Science Translational Medicine最新文献

{"title":"Leucine-rich α-2-glycoprotein 1 initiates the onset of diabetic retinopathy in mice","authors":"Giulia De Rossi,&nbsp;Ao-wang Qiu,&nbsp;Maxime Berg,&nbsp;Thomas Burgoyne,&nbsp;Andrea Martello,&nbsp;Marlene E. Da Vitoria Lobo,&nbsp;Matteo Rizzi,&nbsp;Sophie Mueller,&nbsp;Jack Blackburn,&nbsp;Yuxuan Meng,&nbsp;Simon Walker-Samuel,&nbsp;Rebecca Shipley,&nbsp;Colin J. Chu,&nbsp;Sobha Sivaprasad,&nbsp;John Greenwood,&nbsp;Stephen E. Moss","doi":"10.1126/scitranslmed.adn6047","DOIUrl":"10.1126/scitranslmed.adn6047","url":null,"abstract":"<div >Diabetic retinopathy (DR) is a common complication of diabetes mellitus and a leading cause of visual impairment and blindness in the working-age population. The early stage of the disease is characterized by retinal capillary dysfunction, but the mechanisms whereby hyperglycemia disturbs capillary homeostasis at this initiating stage are poorly understood, posing a barrier to the development of effective early treatments. We used two mouse models of type I diabetes that replicate early features of human retinal vascular pathology. In both the streptozotocin (STZ) model, where hypoinsulinemia is chemically induced, and in the Ins2Akita model, which develops it spontaneously because of a mutation in the insulin gene, we observed early induction of the secreted glycoprotein gene leucine-rich α-2-glycoprotein 1 (<i>Lrg1</i>). Using the Ins2Akita mice, we showed that <i>Lrg1</i> induction preceded that of vascular endothelial growth factor A (<i>Vegfa</i>). LRG1 initiated retinal microvascular dysfunction by modifying transforming growth factor–β (TGFβ) signaling in pericytes, driving transdifferentiation to a more contractile fibrotic phenotype, resulting in narrower capillaries and thickened basement membrane. Using computational modeling, we showed that these early vascular changes impaired retinal blood flow and oxygen delivery, consistent with a defect in visual transduction observed in both models. This early retinal phenotype could be rescued by <i>Lrg1</i> knockout or by treatment with an LRG1 function–blocking antibody in both the STZ and Ins2Akita mice. These results demonstrate that LRG1 is a driver of vascular dysfunction that contributes to the onset of DR and presents itself as a potential preemptive therapeutic target.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"17 821","pages":""},"PeriodicalIF":14.6,"publicationDate":"2025-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145339220","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}

{"title":"Generating functionally stable and antigen-specific Treg cells from effector T cells for cell therapy of inflammatory diseases","authors":"Norihisa Mikami,&nbsp;Ryoji Kawakami,&nbsp;Atsushi Sugimoto,&nbsp;Masaya Arai,&nbsp;Shimon Sakaguchi","doi":"10.1126/scitranslmed.adr6049","DOIUrl":"10.1126/scitranslmed.adr6049","url":null,"abstract":"<div >One strategy for antigen-specific immunosuppression is to convert antigen-specific conventional T (T_conv) cells into Foxp3⁺ regulatory T (T_reg) cells that are as stably suppressive as naturally occurring T_reg (nT_reg) cells. To achieve the conversion in vitro for mice and humans, we induced high Foxp3 expression in antigen- and interleukin-2 (IL-2)–stimulated T_conv cells by CDK8/19 inhibition. We further established T_reg cell–specific epigenetic changes by depriving CD28 costimulation during in vitro T_reg cell induction to specifically promote the expression of T_reg cell signature genes, especially <i>Foxp3</i>. Repeating this process, with intermittent resting cultures containing IL-2 only, enabled efficient conversion of naïve as well as effector/memory CD4⁺ T_conv cells, including T helper 1 (T_H1), T_H2, and T_H17 cells, into Foxp3⁺ T_reg cells. These induced T_reg (iT_reg) cells were similar to nT_reg cells in transcription and epigenetic modification and were functionally and phenotypically stable in vivo. Moreover, they effectively suppressed inflammatory bowel disease and graft-versus-host disease in mouse models. Adoptive cell therapy with such effector/memory T_conv cell–derived, functionally stable, iT_reg cells may represent a strategy to achieve antigen- and disease-specific treatment of immunological diseases.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"17 821","pages":""},"PeriodicalIF":14.6,"publicationDate":"2025-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145339222","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}

