The Journal of Clinical Investigation最新文献

{"title":"Neuromuscular junction failure in sarcopenia is linked to NaV1.4 loss and reversed by ClC-1 inhibition.","authors":"W David Arnold,Jeanette Jeppesen Morgen,Pernille Bogetofte Thomasen,Martin Broch-Lips,Leatha A Clark,Thomas Groennebaek,Martin Skov,Jeppe Blichfeldt Winther,Abdullah F Ramadan,Philippa A Rust,Jessica H Myers,Fereshteh B Darvishi,Anna R Dashtmian,Lauren A Fish,Deepti Chugh,Jane Bold,Jorge A Quiroz,John Hutchison,Hiroshi Nishimune,Ross A Jones,Xueyong Wang,Justin R Fallon,Thomas H Gillingwater,Mark M Rich,Thomas Holm Pedersen,Brian C Clark","doi":"10.1172/jci190646","DOIUrl":"https://doi.org/10.1172/jci190646","url":null,"abstract":"Sarcopenia is the age-related loss of muscle strength and size that leads to mobility limitations and loss of independence in older adults. The underlying cellular mechanisms remain unclear, and treatments are limited. As the critical interface between the nervous system and muscle, the neuromuscular junction (NMJ) is essential for muscle activation and force production. Here, we demonstrate that weak older individuals exhibit NMJ transmission failure that correlates with muscle weakness severity. Preclinical experiments showed similar NMJ transmission failure in aged rodents that was associated with localized loss of muscle fiber excitability at the NMJ. This excitability defect, distinct from potential synaptic cholinergic transmission abnormalities, represents a novel disease mechanism of sarcopenia. Across species, immunohistochemistry identified a localized reduction in the voltage-gated sodium channel specific for skeletal muscle (NaV1.4) at the post-synaptic NMJ membrane. Acute NaV1.4 inhibition with μ-conotoxin GIIIB in adult rats reproduced findings of NMJ transmission failure observed in aged rodents and humans. Finally, ClC-1 chloride ion channel inhibition enhanced muscle excitability and improved NMJ transmission and muscle function in old rodents. Together, these findings demonstrate that NMJ transmission deficits are a key, reversible driver of sarcopenia and reveal a novel therapeutic target for addressing muscle weakness in aging.","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":"12 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148415869","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Markers of compromised gut epithelial barrier integrity increase during the menopause transition.","authors":"Albert Shieh,Marta Epeldegui,Arun S Karlamangla,Rheinallt Jones,Roberto Pacifici,Gail A Greendale","doi":"10.1172/jci205059","DOIUrl":"https://doi.org/10.1172/jci205059","url":null,"abstract":"BACKGROUNDIn female murine models, one source of inflammation is a menopause-related increase in gut permeability. We examined whether the menopause transition (MT) in women is associated with an increase in markers of gut epithelial dysfunction and gut microbial product translocation, signals of compromised gut epithelial barrier integrity.METHODSIn 964 women, we measured markers of gut epithelial dysfunction (fatty acid binding protein 2, FABP2) and gut microbial antigen translocation (soluble CD14, sCD14) using sera collected before, during and after the MT. Multivariable mixed effects regressions fit piece-wise linear models to repeated FABP2 or sCD14 measures relative to time from final menstrual period (FMP). Covariates were age at FMP, race/ethnicity, and BMI.RESULTSFABP2 and sCD14 did not change significantly until 2.5 years pre-FMP. At that point, FABP2 began rising; sCD14 began increasing 6 months later. FABP2 and sCD14 peaked 6 and 6.5 years post-FMP, respectively; subsequent levels remained stable. During the ~9-year interval of MT-related gain in gut barrier compromise markers, annual FABP2 and sCD14 increases were 2.6% (95% CI: 1.7 to 3.4%) and 0.8% (95% CI: 0.6 to 1.1%), respectively, among white women with sample-average BMI and age at FMP. FABP2 and sCD14 change rates did not differ significantly by race/ethnicity, BMI, or age at FMP.CONCLUSIONSThe MT is associated with a rise in markers of compromised gut barrier integrity, suggesting that this pathway of inflammation, previously described in animal models, occurs in humans.FUNDINGNIH U01NR004061, U01AG012505, U01AG012535, U01AG012531, U01AG012539, U01AG012546, U01AG012553, U01AG012554, U01AG012495, 