Pub Date : 2025-10-21DOI: 10.1038/s41551-025-01527-0
Ángel Ramírez-Fernández,Alexander J Dimitri,Fang Chen,Robert Bartoszek,Gregory M Chen,Laura Córdoba-Espejo,Yuqi Zhou,Yun-Hsin Tang,Chien-Ting Lin,Reyes Acosta,John Scholler,Guido Ghilardi,Patrizia Porazzi,Mireia Pellicer,Núria Profitós-Pelejà,Stefan K Barta,Anne Chew,Julie K Jadlowsky,Vanessa E Gonzalez,Donald L Siegel,Bruce L Levine,Gaël Roué,Marco Ruella,Michael T Lotze,Carl H June,James L Riley,Joseph A Fraietta
Immune-based cell therapy offers a promising approach to cancer treatment. While autologous chimeric antigen receptor (CAR) T cells have shown success, production is time-consuming, costly and patient specific. Gamma-delta (γδ) T cells are promising for 'off-the-shelf' CAR T cell therapy. However, clinical translation of γδ CAR T cells is hampered by low frequency, resistance to genetic manipulation and advanced differentiation after expansion, limiting therapeutic feasibility. Here we demonstrate a method for in vitro activation and expansion of peripheral blood γδ T cells, facilitating high rates of gene editing and efficient CAR integration. Using artificial antigen-presenting cells, we produce minimally differentiated, highly functional γδ CAR T cells. By targeting a US Food and Drug Administration-approved CD19 CAR to the CCR5 locus, we generate CCR5-deficient γδ CD19 CAR T cells (γδ CCR5KI-CAR19), which demonstrated resistance to HIV-mediated depletion and robust antitumour responses against B cell lymphoma and leukaemia. γδ CCR5KI-CAR19 T cells enable the immunotherapy of HIV-associated B cell malignancies. These studies provide preclinical evidence supporting large-scale development of potent allogeneic γδ CAR T cells for diverse immunotherapies.
免疫细胞疗法为癌症治疗提供了一种很有前途的方法。虽然自体嵌合抗原受体（CAR） T细胞已经取得了成功，但生产过程耗时、成本高且患者特异性强。γ - δ (γδ) T细胞有望用于“现成的”CAR - T细胞治疗。然而，γδ CAR - T细胞的临床翻译受到低频、对基因操作的抗性和扩增后的晚期分化的阻碍，限制了治疗的可行性。在这里，我们展示了一种体外激活和扩增外周血γδ T细胞的方法，促进了高速率的基因编辑和高效的CAR整合。利用人工抗原呈递细胞，我们生产了分化程度最低、功能强大的γδ CAR - T细胞。通过将美国食品和药物管理局批准的CD19 CAR靶向CCR5位点，我们产生了CCR5缺陷的γδ CD19 CAR - T细胞（γδ CCR5KI-CAR19），其表现出对hiv介导的衰竭的抵抗和对B细胞淋巴瘤和白血病的强大抗肿瘤反应。γδ CCR5KI-CAR19 T细胞能够免疫治疗hiv相关的B细胞恶性肿瘤。这些研究为大规模开发有效的同种异体γδ CAR - T细胞用于多种免疫疗法提供了临床前证据。
{"title":"CCR5-targeted allogeneic gamma-delta CD19 chimeric antigen receptor T cells for HIV-associated B cell-malignancy immunotherapy.","authors":"Ángel Ramírez-Fernández,Alexander J Dimitri,Fang Chen,Robert Bartoszek,Gregory M Chen,Laura Córdoba-Espejo,Yuqi Zhou,Yun-Hsin Tang,Chien-Ting Lin,Reyes Acosta,John Scholler,Guido Ghilardi,Patrizia Porazzi,Mireia Pellicer,Núria Profitós-Pelejà,Stefan K Barta,Anne Chew,Julie K Jadlowsky,Vanessa E Gonzalez,Donald L Siegel,Bruce L Levine,Gaël Roué,Marco Ruella,Michael T Lotze,Carl H June,James L Riley,Joseph A Fraietta","doi":"10.1038/s41551-025-01527-0","DOIUrl":"https://doi.org/10.1038/s41551-025-01527-0","url":null,"abstract":"Immune-based cell therapy offers a promising approach to cancer treatment. While autologous chimeric antigen receptor (CAR) T cells have shown success, production is time-consuming, costly and patient specific. Gamma-delta (γδ) T cells are promising