>+</sup> T cell suppression. Mechanistically, LAG-3 forms condensate with TCR signaling component CD3ε through its intracellular FSAL motif, disrupting CD3ε/lymphocyte-specific protein kinase (Lck) association. To exploit LAG-3’s proximity to TCR and maximize LAG-3-dependent T cell suppression, we develop an Fc-attenuated LAG-3/TCR inhibitory bispecific antibody to bypass the requirement of cognate peptide-MHC class II. This approach allows for potent suppression of both CD4<sup>+</sup> and CD8<sup>+</sup> T cells and effectively alleviates autoimmune symptoms in mouse models. Our findings reveal an intricate and conditional checkpoint modulatory mechanism and highlight targeting of LAG-3/TCR <em>cis</em>-proximity for T cell-driven autoimmune diseases lacking effective and well-tolerated immunotherapies.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"38 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2025-06-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144516358","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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