5R01AR081794.","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":"39 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148415868","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A peripheral subpopulation of retinal pigment epithelium resists oxidative damage through SERPINE3-mediated Caspase-1 inhibition.","authors":"Huirong Li,Takerra Johnson-Stephenson,Vincent P Kunze,Wei Yan,David M McGaughey,Temesgen D Fufa,Koray Dogan Kaya,Ashley M Rasys,Davide Ortolan,Dominik Reichert,Congxiao Zhang,Ruchi Sharma,Lijin Dong,Bin Guan,Brian P Brooks,Tiansen Li,Wei Li,Wencan Wu,Kapil Bharti,Robert B Hufnagel","doi":"10.1172/jci191272","DOIUrl":"https://doi.org/10.1172/jci191272","url":null,"abstract":"Heterogeneous degeneration of the retinal pigment epithelium (RPE) leads to irreversible blindness in diseases associated with macular atrophy. However, the underlying mechanisms of regional RPE degeneration remain poorly understood. To address this gap, this study identifies a peripheral RPE subpopulation through spatial, transcriptomic, and functional analyses, thereby contributing to the understanding of the heterogeneity of degenerative RPE cells. Specifically, omics analyses in human and macaque RPE reveal a peripheral RPE cell population with high SERPINE3 expression, while SERPINE3-GFP knock-in mice show comparable expression patterns. In addition, SMART-seq2 analysis further distinguishes transcriptomic profiles between GFP-positive and GFP-negative RPE cells. Under oxidative stress, SERPINE3 expression increases, and GFP-positive cells exhibit improved survival and reentry into the cell cycle. Notably, genetic studies indicate that SERPINE3 is essential for the oxidative stress resistance of GFP-positive cells. Moreover, loss of SERPINE3 results in regional RPE degeneration and increased microglial accumulation in aged mice. Mechanistically, proteinase screening and co-immunoprecipitation indicate that SERPINE3 targets Caspase-1. Importantly, delivery of SERPINE3 via AAV-Serpine3 partially reduces RPE degeneration in an oxidative damage model. These findings advance the understanding of RPE heterogeneous degeneration and highlight SERPINE3 as a protective factor with therapeutic potential for macular atrophy.","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":"13 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-07-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148400799","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"CD20+ T follicular helper-like cells drive antigen-specific autoimmunity in bullous pemphigoid.","authors":"Hui Fang,Shengxian Shen,Kang Li,Tianyu Cao,Bing Wang,Haijun Miao,Ke Xue,Yaxing Bai,Liang Li,Xia Li,Pei Qiao,Jieyu Zhang,Huanhuan Qu,Chen Zhang,Chunying Xiao,Bingyu Pang,Meng Fu,Hongjiang Qiao,Shuai Shao,Erle Dang,Gang Wang","doi":"10.1172/jci197665","DOIUrl":"https://doi.org/10.1172/jci197665","url":null,"abstract":"CD20+ T cells are increasingly recognized as drivers of autoimmune and inflammatory diseases. However, their origin, development, and specific role in autoimmune skin diseases remain poorly understood. In this study, we observed an expansion of CD20+ T cells in the peripheral blood and skin lesions of patients with bullous pemphigoid (BP), which correlated with the levels of pathogenic autoantibodies and disease severity. Compared with CD20- T cells, CD20+ T cells exhibited enhanced metabolic and proinflammatory activities. In particular, antigen-specific BP180-NC16A-reactive T cells were enriched within the CD4+CD20+ subset. In both patients with BP and BP180-immunized mice, CD4+CD20+ T cells exhibited an antigen-specific follicular helper T (Tfh)-like phenotype, facilitating antibody production and B cell differentiation, whereas CD8+CD20+ T cells displayed cytotoxic and proinflammatory features. Mechanistically, we found that expression of the CD20-encoding gene MS4A1 in T cells was regulated by PAX5 in a DNA methylation-dependent manner. Therefore, our study elucidates the regulatory mechanisms governing CD20+ T cells and highlights their important role in the pathogenesis of BP.","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":"52 