{"title":"HIVEP1 aggravates NASH by reprogramming polyamine metabolism in TH17 cells","authors":"Yidan Ren,&nbsp;Xiaoyan Liu,&nbsp;Maoxiao Feng,&nbsp;Jianxiong Zhao,&nbsp;Yangmiao Duan,&nbsp;Guoying Dong,&nbsp;Huiru Gao,&nbsp;Xiaodong Hao,&nbsp;Qin Wang,&nbsp;Jiaying Yao,&nbsp;Zan Yuan,&nbsp;Xu Jing,&nbsp;Jing Wu,&nbsp;Yihai Cao,&nbsp;Yunshan Wang","doi":"10.1126/scitranslmed.adn1150","DOIUrl":"10.1126/scitranslmed.adn1150","url":null,"abstract":"<div >Nonalcoholic steatohepatitis (NASH) is a chronic, inflammatory form of nonalcoholic fatty liver disease (NAFLD) that frequently progresses to cirrhosis and hepatocellular carcinoma (HCC). However, the role of various immune cells in switching from NAFLD to NASH remains elusive. Here, we took an unbiased single-cell assay for transposase accessible chromatin sequencing (scATAC-seq) approach to investigate the cellular composition, gene expression profiling, and causative roles of immune cells in NASH development. T helper 17 (T_H17) cells were identified as the most abundant subpopulation of immune cells in mouse livers with NASH. Further analysis of scATAC-seq data and single-cell RNA sequencing (scRNA-seq) data from the GEO database showed that human immunodeficiency virus type I enhancer binding protein 1 (HIVEP1) is a critical transcription factor (TF) regulating T_H17 cell differentiation and cytokine production. Specific knockout of <i>Hivep1</i> in IL-17A⁺ and CD4⁺ T cells in mice showed impairment of T_H17 cell differentiation and alleviation of NASH development. Mechanistically, HIVEP1 transcriptionally regulated ornithine decarboxylase 1 (ODC1), the rate-limiting enzyme of polyamine metabolism, to modulate T_H17 cell differentiation and cytokine production. Consequently, pharmacological inhibition of ODC1 decreased cytokine production, alleviated inflammation, and prevented the NAFLD-to-NASH transition. Together, our findings elucidate the role of polyamine metabolism in T_H17 cell–mediated NASH development and identify potential therapeutic targets for the effective treatment of NASH.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"17 821","pages":""},"PeriodicalIF":14.6,"publicationDate":"2025-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/scitranslmed.adn1150","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145339219","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}

{"title":"LRRC8A constitutively inhibits pain hypersensitivity in rodent models by restraining NMDA receptor activity at spinal cord synapses","authors":"Meichun Deng,&nbsp;Shao-Rui Chen,&nbsp;Meng-Hua Zhou,&nbsp;Jixiang Zhang,&nbsp;Yuying Huang,&nbsp;Hong Chen,&nbsp;Fernando Benavides,&nbsp;Rajan Sah,&nbsp;Hui-Lin Pan","doi":"10.1126/scitranslmed.adu4879","DOIUrl":"10.1126/scitranslmed.adu4879","url":null,"abstract":"<div >Amplification of nociceptive transmission due to aberrant <i>N</i>-methyl-<span>d</span>-aspartate receptor (NMDAR) hyperactivity in the spinal cord is a key characteristic of neuropathic pain. However, under normal conditions, both presynaptic and postsynaptic NMDARs in the spinal dorsal horn are largely inactive. The mechanisms restraining synaptic NMDAR activity remain enigmatic. Leucine-rich repeat-containing protein 8A (LRRC8A or SWELL1) is an essential component of volume-regulated anion channels typically involved in regulating cell volume. Here, we report that LRRC8A was highly expressed in dorsal root ganglion (DRG) and spinal dorsal horn neurons of rats. Nerve injury persistently reduced LRRC8A expression in the DRG. siRNA-mediated <i>Lrrc8a</i> knockdown in rats or