Endothelial dysfunction plays a critical role in the initiation and progression of vascular remodeling and pulmonary arterial hypertension (PAH). Sine oculis homeobox 1 (SIX1) is a developmentally restricted transcription factor, and its expression ceases upon the completion of embryonic development. Deletion of Six1 impairs the differentiation of pulmonary vascular endothelial cells, resulting in pulmonary vascular defects and postnatal death. In this study, we found that SIX1 was increased in the endothelia of pulmonary arteries from patients with PAH and from patients with idiopathic pulmonary fibrosis–associated pulmonary hypertension (PH). Silencing SIX1 using siRNA inhibited hypoxia-induced endothelial dysfunction in vitro, including proliferation, endothelial-to-mesenchymal transition, and endothelin-1 release. Endothelial-specific Six1 knockout improved pulmonary hemodynamics, endothelial dysfunction, pulmonary artery remodeling, and right ventricular function in SU5416/hypoxia (SuHx)–induced PH mice. Moreover, endothelial-specific Six1 overexpression mediated by adeno-associated virus induced a spontaneous PH in wild-type C57BL/6 mice. Structure-based virtual screening and surface plasmon resonance analysis demonstrated that zafirlukast was an inhibitor of SIX1 transcriptional activity. Zafirlukast suppressed hypoxia-induced endothelial dysfunction in vitro and reversed SuHx-induced PH in Sprague-Dawley rats. Mechanistically, multiomics profiling of hypoxia-induced endothelial dysfunction in vitro revealed that microtubule-associated serine/threonine kinase family member 4 (MAST4) was a target of SIX1. MAST4 phosphorylated the Thr185/202 sites of mitogen-activated protein kinases 1 and 3 (MAPK1/3), resulting in endothelial dysfunction. Overall, we found that SIX1 was a driver for endothelial dysfunction and PH through regulating MAST4 transcription and subsequently MAPK1/3 activation. Targeting SIX1 may be a promising strategy for PAH treatment and drug development.
{"title":"Sine oculis homeobox 1 drives endothelial dysfunction in preclinical pulmonary arterial hypertension","authors":"Ting Liu, Wei Zhou, Cheng Fang, Yao Liang, Zhenyu Zhao, Anqi Cai, Xueying Peng, Xiaoli Ye, Mengru Bai, Xiaoping Hu, Nengming Lin, Xiaozhou Zou, Ping Huang","doi":"10.1126/scitranslmed.adu6425","DOIUrl":"10.1126/scitranslmed.adu6425","url":null,"abstract":"<div >Endothelial dysfunction plays a critical role in the initiation and progression of vascular remodeling and pulmonary arterial hypertension (PAH). Sine oculis homeobox 1 (<i>SIX1</i>) is a developmentally restricted transcription factor, and its expression ceases upon the completion of embryonic development. Deletion of <i>Six1</i> impairs the differentiation of pulmonary vascular endothelial cells, resulting in pulmonary vascular defects and postnatal death. In this study, we found that SIX1 was increased in the endothelia of pulmonary arteries from patients with PAH and from patients with idiopathic pulmonary fibrosis–associated pulmonary hypertension (PH). Silencing <i>SIX1</i> using siRNA inhibited hypoxia-induced endothelial dysfunction in vitro, including proliferation, endothelial-to-mesenchymal transition, and endothelin-1 release. Endothelial-specific <i>Six1</i> knockout improved pulmonary hemodynamics, endothelial dysfunction, pulmonary artery remodeling, and right ventricular function in SU5416/hypoxia (SuHx)–induced PH mice. Moreover, endothelial-specific <i>Six1</i> overexpression mediated by adeno-associated virus induced a spontaneous PH in wild-type C57BL/6 mice. Structure-based virtual screening and surface plasmon resonance analysis demonstrated that zafirlukast