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-07-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148400803","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Fate-mapping infiltrating monocytes following experimental myocardial infarction revealsdifferentiation trajectories in the infarcted heart.","authors":"Andrew L Koenig,Farid F Kadyrov,Junedh M Amrute,Steven Yang,Carla J Weinheimer,Jessica M Nigro,Attila Kovacs,Wenjun Li,Gabriella B Smith,Lance Yeh,Daniel Kreisel,Kory J Lavine","doi":"10.1172/jci189684","DOIUrl":"https://doi.org/10.1172/jci189684","url":null,"abstract":"Inflammation contributes to the pathogenesis of myocardial infarction and heart failure and represents a viable therapeutic target. Monocytes and their progeny are highly abundant and display striking functional diversity, serving as key determinants of myocardial inflammation and tissue repair. Much remains to be learned regarding mechanisms and signaling events that instruct monocyte fate decisions. We devised a genetic lineage tracing strategy using Ccr2crERT2Rosa26LSL-tdTomato mice in combination with single cell RNA-sequencing to map the differentiation trajectories of monocytes that infiltrate the heart after reperfused myocardial infarction. Monocytes were recruited to the heart early after injury and gave rise to transcriptionally distinct and spatially restricted macrophage and dendritic cell-like subsets that were specified prior to extravasation and chronically persisted within the myocardium. Pseudotime analysis predicted two differentiation trajectories of monocyte-derived macrophages that are partitioned into the border and infarct zones, respectively. Among these trajectories, we demonstrated that macrophages expressing a type I interferon responsive signature were an intermediate population that gave rise to MHC-IIhi macrophages, were localized within the border zone, induce regulatory T cells, and promote myocardial protection. Collectively, these data uncover complexities of monocyte differentiation in the infarcted heart and suggest that modulating monocyte fate decisions may have clinical implications.","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":"37 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-07-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148400802","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"ATR senses stiff extracellular matrix to promote epithelial-to-mesenchymal transition and immune suppression.","authors":"Xinyi Tu,Xiangyu Zeng,Yaoliang Sun,Yaobin Ouyang,Lingling Zhu,Ping Yin,Kevin D Pavelko,Roberto A Leon-Ferre,Yanxia Jiang,Haidong Dong,Jodi M Carter,Shouhai Zhu,Jann N Sarkaria,Liewei Wang,Jinzhou Huang,Kuntian Luo,Yiqun Han,Zheming Wu,Zhenkun Lou,Robert W Mutter","doi":"10.1172/jci192285","DOIUrl":"https://doi.org/10.1172/jci192285","url":null,"abstract":"Our research uncovers a new role for ATR in responding to extracellular matrix (ECM) stiffness and promoting epithelial-to-mesenchymal transition (EMT) and metastasis. ATR, when deubiquitinated and upregulated by USP21 under enhanced ECM stiffness conditions, phosphorylates the nuclear protein SUN2 which promotes β-catenin nuclear translocation and EMT. ATM mediated EMT promotes polymorphonuclear myeloid-derived suppressor cell recruitment and inhibits CD103+ dendritic cells, fostering an immunosuppressive tumor milieu. ATR inhibition disrupts this malignant cascade by promoting mesenchymal to epithelial transition to enhance anti-tumor immunity and mitigate metastases. Consistently, circulating HLA-DR+ dendritic cells were also enhanced following treatment with the ATR inhibitor, Berzosertib, in patients with therapeutically resistant early-stage breast cancer. Our data suggest that ATR targeted therapy may be optimized by considering both DNA damage dependent and EMT inducing effects of ATR.","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":"65 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-07-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148400800","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"PTEN deficiency confers sensitivity to ATR inhibitor-based treatment in high-grade serous ovarian cancer.","authors":"Jie Hao,Bose Kochupurakkal,Timothy B Branigan,Ozge Sezin Somuncu,Renyan Liu,Heta Jadhav,Alexandre Andre Ba da Costa,Yuqing Jiao,Jenny Z Yu,David B Martignetti,Golbahar Sadatrezaei,Sirisha