for 'off-the-shelf' CAR T cell therapy. However, clinical translation of γδ CAR T cells is hampered by low frequency, resistance to genetic manipulation and advanced differentiation after expansion, limiting therapeutic feasibility. Here we demonstrate a method for in vitro activation and expansion of peripheral blood γδ T cells, facilitating high rates of gene editing and efficient CAR integration. Using artificial antigen-presenting cells, we produce minimally differentiated, highly functional γδ CAR T cells. By targeting a US Food and Drug Administration-approved CD19 CAR to the CCR5 locus, we generate CCR5-deficient γδ CD19 CAR T cells (γδ CCR5KI-CAR19), which demonstrated resistance to HIV-mediated depletion and robust antitumour responses against B cell lymphoma and leukaemia. γδ CCR5KI-CAR19 T cells enable the immunotherapy of HIV-associated B cell malignancies. These studies provide preclinical evidence supporting large-scale development of potent allogeneic γδ CAR T cells for diverse immunotherapies.","PeriodicalId":19063,"journal":{"name":"Nature Biomedical Engineering","volume":"18 1","pages":""},"PeriodicalIF":28.1,"publicationDate":"2025-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145338533","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 : 2025-10-21DOI: 10.1038/s41551-025-01479-5
Kellen Chen,Michelle Griffin,Dominic Henn,Katharina S Berryman,Dharshan Sivaraj,Hudson C Kussie,Clark A Bonham,Eamonn McKenna,Maria Gracia Mora Pinos,Abdelrahman M Alsharif,Fidel Saenz,Nicholas E Matthews,Maisam Jafri,Jonathan P Yasmeh,Mimi R Borrelli,Savana Huskins,Sydney Steele,Amelia B Knochel,Mansi Singh,Andrew C Hostler,Melissa Leeolou,William W Hahn,David Perrault,Darren Abbas,Nicholas Guardino,Benjamin Thomas,Janos A Barrera,Chikage Noishiki,Artem A Trotsyuk,Jagannath Padmanabhan,Michael Januszyk,Mohammad Khreiss,Michael T Longaker,Geoffrey C Gurtner
In response to injury, a variety of different cells are recruited to sites of injury to facilitate healing. Recent studies have examined the importance of the heterogeneity of tissue resident fibroblasts and mechanical signalling pathways in healing and fibrosis. However, tissue repair and the inflammatory response also involves blood cells that are recruited from the circulation. Here we identify mechanoresponsive myeloid subpopulations present in scar and unwounded skin. We then modulate these subpopulations by manipulating mechanical strain in vivo and in vitro and find that specifically targeting myeloid mechanical signalling is sufficient to reduce the pro-fibrotic myeloid subpopulations and restore the native, anti-inflammatory subpopulations. In addition, myeloid-specific mechanotransduction ablation also downregulates downstream pro-fibrotic fibroblast transcriptional profiles, reducing scar formation. As inflammatory cells circulate and home to injury sites during the initial healing phases in all organs, focusing on mechanoresponsive myeloid subpopulations may generate additional directions for systemic immunomodulatory therapies to target fibrosis and other diseases across other internal organ systems.