conditional <i>Lrrc8a</i> knockout in DRG neurons in mice consistently caused a pain hypersensitivity phenotype that was readily reversed by NMDAR antagonists. Correspondingly, <i>Lrrc8a</i> knockdown or conditional <i>Lrrc8a</i> knockout in DRG neurons markedly augmented synaptic localization and activity of NMDARs in the spinal cord. LRRC8A interacted with NMDARs in both rat and human spinal cord tissues primarily through its C-terminal LRR domain, restricting the synaptic trafficking and activity of NMDARs. Furthermore, <i>Lrrc8a^ebo/ebo</i> mutant mice, which lack the LRR domain, exhibited NMDAR-dependent pain hypersensitivity and synaptic NMDAR hyperactivity in the spinal cord. Additionally, intrathecal <i>Lrrc8a</i> gene delivery eliminated nerve injury–induced pain hypersensitivity and synaptic NMDAR hyperactivity in rats. These findings reveal that LRRC8A physically interacts with NMDARs and constitutively restricts their synaptic expression in the spinal cord. Reduced LRRC8A-NMDAR interactions increase synaptic expression of “unleashed” NMDARs, contributing to NMDAR hyperactivity and neuropathic pain in rodent models.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"17 821","pages":""},"PeriodicalIF":14.6,"publicationDate":"2025-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145339221","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}

{"title":"Conversion of pathogenic T cells into functionally stabilized Treg cells for antigen-specific immunosuppression in pemphigus vulgaris","authors":"Miho Mukai,&nbsp;Hayato Takahashi,&nbsp;Yoko Kubo,&nbsp;Yasuhiko Asahina,&nbsp;Hisato Iriki,&nbsp;Hisashi Nomura,&nbsp;Aki Kamata,&nbsp;Hiromi Ito,&nbsp;Yutaka Kurebayashi,&nbsp;Jun Yamagami,&nbsp;Norihisa Mikami,&nbsp;Shimon Sakaguchi,&nbsp;Masayuki Amagai","doi":"10.1126/scitranslmed.adq9913","DOIUrl":"10.1126/scitranslmed.adq9913","url":null,"abstract":"<div >Antigen-specific immunotherapy represents one candidate strategy for treating autoimmune diseases such as pemphigus vulgaris, a skin autoimmune disorder mediated by anti–desmoglein 3 (Dsg3) autoantibodies. We developed a therapeutic strategy by which Dsg3-specific pathogenic autoreactive CD4⁺ T cells were converted in vitro into functionally stable Foxp3⁺ regulatory T (T_reg) cells, designated stable and functional induced T_reg (S/F-iT_reg) cells. The conversion was achieved by pharmacological induction of Foxp3 and costimulation-dependent installation of T_reg cell–specific epigenetic changes. In an animal model of pemphigus vulgaris, the Dsg3-specific S/F-iT_reg cells expanded specifically in the skin-draining lymph nodes through recognition of endogenous Dsg3. They selectively inhibited Dsg3-specific T follicular helper cell and B cell proliferation and, consequently, anti-Dsg3 autoantibody formation, without affecting the total B cell population, thereby mitigating disease progression without inducing systemic immunosuppression. Human S/F-iT_reg cells with similar functions could also be efficiently generated from peripheral blood T cells of patients with pemphigus vulgaris. This study demonstrates that pathogenic autoreactive T cells can be converted into disease-specific T_reg cells retaining antigen specificity, enabling antigen- and disease-specific treatment of autoimmune disease.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"17 821","pages":""},"PeriodicalIF":14.6,"publicationDate":"2025-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145339223","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}