was an inhibitor of SIX1 transcriptional activity. Zafirlukast suppressed hypoxia-induced endothelial dysfunction in vitro and reversed SuHx-induced PH in Sprague-Dawley rats. Mechanistically, multiomics profiling of hypoxia-induced endothelial dysfunction in vitro revealed that microtubule-associated serine/threonine kinase family member 4 (<i>MAST4</i>) was a target of SIX1. MAST4 phosphorylated the Thr<sup>185/202</sup> sites of mitogen-activated protein kinases 1 and 3 (MAPK1/3), resulting in endothelial dysfunction. Overall, we found that SIX1 was a driver for endothelial dysfunction and PH through regulating <i>MAST4</i> transcription and subsequently MAPK1/3 activation. Targeting SIX1 may be a promising strategy for PAH treatment and drug development.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"18 835","pages":""},"PeriodicalIF":14.6,"publicationDate":"2026-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146111404","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 : 2026-02-04DOI: 10.1126/scitranslmed.adr9382
Ivan J. Cohen, Audrey C. Bochi-Layec, Jean Lemoine, Scott Jenks, Pedram Bayat, Ki Hyun Kim, Huiwu Zhao, Ositadimma Ugwuanyi, Federico Stella, Guido Ghilardi, Giulia Gabrielli, Sarah McCuaig, Anastasia Iatrou, Elisavet Vlachonikola, Maria Karipidou, Eleni Bouziani, David Espie, Ranjani Ramasubramanian, Andreas Agathangelidis, Aditya Bhosale, Luca Paruzzo, Giovanni Medico, Bronte Kolar, Regina Bugrovsky, Puneeth Guruprasad, Li-Ping Wang, Jaryse Harris, Evgeny Arons, Yunlin Zhang, Raymone Pajarillo, Portia A. Kreiger, Chi-Ping Day, S. Cenk Sahinalp, Chih Hao Wu, Alessia Santi, Bria Fulmer, Marcos Cases, Matthew B. Palmer, Patrizia Porazzi, E. John Wherry, Robert J. Kreitman, Enrico Tiacci, Sokratis A. Apostolidis, Edward M. Behrens, Vijay Bhoj, Ignacio Sanz, Giorgio Inghirami, Stephen J. Schuster, Paolo Ghia, Kostas Stamatopoulos, Marco Ruella
Current US Food and Drug Administration–approved chimeric antigen receptor (CAR) T cell therapies for B cell leukemias and lymphomas target CD19, which is widely expressed across the B cell lineage, often leading to on-target, off-tumor B cell depletion, prolonged immune suppression, and antigen-negative escape in a subset of patients. In contrast, B cell receptor (BcR) signaling is essential for the survival of most mature B cell neoplasms, and BcRs carrying the immunoglobulin heavy variable gene IGHV4-34 are highly enriched in B cell malignancies compared with normal B cells. Further, self-reactive IGHV4-34+ serum autoantibodies are enriched in aggressive systemic lupus erythematosus (SLE) and other autoimmune diseases. Here, we developed CAR T cells targeting the BcR carrying IGHV4-34 (CART4-34). We found that CART4-34 showed specific cytotoxicity and cytokine secretion toward IGHV4-34+ malignant B cells. In addition, although CD19 was down-regulated upon relapse after treatment with CART19, IGHV4-34+ BcR levels remained intact upon relapse after treatment with CART4-34, suggesting reduced risk of antigen-negative escape. In IGHV4-34+ HBL1 cell line–derived xenograft mouse models, CART4-34 showed robust expansion and antitumor activity comparable to those of CART19. Optimized CAR:BcR binding using shorter CAR hinge domains improved immune synapse morphology and in vivo activity. In addition, we showed that CART4-34 could target human IGHV4-34+ SLE B cells and deplete IGHV4-34+ autoantibodies ex vivo, without targeting healthy B cells or affecting total IgG titers. In conclusion, we developed a CAR T cell product that specifically targets pathogenic B cells in lymphoid malignancies and SLE, offering potential for precision cell therapy for these indications.