{"title":"Targeting circulating mechanoresponsive monocytes and macrophages to reduce fibrosis.","authors":"Kellen Chen,Michelle Griffin,Dominic Henn,Katharina S Berryman,Dharshan Sivaraj,Hudson C Kussie,Clark A Bonham,Eamonn McKenna,Maria Gracia Mora Pinos,Abdelrahman M Alsharif,Fidel Saenz,Nicholas E Matthews,Maisam Jafri,Jonathan P Yasmeh,Mimi R Borrelli,Savana Huskins,Sydney Steele,Amelia B Knochel,Mansi Singh,Andrew C Hostler,Melissa Leeolou,William W Hahn,David Perrault,Darren Abbas,Nicholas Guardino,Benjamin Thomas,Janos A Barrera,Chikage Noishiki,Artem A Trotsyuk,Jagannath Padmanabhan,Michael Januszyk,Mohammad Khreiss,Michael T Longaker,Geoffrey C Gurtner","doi":"10.1038/s41551-025-01479-5","DOIUrl":"https://doi.org/10.1038/s41551-025-01479-5","url":null,"abstract":"In response to injury, a variety of different cells are recruited to sites of injury to facilitate healing. Recent studies have examined the importance of the heterogeneity of tissue resident fibroblasts and mechanical signalling pathways in healing and fibrosis. However, tissue repair and the inflammatory response also involves blood cells that are recruited from the circulation. Here we identify mechanoresponsive myeloid subpopulations present in scar and unwounded skin. We then modulate these subpopulations by manipulating mechanical strain in vivo and in vitro and find that specifically targeting myeloid mechanical signalling is sufficient to reduce the pro-fibrotic myeloid subpopulations and restore the native, anti-inflammatory subpopulations. In addition, myeloid-specific mechanotransduction ablation also downregulates downstream pro-fibrotic fibroblast transcriptional profiles, reducing scar formation. As inflammatory cells circulate and home to injury sites during the initial healing phases in all organs, focusing on mechanoresponsive myeloid subpopulations may generate additional directions for systemic immunomodulatory therapies to target fibrosis and other diseases across other internal organ systems.","PeriodicalId":19063,"journal":{"name":"Nature Biomedical Engineering","volume":"12 1","pages":""},"PeriodicalIF":28.1,"publicationDate":"2025-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145338534","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 : 2025-10-17DOI: 10.1038/s41551-025-01521-6
Min Zhou,Yan Wang,Bin Yang,Yang Zhang,Ling Zhong,Kaiyao Hu,Wendan Pu,Gaoxing Luo,Jianxiang Zhang
Uncontrolled and sustained inflammation is inextricably associated with the pathogenesis of numerous diseases. However, there is still demand for effective and safe anti-inflammatory therapies. Here we report a potent anti-inflammatory macromolecular therapy named HPL, created by conjugating polyethylene glycol and luminol onto a multivalent and hydrolysable cyclic structure. Leveraging its amphiphilic nature, HPL can spontaneously self-assemble into micelles capable of targeting inflamed tissues and localizing in inflammatory cells. In mice with acute lung, kidney and liver injuries, as well as endotoxaemia, HPL shows anti-inflammatory effects that rivals or surpasses those of two commonly used anti-inflammatory drugs. HPL micelles can act as bioactive and inflammation-responsive carriers for site-specific delivery to release anti-inflammatory drugs. Mechanistically, HPL exerts its anti-inflammatory activity mainly by inhibiting the IL-6/JAK2/STAT3 signalling pathway. HPL shows favourable safety profiles in mice at doses at least 5-fold higher than those used in therapeutic studies. These findings suggest that HPL holds great promise as a highly potent, cost-effective and safe JAK2 inhibitor for treating various diseases associated with inflammation.
{"title":"Engineering a macromolecular JAK inhibitor for treating acute inflammation and endotoxaemia.","authors":"Min Zhou,Yan Wang,Bin Yang,Yang Zhang,Ling Zhong,Kaiyao Hu,Wendan Pu,Gaoxing Luo,Jianxiang Zhang","doi":"10.1038/s41551-025-01521-6","DOIUrl":"https://doi.org/10.1038/s41551-025-01521-6","url":null,"abstract":"Uncontrolled and sustained inflammation is inextricably associated with the pathogenesis of numerous diseases. However, there is still demand for effective and safe anti-inflammatory therapies. Here we report a potent anti-inflammatory macromolecular therapy named HPL, created by conjugating polyethylene glycol and luminol onto a multivalent and hydrolysable cyclic structure. Leveraging its amphiphilic nature, HPL can spontaneously self-assemble into micelles capable of targeting inflamed tissues and localizing in inflammatory cells. In mice with acute lung, kidney and liver injuries, as well as endotoxaemia, HPL shows anti-inflammatory effects that rivals or surpasses those of two commonly used anti-inflammatory drugs. HPL micelles can act as bioactive and inflammation-responsive carriers for site-specific delivery to release anti-inflammatory drugs. Mechanistically, HPL exerts its anti-inflammatory activity mainly by inhibiting the IL-6/JAK2/STAT3 signalling pathway. HPL shows favourable safety profiles in mice at doses at least 5-fold higher than those used in therapeutic studies. These findings suggest that HPL holds great promise as a highly potent, cost-effective and safe JAK2 inhibitor for treating various diseases associated with inflammation.","PeriodicalId":19063,"journal":{"name":"Nature Biomedical Engineering","volume":"16 1","pages":""},"PeriodicalIF":28.1,"publicationDate":"2025-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145311252","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 : 2025-10-17DOI: 10.1038/s41551-025-01540-3
Diana Romero
{"title":"Next-generation anti-Aβ antibodies show promise in a mouse model of Alzheimer disease","authors":"Diana Romero","doi":"10.1038/s41551-025-01540-3","DOIUrl":"10.1038/s41551-025-01540-3","url":null,"abstract":"","PeriodicalId":19063,"journal":{"name":"Nature Biomedical Engineering","volume":"9 10","pages":"1564-1564"},"PeriodicalIF":26.8,"publicationDate":"2025-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145311457","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 : 2025-10-17DOI: 10.1038/s41551-025-01551-0
We take a look at how scientific articles have evolved over time and envision possible changes to how research findings are communicated in the age of digital media and artificial intelligence.