{"title":"An intramuscular prime and mucosal boost vaccine regimen protects against lethal clade 2.3.4.4b H5N1 challenge in cynomolgus macaques","authors":"Ninaad Lasrado,&nbsp;Liping Wang,&nbsp;Jinyan Liu,&nbsp;Annika Rössler,&nbsp;Jayeshbhai Chaudhari,&nbsp;Qixin Wang,&nbsp;Jonathon J. Stone,&nbsp;Francisco Armando Granados-Contreras,&nbsp;Jessica Wu,&nbsp;Dalia N. Cabrera-Barragan,&nbsp;Alejandra Waller-Pulido,&nbsp;Samuel J. Nangle,&nbsp;Krishna Shah,&nbsp;Reed Boduch,&nbsp;Siddhesh Warke,&nbsp;Anthony Cook,&nbsp;Christopher Kitajewski,&nbsp;Laurent Pessaint,&nbsp;Mark G. Lewis,&nbsp;Hanne Andersen,&nbsp;Amanda J. Martinot,&nbsp;Ryan P. McNamara,&nbsp;Dan H. Barouch","doi":"10.1126/scitranslmed.ady2282","DOIUrl":"10.1126/scitranslmed.ady2282","url":null,"abstract":"<div >The H5N1 clade 2.3.4.4b avian influenza virus outbreak in poultry and dairy cattle is a potential pandemic threat for humans. A safe and effective H5N1 influenza vaccine will be needed if the virus acquires the capacity for efficient human-to-human transmission and may also be useful as a veterinary vaccine. In this study, we demonstrate robust vaccine protection in a lethal model of H5N1 clade 2.3.4.4b influenza infection in cynomolgus macaques. We vaccinated 24 cynomolgus macaques with mRNA or rhesus adenovirus serotype 52 (RhAd52) vaccines expressing the hemagglutinin (HA) from H5N1 clade 2.3.4.4b by the intramuscular or intratracheal route and challenged them with the H5N1 human isolate hu-TX37-H5N1. Of sham control animals, 83% (five of six) developed severe rapidly progressive consolidative pneumonia and were euthanized by days 5 to 7 after challenge. In contrast, 100% (17 of 17) of vaccinated macaques survived and controlled virus replication to undetectable titers in both the upper and lower respiratory tracts by days 4 to 14 after challenge. Mucosal boosting with the RhAd52 HA vaccine generated robust mucosal antibody and T cell responses and afforded 6.3 and 5.1 log₁₀ median viral load reductions in viral RNA with no detectable infectious virus titers compared with sham controls in bronchoalveolar lavage and nasal swabs, respectively. These data demonstrate that an adenovirus-vectored vaccine can protect against lethal H5N1 clade 2.3.4.4b challenge in nonhuman primates and further highlight the importance of vaccine-elicited mucosal immunity.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"17 820","pages":""},"PeriodicalIF":14.6,"publicationDate":"2025-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/scitranslmed.ady2282","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145295130","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}

{"title":"Deletion of the X-chromosomal gene Kdm6a in microglia of female mice ameliorates neuroinflammation and restores translatome profiles","authors":"Yuichiro Itoh,&nbsp;Noriko Itoh,&nbsp;Sophia Wendin,&nbsp;Nadya Higgins,&nbsp;Rhonda R. Voskuhl","doi":"10.1126/scitranslmed.adq3401","DOIUrl":"10.1126/scitranslmed.adq3401","url":null,"abstract":"<div >Women are more susceptible to multiple sclerosis (MS) than men, with a reported incidence ratio of ~3:1. <i>Kdm6a</i> is an X-chromosomal gene that escapes X inactivation, leading to higher expression of the histone demethylase KDM6A in females compared with males. Here, we focused on the role of <i>Kdm6a</i> in microglia in MS because this cell type plays a key role in the neuropathology of MS. <i>Kdm6a</i> was selectively deleted from microglia in experimental autoimmune encephalomyelitis (EAE) mice, an established model of MS. Deletion of <i>Kdm6a</i> in microglia ameliorated pathology, reduced the expression of disease-associated markers, increased the expression of resting microglial markers, and reversed other translatome changes in spinal cord tissues of female EAE mice. Deletion of <i>Kdm6a</i> in microglia had only very minor effects on EAE in male mice. The diabetes medicine metformin, which also blocks KDM6A’s histone demethylase activity, ameliorated EAE in females, but not males, and normalized translatome profiles in microglia. CUT&amp;RUN and sequencing analysis of microglial nuclei identified genes bound by KDM6A. When combined with translatomic analysis, this revealed correspondence between KDM6A protein binding and gene expression changes. Transcriptomic analysis of human microglia confirmed the higher expression of <i>KDM6A</i> in women compared with men and revealed that more microglial genes were dysregulated in women than in men with MS. Our results suggest that <i>KDM6A</i> might contribute to sex differences in susceptibility to MS.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"17 820","pages":""},"PeriodicalIF":14.6,"publicationDate":"2025-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145295132","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}