{"title":"Chimeric antigen receptor T cells against the IGHV4-34 B cell receptor specifically eliminate neoplastic and autoimmune B cells","authors":"Ivan J. Cohen, Audrey C. Bochi-Layec, Jean Lemoine, Scott Jenks, Pedram Bayat, Ki Hyun Kim, Huiwu Zhao, Ositadimma Ugwuanyi, Federico Stella, Guido Ghilardi, Giulia Gabrielli, Sarah McCuaig, Anastasia Iatrou, Elisavet Vlachonikola, Maria Karipidou, Eleni Bouziani, David Espie, Ranjani Ramasubramanian, Andreas Agathangelidis, Aditya Bhosale, Luca Paruzzo, Giovanni Medico, Bronte Kolar, Regina Bugrovsky, Puneeth Guruprasad, Li-Ping Wang, Jaryse Harris, Evgeny Arons, Yunlin Zhang, Raymone Pajarillo, Portia A. Kreiger, Chi-Ping Day, S. Cenk Sahinalp, Chih Hao Wu, Alessia Santi, Bria Fulmer, Marcos Cases, Matthew B. Palmer, Patrizia Porazzi, E. John Wherry, Robert J. Kreitman, Enrico Tiacci, Sokratis A. Apostolidis, Edward M. Behrens, Vijay Bhoj, Ignacio Sanz, Giorgio Inghirami, Stephen J. Schuster, Paolo Ghia, Kostas Stamatopoulos, Marco Ruella","doi":"10.1126/scitranslmed.adr9382","DOIUrl":"10.1126/scitranslmed.adr9382","url":null,"abstract":"<div >Current US Food and Drug Administration–approved chimeric antigen receptor (CAR) T cell therapies for B cell leukemias and lymphomas target CD19, which is widely expressed across the B cell lineage, often leading to on-target, off-tumor B cell depletion, prolonged immune suppression, and antigen-negative escape in a subset of patients. In contrast, B cell receptor (BcR) signaling is essential for the survival of most mature B cell neoplasms, and BcRs carrying the immunoglobulin heavy variable gene <i>IGHV4-34</i> are highly enriched in B cell malignancies compared with normal B cells. Further, self-reactive IGHV4-34<sup>+</sup> serum autoantibodies are enriched in aggressive systemic lupus erythematosus (SLE) and other autoimmune diseases. Here, we developed CAR T cells targeting the BcR carrying IGHV4-34 (CART4-34). We found that CART4-34 showed specific cytotoxicity and cytokine secretion toward IGHV4-34<sup>+</sup> malignant B cells. In addition, although CD19 was down-regulated upon relapse after treatment with CART19, IGHV4-34<sup>+</sup> BcR levels remained intact upon relapse after treatment with CART4-34, suggesting reduced risk of antigen-negative escape. In IGHV4-34<sup>+</sup> HBL1 cell line–derived xenograft mouse models, CART4-34 showed robust expansion and antitumor activity comparable to those of CART19. Optimized CAR:BcR binding using shorter CAR hinge domains improved immune synapse morphology and in vivo activity. In addition, we showed that CART4-34 could target human IGHV4-34<sup>+</sup> SLE B cells and deplete IGHV4-34<sup>+</sup> autoantibodies ex vivo, without targeting healthy B cells or affecting total IgG titers. In conclusion, we developed a CAR T cell product that specifically targets pathogenic B cells in lymphoid malignancies and SLE, offering potential for precision cell therapy for these indications.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"18 835","pages":""},"PeriodicalIF":14.6,"publicationDate":"2026-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146111406","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}
Dysregulation of RNA N6-methyladenosine (m6A) readers has been linked to various diseases, but the therapeutic potential of small-molecule inhibitors targeting them is of interest. Here, we reported the identification and characterization of a potent and selective first-in-class inhibitor (YL-5092) of YTHDC1, a nuclear RNA m6A reader. We provided a high-resolution cocrystal structure of the YTHDC1–YL-5092 complex. In acute myeloid leukemia (AML) models, YL-5092 blocked the binding of YTHDC1 to its m6A substrates and reduced mRNA stability, resulting in apoptosis of AML cells and myeloid differentiation. In multiple xenograft models of AML representing disease heterogeneity, YL-5092 alone or in combination with standard AML therapy eliminated leukemia and extended survival. Moreover, YL-5092 functionally impaired leukemia stem cells yet spared normal hematopoietic counterparts. Collectively, our work demonstrates the efficacy of a selective YTHDC1 inhibitor and suggests that targeting of m6A readers is a potential strategy in the treatment of hematologic cancers.
