Pub Date : 2025-12-10DOI: 10.1038/s41551-025-01569-4
Changrui Yang, Shanni Guo, Kaiyan Ye, Yizong Ding, Xingzhong Zhao, Yucheng T. Yang, Bowen Sun, Shuyi Qian, Mei-Chun Cai, Luyan Liu, Libing Xiang, Xia Yin, Xing-Ming Zhao, Jieyi Wang, Jiwei Zhang, Wen Di, Guanglei Zhuang, Fan Yang
Immunologically unresponsive tumours often resist immune checkpoint inhibitors due to the low abundance of tumour-specific T cells and an immunosuppressive microenvironment, despite pronounced infiltration of non-tumour-specific (bystander) T cells. Here we analysed single-cell RNA sequencing data from 300 patients across 17 tumour types, identifying abundant but functionally restrained bystander T cells in multiple malignancies, including ovarian and colorectal cancer. To enhance antitumour immunity in such contexts, we engineered B7H3xCD3xPDL1, a trispecific immunoglobulin-based T cell engager targeting B7H3, CD3 and PDL1, to redirect T cells while mitigating immunosuppression. Functional validation in co-culture systems, patient-derived tumour suspensions and fragments, and humanized mouse models showed T cell activation and tumour killing. Imaging cytometry and single-cell transcriptomics revealed IFNγ-dependent macrophage reprogramming and IL-15 secretion, establishing a feed-forward loop that augments T cell functionality. A machine learning model trained on ex vivo cytotoxicity and transcriptomic data predicted patient responsiveness, supporting data-driven clinical stratification for solid tumour immunotherapy.
{"title":"A trispecific antibody engaging T cells with tumour and myeloid cells augments antitumour immunity","authors":"Changrui Yang, Shanni Guo, Kaiyan Ye, Yizong Ding, Xingzhong Zhao, Yucheng T. Yang, Bowen Sun, Shuyi Qian, Mei-Chun Cai, Luyan Liu, Libing Xiang, Xia Yin, Xing-Ming Zhao, Jieyi Wang, Jiwei Zhang, Wen Di, Guanglei Zhuang, Fan Yang","doi":"10.1038/s41551-025-01569-4","DOIUrl":"https://doi.org/10.1038/s41551-025-01569-4","url":null,"abstract":"Immunologically unresponsive tumours often resist immune checkpoint inhibitors due to the low abundance of tumour-specific T cells and an immunosuppressive microenvironment, despite pronounced infiltration of non-tumour-specific (bystander) T cells. Here we analysed single-cell RNA sequencing data from 300 patients across 17 tumour types, identifying abundant but functionally restrained bystander T cells in multiple malignancies, including ovarian and colorectal cancer. To enhance antitumour immunity in such contexts, we engineered B7H3xCD3xPDL1, a trispecific immunoglobulin-based T cell engager targeting B7H3, CD3 and PDL1, to redirect T cells while mitigating immunosuppression. Functional validation in co-culture systems, patient-derived tumour suspensions and fragments, and humanized mouse models showed T cell activation and tumour killing. Imaging cytometry and single-cell transcriptomics revealed IFNγ-dependent macrophage reprogramming and IL-15 secretion, establishing a feed-forward loop that augments T cell functionality. A machine learning model trained on ex vivo cytotoxicity and transcriptomic data predicted patient responsiveness, supporting data-driven clinical stratification for solid tumour immunotherapy.","PeriodicalId":19063,"journal":{"name":"Nature Biomedical Engineering","volume":"144 1","pages":""},"PeriodicalIF":28.1,"publicationDate":"2025-12-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145711553","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-08DOI: 10.1038/s41551-025-01589-0
Yuanhao Qu, Kaixuan Huang, Ming Yin, Kanghong Zhan, Dyllan Liu, Di Yin, Henry C. Cousins, William A. Johnson, Xiaotong Wang, Mihir Shah, Russ B. Altman, Denny Zhou, Mengdi Wang, Le Cong