{"title":"Low-dose glucocorticoids attenuate crescentic glomerulonephritis by inhibiting the local differentiation of proinflammatory neutrophils","authors":"Junping Yin,&nbsp;Melanie Eichler,&nbsp;Darius P. Schaub,&nbsp;Nariaki Asada,&nbsp;Jonas Engesser,&nbsp;Clivia Lisowski,&nbsp;Hans-Joachim Paust,&nbsp;Christina Katharina Weisheit,&nbsp;Jian Li,&nbsp;Daniela Klaus,&nbsp;Natalio Garbi,&nbsp;Sibylle von Vietinghoff,&nbsp;Christian F. Krebs,&nbsp;Ulf Panzer,&nbsp;Christian Kurts","doi":"10.1126/scitranslmed.adu0351","DOIUrl":"10.1126/scitranslmed.adu0351","url":null,"abstract":"<div >Glucocorticoids are widely used to treat autoimmune diseases like crescentic glomerulonephritis (cGN), but their immunosuppressive functions are not fully understood. Here, we generated a single immune cell sequencing atlas at different stages of experimental cGN. We identified a proinflammatory neutrophil subset as important for disease progression and as a glucocorticoid target. Such neutrophils produced proinflammatory cytokines known to drive cGN and expressed Siglec-F and decoy tumor necrosis factor–related apoptosis-inducing ligand receptor 1 (dcTRAIL-R1) in mice and SIGLEC8 in humans. Depleting such neutrophils attenuated disease in mice, whereas their adoptive transfer aggravated disease. They differentiated within the inflamed kidney in response to granulocyte-macrophage colony-stimulating factor (GM-CSF) secreted by clonally expanded CD4⁺ T helper 17 (T_H17) cells and persisted locally longer than normal neutrophils. Glucocorticoids decreased intrarenal numbers of T_H17 cells and down-regulated GM-CSF receptor expression by neutrophils and reduced their cytokine production. Selective genetic reduction of glucocorticoid receptor expression in neutrophils reenabled their in vivo differentiation during glucocorticoid therapy and aggravated cGN. Low glucocorticoid doses were sufficient to prevent intrarenal neutrophil differentiation in mice, if applied repetitively, even without an initial high-dose steroid pulse. Spatial sequencing of kidney biopsies, especially from patients with high disease activity, uncovered similar neutrophils in intrarenal inflammatory niches, and their abundance was lower after repetitive low-dose glucocorticoid application. These findings identify proinflammatory neutrophils as progression drivers in cGN and suggest that low-dose glucocorticoid therapy may be sufficient to suppress them.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"17 820","pages":""},"PeriodicalIF":14.6,"publicationDate":"2025-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145295131","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}

{"title":"Biselective remodeling of the melanoma tumor microenvironment prevents metastasis and enhances immune activation in mouse models","authors":"Nikolaos A. Afratis,&nbsp;Shivang Parikh,&nbsp;Idan Adir,&nbsp;Roma Parikh,&nbsp;Inna Solomonov,&nbsp;Orit Kollet,&nbsp;Sivan Gelb,&nbsp;Yuval Sade,&nbsp;Hananya Vaknine,&nbsp;Valentina Zemser-Werner,&nbsp;Ronen Brener,&nbsp;Eran Nizri,&nbsp;Dov Hershkovitz,&nbsp;Sylvie Ricard-Blum,&nbsp;Carmit Levy,&nbsp;Irit Sagi","doi":"10.1126/scitranslmed.adp3236","DOIUrl":"10.1126/scitranslmed.adp3236","url":null,"abstract":"<div >The extracellular matrix (ECM) plays a crucial role in supporting metastasis in solid malignancies, yet effective ECM-targeted therapies remain scarce. Here, we introduce a dual-targeting strategy to combat melanoma by leveraging bispecific agents that disrupt key ECM and tumor-associated pathways. Building on the inhibitory properties of lysyl oxidase–propeptide (LOX-PP), we engineered biselective decoys that simultaneously target the collagen cross-linking enzyme LOX and heat shock protein 70 (HSP70), both of which are up-regulated during