{"title":"Small-molecule inhibition of YTHDC1 as a strategy against acute myeloid leukemia in mouse models","authors":"Hailin Zhang, Yueshan Li, Yin Zhao, Falu Wang, Guifeng Lin, Ting Niu, He Li, Yueyue Li, Lina Liu, Yue Liang, Yu Shen, Yuyao Yi, Hui Zhou, Shang Lou, Yishan Ye, Yanmin He, Ruicheng Yang, Rui Yao, Chenyu Tian, Pei Zhou, Mengdan Wu, Mingxin Chen, Haixing Xu, Jing You, Yi Liao, Chenlu Yang, Ailin Zhao, Chong Chen, Linli Li, Shanshan Pei, Shengyong Yang","doi":"10.1126/scitranslmed.adu3137","DOIUrl":"10.1126/scitranslmed.adu3137","url":null,"abstract":"<div >Dysregulation of RNA N<sup>6</sup>-methyladenosine (m<sup>6</sup>A) readers has been linked to various diseases, but the therapeutic potential of small-molecule inhibitors targeting them is of interest. Here, we reported the identification and characterization of a potent and selective first-in-class inhibitor (YL-5092) of YTHDC1, a nuclear RNA m<sup>6</sup>A reader. We provided a high-resolution cocrystal structure of the YTHDC1–YL-5092 complex. In acute myeloid leukemia (AML) models, YL-5092 blocked the binding of YTHDC1 to its m<sup>6</sup>A substrates and reduced mRNA stability, resulting in apoptosis of AML cells and myeloid differentiation. In multiple xenograft models of AML representing disease heterogeneity, YL-5092 alone or in combination with standard AML therapy eliminated leukemia and extended survival. Moreover, YL-5092 functionally impaired leukemia stem cells yet spared normal hematopoietic counterparts. Collectively, our work demonstrates the efficacy of a selective YTHDC1 inhibitor and suggests that targeting of m<sup>6</sup>A readers is a potential strategy in the treatment of hematologic cancers.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"18 835","pages":""},"PeriodicalIF":14.6,"publicationDate":"2026-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146111401","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 : 2026-02-04DOI: 10.1126/scitranslmed.adq6647
Hai-Cheng Huang, Qing Deng, Lei Guo, Teresa Gorria, Federica Pecci, Daniella Yang, Scott Rodig, Luis De Las Casas, Jill Hallin, James G. Christensen, Mark M. Awad, Lin Xu, Biagio Ricciuti, Esra A. Akbay
The development of allele-specific KRAS inhibitors underscores the importance of understanding the distinct tumor biology associated with common KRAS mutations, G12D and G12C, in genetically engineered mouse models (GEMMs) of non–small cell lung cancer (NSCLC) and patient samples. Lung tumors driven by the most common KRAS mutation, G12C, show delayed onset and slower progression compared with those driven by KRAS G12D in patients and mice. G12C tumors display lower proliferation and increased immune cell engagement, the latter of which is consistent with observations in patient tumors. Allele-specific KRAS G12C/D inhibitors effectively suppress the growth of respective autochthonous lung tumors. However, G12D-driven tumors relapse more rapidly than G12C-driven tumors in autochthonous models, reflecting greater intrinsic aggressiveness. Given this aggressive clinical behavior, we focused on elucidating the mechanism of action and strategies to potentiate KRASG12D inhibition in nonimmunogenic and immunogenic lung cancer models. G12D inhibition enhances tumor antigen presentation, activates T cells, and enables antigen-specific cytotoxicity, leading to efficacy with immune checkpoint blockade combination. This combination induces durable immune memory in immunogenic models but not in nonimmunogenic settings. Our findings underscore key differences between KRAS G12D and G12C mutations in shaping lung cancer biology, reveal distinct resistance dynamics under long-term targeted therapy, and uncover immune-mediated mechanisms specific to KRASG12D inhibition with direct clinical and translational relevance.