{"title":"Publisher Correction: CRISPR-GPT for agentic automation of gene-editing experiments","authors":"Yuanhao Qu, Kaixuan Huang, Ming Yin, Kanghong Zhan, Dyllan Liu, Di Yin, Henry C. Cousins, William A. Johnson, Xiaotong Wang, Mihir Shah, Russ B. Altman, Denny Zhou, Mengdi Wang, Le Cong","doi":"10.1038/s41551-025-01589-0","DOIUrl":"10.1038/s41551-025-01589-0","url":null,"abstract":"","PeriodicalId":19063,"journal":{"name":"Nature Biomedical Engineering","volume":"10 2","pages":"405-405"},"PeriodicalIF":26.8,"publicationDate":"2025-12-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41551-025-01589-0.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145704662","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-08DOI: 10.1038/s41551-025-01536-z
Guy H Wilson,Elias A Stein,Foram Kamdar,Donald T Avansino,Tsam Kiu Pun,Ronnie Gross,Tommy Hosman,Tyler Singer-Clark,Anastasia Kapitonava,Leigh R Hochberg,John D Simeral,Krishna V Shenoy,Shaul Druckmann,Jaimie M Henderson,Francis R Willett
Intracortical brain-computer interfaces (iBCIs) require frequent recalibration to maintain robust performance due to changes in neural activity that accumulate over time, which result in periods when users cannot use their device. Here we introduce a hidden Markov model to infer which targets users are moving towards during iBCI use and we retrain the system using these inferred targets, enabling unsupervised adaptation to changing neural activity. Our approach outperforms distribution alignment methods in large-scale, closed-loop simulations over two months, as well as in a closed loop with a human iBCI user over one month. Leveraging an offline dataset spanning five years of iBCI recordings, we show how target inference recalibration methods appear capable of long-term unsupervised recalibration, whereas recently proposed data-distribution-matching approaches appear to accumulate compounding errors over time. We show offline that our approach performs well on freeform datasets of a person using a home computer with an iBCI. Our results demonstrate the use of task structure to bootstrap a noisy decoder into a highly performant one, thereby overcoming one of the major barriers to clinically translating BCIs.
{"title":"Long-term unsupervised recalibration of cursor-based intracortical brain-computer interfaces using a hidden Markov model.","authors":"Guy H Wilson,Elias A Stein,Foram Kamdar,Donald T Avansino,Tsam Kiu Pun,Ronnie Gross,Tommy Hosman,Tyler Singer-Clark,Anastasia Kapitonava,Leigh R Hochberg,John D Simeral,Krishna V Shenoy,Shaul Druckmann,Jaimie M Henderson,Francis R Willett","doi":"10.1038/s41551-025-01536-z","DOIUrl":"https://doi.org/10.1038/s41551-025-01536-z","url":null,"abstract":"Intracortical brain-computer interfaces (iBCIs) require frequent recalibration to maintain robust performance due to changes in neural activity that accumulate over time, which result in periods when users cannot use their device. Here we introduce a hidden Markov model to infer which targets users are moving towards during iBCI use and we retrain the system using these inferred targets, enabling unsupervised adaptation to changing neural activity. Our approach outperforms distribution alignment methods in large-scale, closed-loop simulations over two months, as well as in a closed loop with a human iBCI user over one month. Leveraging an offline dataset spanning five years of iBCI recordings, we show how target inference recalibration methods appear capable of long-term unsupervised recalibration, whereas recently proposed data-distribution-matching approaches appear to accumulate compounding errors over time. We show