melanoma progression in both human and mouse models. This dual-targeting strategy offers a new avenue for disrupting ECM-driven tumor progression and enhancing therapeutic efficacy. Administered to mouse models of melanoma, the decoys reduced tumor burden and circulating melanoma cells by inhibiting proliferation and lung metastasis. Mechanistically, the decoys suppressed cancer-supporting ECM organization, inhibited ECM-remodeling pathways and associated enzymes, and reshaped the tumor immune microenvironment. The treatment modulated immune responses by enhancing neutrophil, B cell, and CD8⁺ T cell infiltration. In combination with immune check point inhibitor, the decoys further promoted melanoma killing by CD8⁺ T cells. The decoys efficiently bound multiple human tumors expressing LOX⁺/HSP70⁺ ex vivo. These findings highlight the potential of dual inhibition as a potential strategy for remodeling melanoma and other tumor microenvironments and enhancing immunotherapy efficacy.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"17 820","pages":""},"PeriodicalIF":14.6,"publicationDate":"2025-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145295828","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}

{"title":"Computationally designed mRNA-launched protein nanoparticle immunogens elicit protective antibody and T cell responses in mice","authors":"Grace G. Hendricks,&nbsp;Lilit Grigoryan,&nbsp;Mary Jane Navarro,&nbsp;Nicholas J. Catanzaro,&nbsp;Miranda L. Hubbard,&nbsp;John M. Powers,&nbsp;Melissa Mattocks,&nbsp;Catherine Treichel,&nbsp;Alexandra C. Walls,&nbsp;Jimin Lee,&nbsp;Daniel Ellis,&nbsp;Jing Yang (John) Wang,&nbsp;Suna Cheng,&nbsp;Marcos C. Miranda,&nbsp;Adian Valdez,&nbsp;Cara W. Chao,&nbsp;Sidney Chan,&nbsp;Christine Men,&nbsp;Max R. Johnson,&nbsp;Samantha K. Zepeda,&nbsp;Sebastian Ols,&nbsp;Harold Hui,&nbsp;Sheng-Yang Wu,&nbsp;Victor Lujan,&nbsp;Hiromi Muramatsu,&nbsp;Paulo J.C. Lin,&nbsp;Molly M.H. Sung,&nbsp;Ying K. Tam,&nbsp;Elizabeth M. Leaf,&nbsp;Norbert Pardi,&nbsp;Ralph S. Baric,&nbsp;Bali Pulendran,&nbsp;David Veesler,&nbsp;Alexandra Schäfer,&nbsp;Neil P. King","doi":"10.1126/scitranslmed.adu2085","DOIUrl":"10.1126/scitranslmed.adu2085","url":null,"abstract":"<div >Messenger RNA (mRNA) vaccines and computationally designed protein nanoparticle vaccines were both clinically derisked and licensed for the first time during the coronavirus disease 2019 (COVID-19) pandemic. These vaccine modalities have complementary immunological benefits that provide strong motivation for their combination. Here, we demonstrate proof of concept for genetic delivery of computationally designed protein nanoparticle immunogens. Using severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) as a model system, we genetically fused a stabilized variant of the Wuhan-Hu-1 spike protein receptor binding domain (RBD) to a protein nanoparticle we previously designed for optimal secretion from human cells. Upon secretion, the nanoparticle formed monodisperse and antigenically intact assemblies displaying 60 copies of the RBD in an immunogenic array. Compared with mRNA vaccines encoding membrane-anchored spike protein and a secreted RBD trimer, an mRNA vaccine encoding the RBD nanoparticle elicited 5- to 28-fold higher titers of neutralizing antibodies in mice. In addition, the “mRNA-launched” RBD nanoparticle vaccine induced higher frequencies of antigen-specific CD8 T cells than the same immunogen delivered as adjuvanted protein and protected mice from either Wuhan-Hu-1 or Omicron BA.5 challenge. These results establish that delivering computationally designed protein nanoparticle immunogens through mRNA can combine the benefits of both vaccine modalities. More broadly, our data highlight the utility of computational protein design in genetic vaccination strategies.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"17 820","pages":""},"PeriodicalIF":14.6,"publicationDate":"2025-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145295129","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}