{"title":"Kras G12C– and G12D–driven lung cancers differ in oncogenic potency, immunogenicity, and relapse after Kras inhibition in mouse models","authors":"Hai-Cheng Huang, Qing Deng, Lei Guo, Teresa Gorria, Federica Pecci, Daniella Yang, Scott Rodig, Luis De Las Casas, Jill Hallin, James G. Christensen, Mark M. Awad, Lin Xu, Biagio Ricciuti, Esra A. Akbay","doi":"10.1126/scitranslmed.adq6647","DOIUrl":"10.1126/scitranslmed.adq6647","url":null,"abstract":"<div >The development of allele-specific KRAS inhibitors underscores the importance of understanding the distinct tumor biology associated with common <i>KRAS</i> mutations, G12D and G12C, in genetically engineered mouse models (GEMMs) of non–small cell lung cancer (NSCLC) and patient samples. Lung tumors driven by the most common <i>KRAS</i> mutation, G12C, show delayed onset and slower progression compared with those driven by KRAS G12D in patients and mice. G12C tumors display lower proliferation and increased immune cell engagement, the latter of which is consistent with observations in patient tumors. Allele-specific KRAS G12C/D inhibitors effectively suppress the growth of respective autochthonous lung tumors. However, G12D-driven tumors relapse more rapidly than G12C-driven tumors in autochthonous models, reflecting greater intrinsic aggressiveness. Given this aggressive clinical behavior, we focused on elucidating the mechanism of action and strategies to potentiate KRAS<sup>G12D</sup> inhibition in nonimmunogenic and immunogenic lung cancer models. G12D inhibition enhances tumor antigen presentation, activates T cells, and enables antigen-specific cytotoxicity, leading to efficacy with immune checkpoint blockade combination. This combination induces durable immune memory in immunogenic models but not in nonimmunogenic settings. Our findings underscore key differences between KRAS G12D and G12C mutations in shaping lung cancer biology, reveal distinct resistance dynamics under long-term targeted therapy, and uncover immune-mediated mechanisms specific to KRAS<sup>G12D</sup> inhibition with direct clinical and translational relevance.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"18 835","pages":""},"PeriodicalIF":14.6,"publicationDate":"2026-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146111403","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 : 2026-02-04DOI: 10.1126/scitranslmed.adz1580
Anna L. Beukenhorst, Robin Rogiers, Keira L. Rice, George Booth, Joost Haasnoot, Joseph Nkolola, Jose Ayala, Liping Wang, Boris Julg, Andrea K. Pastini, Helene Vietsch, Zoltán Magyarics, Evmorfia Chatzifotiou, Nigel Temperton, Kelly A. S. da Costa, Martin H. Koldijk, Justin Crawford, Sagrario Arias Rivas, Dan H. Barouch, Clarissa M. Koch, Jaap Goudsmit
Systemic administration of influenza virus–specific monoclonal antibodies achieves low concentrations in the nasal mucosa, the portal of infection. Intranasal administration may be more relevant for preventing infection, but the pharmacokinetics of intranasal influenza antibodies is unknown. We present results of preclinical studies and first-in-human phase 1 trials of the intranasally administered CR9114, an anti–hemagglutinin stem antibody that protects against influenza A and B viruses. We tested safety and tolerability of different schedules and doses; pharmacokinetics in nasal mucosal lining fluid of the nose and nasopharynx, saliva, and serum; and ex vivo functionality. We evaluated in vivo efficacy of CR9114 in mice and nonhuman primates. Intranasal CR9114 was safe and well tolerated across all doses and schedules. The half-life of CR9114 in the nose was ~3 hours. Steady-state concentrations were rapidly attained and sustained with multidosing. Trough concentrations were up to 92-fold higher with twice-daily administration compared with once-daily administration. Pharmacokinetics of intranasal CR9114 in nonhuman primates mirrored that of humans better than mice. Postdose nasal samples potently bound hemagglutinin from diverse strains of influenza A and B viruses and, particularly at the 10-milligram dose, neutralized A/H1N1, A/H5N1, and A/H3N2 more potently than baseline samples. Twice-daily administration of CR9114 protected nonhuman primates against influenza virus challenge with the same intranasal formulation and device as used in humans, providing evidence for the efficacy of intranasal multidosing. Together, these study findings characterize the pharmacokinetics of CR9114 after intranasal administration and provide proof of concept that intranasal antibodies can elicit efficacious passive immunity against influenza viruses.