offline that our approach performs well on freeform datasets of a person using a home computer with an iBCI. Our results demonstrate the use of task structure to bootstrap a noisy decoder into a highly performant one, thereby overcoming one of the major barriers to clinically translating BCIs.","PeriodicalId":19063,"journal":{"name":"Nature Biomedical Engineering","volume":"79 1","pages":""},"PeriodicalIF":28.1,"publicationDate":"2025-12-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145704661","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-04DOI: 10.1038/s41551-025-01567-6
{"title":"A bioorthogonal ligation system induces controlled proximity for cancer therapy.","authors":"","doi":"10.1038/s41551-025-01567-6","DOIUrl":"https://doi.org/10.1038/s41551-025-01567-6","url":null,"abstract":"","PeriodicalId":19063,"journal":{"name":"Nature Biomedical Engineering","volume":"10 1","pages":""},"PeriodicalIF":28.1,"publicationDate":"2025-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145674447","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-28DOI: 10.1038/s41551-025-01552-z
C. Andrew Stewart, Shaji Daniel, Elizabeth J. Curvino, Yi Zhang, Hafsa Kamboh, Kirill Sergueev, Minhtran N. Casi, Adam Chowdhury, Heng Xu, Youqiang Li, Mehmet Tosun, Matthew T. Duvernay, Yufei Shan, Mame Djigal, Maria Kireeva, Jennifer L. Biaksangi, Taylor Glassband, Fevzi Altuntas, Tuğçe Nur Yiğenoğlu, Ralph Boccia, Jesus Bardeja, Tamna Wangjam, Michael S. Singer, Murat V. Kalayoglu, Metin Kurtoglu, Albina Benson, Emily P. English, Lisa H. Tostanoski, Milos D. Miljkovic, Christopher M. Jewell
{"title":"mRNA engineering of allogeneic mesenchymal stem cells enables coordinated delivery of T cell engagers and immunotherapeutic cues","authors":"C. Andrew Stewart, Shaji Daniel, Elizabeth J. Curvino, Yi Zhang, Hafsa Kamboh, Kirill Sergueev, Minhtran N. Casi, Adam Chowdhury, Heng Xu, Youqiang Li, Mehmet Tosun, Matthew T. Duvernay, Yufei Shan, Mame Djigal, Maria Kireeva, Jennifer L. Biaksangi, Taylor Glassband, Fevzi Altuntas, Tuğçe Nur Yiğenoğlu, Ralph Boccia, Jesus Bardeja, Tamna Wangjam, Michael S. Singer, Murat V. Kalayoglu, Metin Kurtoglu, Albina Benson, Emily P. English, Lisa H. Tostanoski, Milos D. Miljkovic, Christopher M. Jewell","doi":"10.1038/s41551-025-01552-z","DOIUrl":"https://doi.org/10.1038/s41551-025-01552-z","url":null,"abstract":"","PeriodicalId":19063,"journal":{"name":"Nature Biomedical Engineering","volume":"18 1","pages":""},"PeriodicalIF":28.1,"publicationDate":"2025-11-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145611564","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-24DOI: 10.1038/s41551-025-01592-5
Jan A. Rath, Lucas S. P. Rudden, Nazila Nouraee, Tiffany X. Y. Que, Christine Von Gunten, Cynthia Perez, Flora Birch, Yashashvi Bhugowon, Andreas Fueglistaler, Aisima Chatzi Souleiman, Patrick Barth, Caroline Arber
{"title":"Author Correction: Computational design of synthetic receptors with programmable signalling activity for enhanced cancer T cell therapy","authors":"Jan A. Rath, Lucas S. P. Rudden, Nazila Nouraee, Tiffany X. Y. Que, Christine Von Gunten, Cynthia Perez, Flora Birch, Yashashvi Bhugowon, Andreas Fueglistaler, Aisima Chatzi Souleiman, Patrick Barth, Caroline Arber","doi":"10.1038/s41551-025-01592-5","DOIUrl":"https://doi.org/10.1038/s41551-025-01592-5","url":null,"abstract":"","PeriodicalId":19063,"journal":{"name":"Nature Biomedical Engineering","volume":"1 1","pages":""},"PeriodicalIF":28.1,"publicationDate":"2025-11-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145583018","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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