Mukkavalli,Prafulla C Gokhale,Su-Chun Cheng,Steven J Skates,Dimitrios Nasioudis,Panagiotis A Konstantinopoulos,Joyce F Liu,Stephanie L Gaillard,Robert L Giuntoli Ii,Lainie P Martin,Janos L Tanyi,Nawar Latif,Ian S Heller,Fiona Simpkins,Kalindi Parmar,Alan D D'Andrea,Geoffrey I Shapiro","doi":"10.1172/jci197645","DOIUrl":"https://doi.org/10.1172/jci197645","url":null,"abstract":"ATR inhibition is under evaluation for treatment of high-grade serous ovarian cancer (HGSOC) to reverse acquired resistance to poly (ADP-ribose) polymerase (PARP) inhibition and to exacerbate chemotherapy-induced replicative stress. Here, we define PTEN deficiency as a predictive biomarker for response to ATR inhibition, as monotherapy and in combination with PARP inhibition or gemcitabine. In response to ATR inhibition and compared to PTEN-proficient cells, PTEN-deficient cells are prone to (1) uncoupling of DNA polymerase and helicase activities, leading to excessive single-stranded DNA and replication stress; (2) cytoplasmic sequestration of CHK1, compromising cell cycle checkpoint control with reduced compensatory effects by ATM and DNA-PK, leading to mitotic catastrophe; and (3) reduced RAD51 recruitment, exacerbating replication fork instability, also leading to lethality. Retrospective analyses demonstrate that patients with HGSOC expressing low PTEN levels experience greater clinical benefit on ATR inhibitor-based trials than those with high levels. These results justify prospective trials evaluating ATR inhibition as a therapeutic strategy for PTEN-deficient tumors.","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":"24 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-07-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148400801","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pharmacokinetics and pharmacodynamics of a long-acting monoclonal antibody against malaria in African adults.","authors":"Tuan M Tran,Zonghui Hu,Kassoum Kayentao,Aissata Ongoiba,Sam Jones,Nada Abla,Sara A Healy,Hamidou Cisse,Bickey H Chang,Jeff Skinner,Leonid Serebryannyy,Sandeep R Narpala,Robin Schlesinger,Kwang Huei Low,Rachel Kazmierski,Bob C Lin,Joana Dias,Safiatou Doumbo,Didier Doumtabe,Anne C Preston,Shanping Li,Mary E Peterson,Amit Oberai,Adam D Shandling,Joseph J Campo,Sean C Murphy,Shinyi Telscher,Emily E Coates,Edmund V Capparelli,Amagana Dolo,Boubacar Traore,Robert A Seder,Peter D Crompton","doi":"10.1172/jci207559","DOIUrl":"https://doi.org/10.1172/jci207559","url":null,"abstract":"BACKGROUNDCIS43LS is a long-acting mAb that targets the Plasmodium falciparum circumsporozoite protein. A phase 2 trial showed that a single dose of CIS43LS conferred >85% sterile protection against infection in Malian adults over 6 months. Understanding the pharmacokinetics and pharmacodynamics (PK/PD) of CIS43LS is critical for the further development of CIS43LS and other anti-malaria mAbs.METHODSUsing 3,777 serum samples collected from 348 trial participants over the 6-month study period, we performed a PK/PD analysis of CIS43LS that included assessments for anti-drug antibodies and target-mediated drug disposition. A two-compartment, non-linear mixed effects population PK model that evaluated demographic, anthropometric, hematologic, baseline parasitemia, and endogenous IgG and IgG1 as potential covariates was used to estimate PK parameters and serum concentrations required to achieve 80% efficacy.RESULTSThe median CIS43LS t1/2 was 63.2 days (95%CI 59.4-67.2 days). Serum concentrations ≥64 μg/mL (95%CI 49-93 μg/mL) corresponded to ≥80% efficacy against infection over 6 months. A simulated dose of 30 mg/kg maintained serum concentrations >64 µg/mL in >97.5% of individuals for 4 months, the timeframe for the World Health Organization preferred product characteristics for anti-malaria mAbs. There was no evidence of anti-drug antibodies. Among infected individuals who received CIS43LS, no marked evidence of target-mediated drug disposition was observed.CONCLUSIONThis study indicates that protective CIS43LS levels can be maintained over the course of a single malaria season and provides guidance for PK/PD analyses of anti-malaria mAbs in malaria-endemic populations.TRIAL REGISTRATIONNCT04329104.FUNDINGNational Institutes of Health and Gates