{"title":"Phase 1 and preclinical studies reveal safety, pharmacokinetics, and efficacy of intranasal delivery of the influenza antibody CR9114","authors":"Anna L. Beukenhorst, Robin Rogiers, Keira L. Rice, George Booth, Joost Haasnoot, Joseph Nkolola, Jose Ayala, Liping Wang, Boris Julg, Andrea K. Pastini, Helene Vietsch, Zoltán Magyarics, Evmorfia Chatzifotiou, Nigel Temperton, Kelly A. S. da Costa, Martin H. Koldijk, Justin Crawford, Sagrario Arias Rivas, Dan H. Barouch, Clarissa M. Koch, Jaap Goudsmit","doi":"10.1126/scitranslmed.adz1580","DOIUrl":"10.1126/scitranslmed.adz1580","url":null,"abstract":"<div >Systemic administration of influenza virus–specific monoclonal antibodies achieves low concentrations in the nasal mucosa, the portal of infection. Intranasal administration may be more relevant for preventing infection, but the pharmacokinetics of intranasal influenza antibodies is unknown. We present results of preclinical studies and first-in-human phase 1 trials of the intranasally administered CR9114, an anti–hemagglutinin stem antibody that protects against influenza A and B viruses. We tested safety and tolerability of different schedules and doses; pharmacokinetics in nasal mucosal lining fluid of the nose and nasopharynx, saliva, and serum; and ex vivo functionality. We evaluated in vivo efficacy of CR9114 in mice and nonhuman primates. Intranasal CR9114 was safe and well tolerated across all doses and schedules. The half-life of CR9114 in the nose was ~3 hours. Steady-state concentrations were rapidly attained and sustained with multidosing. Trough concentrations were up to 92-fold higher with twice-daily administration compared with once-daily administration. Pharmacokinetics of intranasal CR9114 in nonhuman primates mirrored that of humans better than mice. Postdose nasal samples potently bound hemagglutinin from diverse strains of influenza A and B viruses and, particularly at the 10-milligram dose, neutralized A/H1N1, A/H5N1, and A/H3N2 more potently than baseline samples. Twice-daily administration of CR9114 protected nonhuman primates against influenza virus challenge with the same intranasal formulation and device as used in humans, providing evidence for the efficacy of intranasal multidosing. Together, these study findings characterize the pharmacokinetics of CR9114 after intranasal administration and provide proof of concept that intranasal antibodies can elicit efficacious passive immunity against influenza viruses.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"18 835","pages":""},"PeriodicalIF":14.6,"publicationDate":"2026-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146111405","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 : 2026-02-04DOI: 10.1126/scitranslmed.aef4957
{"title":"Erratum for the Research Article “Calmodulin inhibitors improve erythropoiesis in Diamond-Blackfan anemia”","authors":"","doi":"10.1126/scitranslmed.aef4957","DOIUrl":"10.1126/scitranslmed.aef4957","url":null,"abstract":"","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"18 835","pages":""},"PeriodicalIF":14.6,"publicationDate":"2026-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146111402","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 : 2026-01-28DOI: 10.1126/scitranslmed.adt1055
Matthew A. Bochenek, Shady Farah, Joshua C. Doloff, Hye Jung Han, Atieh Sadraei, William J. Jeang, Merna Shaheen-Mualim, Neta Kutner, Edwar Odeh, Amanda Facklam, Amy DiNardo, Elise N. Engquist, Peter Rios, Douglas Isa, Sofia Ghani, Ira Joshi, Yuan Xing, Yong Wang, Ramona Pop, Dale L. Greiner, Jose Oberholzer, Robert Langer, Daniel G. Anderson