{"title":"The ever-changing communication of scientific discovery","authors":"","doi":"10.1038/s41551-025-01551-0","DOIUrl":"10.1038/s41551-025-01551-0","url":null,"abstract":"We take a look at how scientific articles have evolved over time and envision possible changes to how research findings are communicated in the age of digital media and artificial intelligence.","PeriodicalId":19063,"journal":{"name":"Nature Biomedical Engineering","volume":"9 10","pages":"1559-1560"},"PeriodicalIF":26.8,"publicationDate":"2025-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41551-025-01551-0.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145311458","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 : 2025-10-17DOI: 10.1038/s41551-025-01495-5
Jiadong Zhang,Yonghao Li,Zheren Li,Zhiming Cui,Pinxiong Li,Jun Li,Zhen Li,Yu Xie,Kannie W Y Chan,Qinrong Zhang,Zhenhui Li,Dinggang Shen
Accurate assessment of human epidermal growth factor receptor 2 (HER2) status is crucial for effective breast cancer treatment planning and improved patient outcomes. Traditional needle biopsies, limited in tissue sampling, often lead to inaccurate assessments due to intratumoural heterogeneity. Here, to address this, we introduce the deep-learning-based HER2 multimodal alignment and prediction (MAP) model, which leverages pretreatment multimodal breast cancer images for a more comprehensive reflection of tumour characteristics and provides more accurate HER2 status prediction. We develop patient response MAP models to demonstrate the HER2 prediction performance of our model compared with needle biopsies from patients receiving neoadjuvant therapy. A large-scale multimodal breast cancer dataset from 4 centres, consisting of 14,472 images from 6,991 cases, is adopted in this study, and the results consistently demonstrate the superiority of our HER2 MAP model in predicting patient response. These findings highlight the substantial advantages of our HER2 predictions. Our study provides physicians with a crucial tool for informed clinical decisions and treatment plans, aiming to improve outcomes in patients with breast cancer.
{"title":"Deep-learning-based HER2 status assessment from multimodal breast cancer data predicts neoadjuvant therapy response.","authors":"Jiadong Zhang,Yonghao Li,Zheren Li,Zhiming Cui,Pinxiong Li,Jun Li,Zhen Li,Yu Xie,Kannie W Y Chan,Qinrong Zhang,Zhenhui Li,Dinggang Shen","doi":"10.1038/s41551-025-01495-5","DOIUrl":"https://doi.org/10.1038/s41551-025-01495-5","url":null,"abstract":"Accurate assessment of human epidermal growth factor receptor 2 (HER2) status is crucial for effective breast cancer treatment planning and improved patient outcomes. Traditional needle biopsies, limited in tissue sampling, often lead to inaccurate assessments due to intratumoural heterogeneity. Here, to address this, we introduce the deep-learning-based HER2 multimodal alignment and prediction (MAP) model, which leverages pretreatment multimodal breast cancer images for a more comprehensive reflection of tumour characteristics and provides more accurate HER2 status prediction. We develop patient response MAP models to demonstrate the HER2 prediction performance of our model compared with needle biopsies from patients receiving neoadjuvant therapy. A large-scale multimodal breast cancer dataset from 4 centres, consisting of 14,472 images from 6,991 cases, is adopted in this study, and the results consistently demonstrate the superiority of our HER2 MAP model in predicting patient response. These findings highlight the substantial advantages of our HER2 predictions. Our study provides physicians with a crucial tool for informed clinical decisions and treatment plans, aiming to improve outcomes in patients with breast cancer.","PeriodicalId":19063,"journal":{"name":"Nature Biomedical Engineering","volume":"19 1","pages":""},"PeriodicalIF":28.1,"publicationDate":"2025-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145311454","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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