Foundation.","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":"223 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148393650","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Tumor cell-derived extracellular vesicles foster the immunosuppressive landscape of pancreatic cancer.","authors":"Zainab Hussain,Claudio Montenegro,Christopher Rovera,Djamila Belghoula,Sarah Simha Tubiana,Pascal Finetti,Eugenie Lohmann,Magda Rodrigues,Thomas Bertran,Ghislain Bidaut,Daniel Isnardon,Sophie Vasseur,Francois Bertucci,Stephane Audebert,Luc Camoin,Moacyr Rego,Richard Tomasini","doi":"10.1172/jci197733","DOIUrl":"https://doi.org/10.1172/jci197733","url":null,"abstract":"Pancreatic cancer remains a devastating disease with limited therapeutic options. Accumulating evidence has shown that cancer-associated fibroblasts (CAFs) and tumor-associated macrophages (TAMs), the predominant cells in the pancreatic cancer (PDAC) tumor microenvironment (TME), hinder anti-tumor immunity. However, the role of extracellular vesicles (EVs) in such process is poorly understood. In this study, using human bone-marrow-derived monocytes and PDAC tumor cells, we show that tumor cell-derived EVs (TC-EVs) induced monocyte differentiation towards M2-like immunosuppressive CD200R+/PD-L1+/HLA-DR- macrophages that express ALOX15b, that we identify as an independent PDAC poor-prognosis biomarker using a human pancreatic cancer metacohort. We also demonstrate that TC-EVs reprogram human primary PDAC CAFs, causing a fibronectin network reorganization associated with changes in extracellular matrix (ECM) composition, including alterations of the Wnt pathway elements such as SFRP1 enrichment. We further reveal that monocytes cultured on rSFRP1-enriched ECM differentiate also into M2-like immunosuppressive macrophages. Lastly, we demonstrate that both directly and indirectly TC-EVs, or rSFRP1-enriched ECM, driven differentiated macrophages hindered T-cell activation and subsequent anti-tumor activity. Our findings highlight novel, dual mechanisms of TC-EVs-mediated crosstalk, involving Alox15b+-Macrophages and SFRP1+-CAFs, that simultaneously contribute to foster the immunosuppressive ecosystem of pancreatic cancer.","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":"24 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148372795","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Extracellular matrix reprogramming by the YAP/TAZ- TGF-ß2 axis drives immune exclusion in cholangiocarcinoma models.","authors":"Marco Jessen,KyungMok Kim,Marie Tollot-Wegner,Anita Cindric Vranesic,Cagla Dönmez,Celina Junker,Tina Lehmann,Advitiya Khandelwal,Yuliya Kurlishchuk,Tom Hünniger,Christin Ritter,Evaristo Di Napoli,Shyam Murali,Konrad Bücking,Viktoria Haug,Sabine Muth,Tracy T Tang,Andreas Rosenwald,Markus Radsak,Donato Inverso,Tanja Deckert-Gaudig,Volker Deckert,Orlando Paciello,Björn von Eyss","doi":"10.1172/jci201579","DOIUrl":"https://doi.org/10.1172/jci201579","url":null,"abstract":"YAP and TAZ, key effectors of the Hippo pathway, are often hyperactivated in cancer, promoting tumor progression and therapy resistance. Their oncogenic role depends on interaction with TEAD transcription factors, making the TEAD-YAP/TAZ complex a promising therapeutic target. Using translational mouse models, we showed here that sustained systemic YAP/TAZ depletion caused severe side effects. These could be avoided through pulsed inhibition, which effectively suppressed tumor growth, even at advanced stages. We identified Tgfb2 as a critical YAP/TAZ target gene for tumor formation and demonstrated that YAP/TAZ drove T cell exclusion via activation of tissue remodeling genes. Consequently, YAP/TAZ inhibition enhanced immune cell infiltration. However, infiltrating T cells rapidly underwent exhaustion. Combining YAP/TAZ inhibition with immune checkpoint blockade (ICB) reversed this exhaustion and sensitized resistant tumors to immunotherapy. This combination reshaped the tumor microenvironment to support immune cell infiltration and activation, representing a therapeutic strategy that maximizes anti-tumor immunity while minimizing toxicity.","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":"35 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148372794","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}