Immunoisolation devices containing therapeutic protein-secreting cells offer potential for long-term therapy without immune suppression. However, scar tissue formation driven by the foreign body response (FBR) hinders nutritional exchange and ultimately leads to graft failure. We previously showed that inhibiting the colony-stimulating factor-1 receptor (CSF1R) pathway in monocytes and macrophages can block the FBR to implanted materials. Here, we demonstrate that coencapsulation of slow-releasing CSF1R inhibitor (GW2580) crystals with human stem cell–derived β cells (SC-β) in alginate spheres enables stable glycemic control for 1 year in immune-competent diabetic C57BL/6 mice. In nonhuman primates (NHPs), GW2580 crystals similarly protected viable, glucose-responsive allogeneic β cells for 1 month without systemic immune suppression. In contrast, the same xenogeneic human SC-β cell formulation that functioned long-term in mice elicited extensive sphere overgrowth and graft failure in NHPs. Serum cytokine profiling and transcriptomic analysis of omental biopsies at day 30 revealed pronounced adaptive immune activation in xenogeneic recipients, including enrichment of CD4+ T cells, CD19+ B cells, and antigen-presenting cell programs marked by elevated MHC class II expression. Chemokines CCL17, CCL22, and CXCL13 were among the most highly up-regulated transcripts, mirroring responses observed previously with profibrotic alginate formulations without cells. These findings underscore the issues associated with xenogeneic cell sources in higher-order species yet indicate that targeting innate immune pathways with localized CSF1R inhibition may be sufficient to enable function of encapsulated allogeneic cell therapies.
{"title":"Crystallized colony-stimulating factor-1 receptor inhibitor protects immunoisolated allo but not xeno transplants in primates","authors":"Matthew A. Bochenek, Shady Farah, Joshua C. Doloff, Hye Jung Han, Atieh Sadraei, William J. Jeang, Merna Shaheen-Mualim, Neta Kutner, Edwar Odeh, Amanda Facklam, Amy DiNardo, Elise N. Engquist, Peter Rios, Douglas Isa, Sofia Ghani, Ira Joshi, Yuan Xing, Yong Wang, Ramona Pop, Dale L. Greiner, Jose Oberholzer, Robert Langer, Daniel G. Anderson","doi":"10.1126/scitranslmed.adt1055","DOIUrl":"10.1126/scitranslmed.adt1055","url":null,"abstract":"<div >Immunoisolation devices containing therapeutic protein-secreting cells offer potential for long-term therapy without immune suppression. However, scar tissue formation driven by the foreign body response (FBR) hinders nutritional exchange and ultimately leads to graft failure. We previously showed that inhibiting the colony-stimulating factor-1 receptor (CSF1R) pathway in monocytes and macrophages can block the FBR to implanted materials. Here, we demonstrate that coencapsulation of slow-releasing CSF1R inhibitor (GW2580) crystals with human stem cell–derived β cells (SC-β) in alginate spheres enables stable glycemic control for 1 year in immune-competent diabetic C57BL/6 mice. In nonhuman primates (NHPs), GW2580 crystals similarly protected viable, glucose-responsive allogeneic β cells for 1 month without systemic immune suppression. In contrast, the same xenogeneic human SC-β cell formulation that functioned long-term in mice elicited extensive sphere overgrowth and graft failure in NHPs. Serum cytokine profiling and transcriptomic analysis of omental biopsies at day 30 revealed pronounced adaptive immune activation in xenogeneic recipients, including enrichment of CD4<sup>+</sup> T cells, CD19<sup>+</sup> B cells, and antigen-presenting cell programs marked by elevated MHC class II expression. Chemokines <i>CCL17</i>, <i>CCL22</i>, and <i>CXCL13</i> were among the most highly up-regulated transcripts, mirroring responses observed previously with profibrotic alginate formulations without cells. These findings underscore the issues associated with xenogeneic cell sources in higher-order species yet indicate that targeting innate immune pathways with localized CSF1R inhibition may be sufficient to enable function of encapsulated allogeneic cell therapies.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"18 834","pages":""},"PeriodicalIF":14.6,"publicationDate":"2026-01-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146058136","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 : 2026-01-28DOI: 10.1126/scitranslmed.adu8570
Bianca Viberti, Simone Bellini, Amarine Chancel, Francesca Coló, Lisa Branca, Anja Probst, Julien Schmidt, Thomas Rusterholz, Patrice Fort, Pierre-Hervé Luppi, Claudio L. A. Bassetti, Antoine Adamantidis, Markus H. Schmidt
Narcolepsy is caused by hypothalamic hypocretin/orexin loss and characterized by cataplexy, a unique brain state triggered by emotion. Cataplexy shares features with rapid eye movement (REM) sleep, including muscle atonia and wake-like electroencephalographic activity. REM sleep is characterized by thermoregulatory suspension and, when the need for thermoregulatory responses is reduced as during ambient thermoneutral warming, melanin-concentrating hormone (MCH) neurons play a critical role in favoring REM sleep expression. However, it remains unknown whether REM sleep and cataplexy share thermomodulatory mechanisms. Here, we demonstrate that reduced skin temperatures and a widening of the distal-to-proximal skin temperature gradient precede cataplexy in both patients with narcolepsy and hypocretin-knockout (Hcrt-KO) narcoleptic mice. To test a causal role for skin temperature in cataplexy modulation, thermoneutral manipulation of skin temperature in Hcrt-KO mice revealed that skin cooling promoted cataplexy, whereas skin warming increased REM sleep. Fiber photometry showed that, at constant ambient temperatures (23°C), cataplexy and REM sleep were associated with increased MCH neuron activity. Skin cooling, however, reduced the MCH calcium imaging dynamics associated with cataplexy. Moreover, MCH optogenetic or chemogenetic manipulation recapitulated these effects, with MCH silencing favoring cataplexy and MCH activation driving REM sleep. Last, using the skin warming condition, we combined cFos staining and retrograde labeling and identified activated monosynaptic inputs from known thermoregulatory hubs such as the median preoptic nucleus, dorsomedial hypothalamus, and the parabrachial nucleus to MCH neurons. These findings unveil an unexplored role for skin thermal dynamics and hypothalamic MCH thermosensitivity in dissociating cataplexy and REM sleep.
{"title":"Skin thermal dynamics and hypothalamic thermosensitivity dissociate REM sleep and cataplexy in narcolepsy","authors":"Bianca Viberti, Simone Bellini, Amarine Chancel, Francesca Coló, Lisa Branca, Anja Probst, Julien Schmidt, Thomas Rusterholz, Patrice Fort, Pierre-Hervé Luppi, Claudio L. A. Bassetti, Antoine Adamantidis, Markus H. Schmidt","doi":"10.1126/scitranslmed.adu8570","DOIUrl":"10.1126/scitranslmed.adu8570","url":null,"abstract":"<div >Narcolepsy is caused by hypothalamic hypocretin/orexin loss and characterized by cataplexy, a unique brain state triggered by emotion. Cataplexy shares features with rapid eye movement (REM) sleep, including muscle atonia and wake-like electroencephalographic activity. REM sleep is characterized by thermoregulatory suspension and, when the need for thermoregulatory responses is reduced as during ambient thermoneutral warming, melanin-concentrating hormone (MCH) neurons play a critical role in favoring REM sleep expression. However, it remains unknown whether REM sleep and cataplexy share thermomodulatory mechanisms. Here, we demonstrate that reduced skin temperatures and a widening of the distal-to-proximal skin temperature gradient precede cataplexy in both patients with narcolepsy and hypocretin-knockout (Hcrt-KO) narcoleptic mice. To test a causal role for skin temperature in cataplexy modulation, thermoneutral manipulation of skin temperature in Hcrt-KO mice revealed that skin cooling promoted cataplexy, whereas skin warming increased REM sleep. Fiber photometry showed that, at constant ambient temperatures (23°C), cataplexy and REM sleep were associated with increased MCH neuron activity. Skin cooling, however, reduced the MCH calcium imaging dynamics associated with cataplexy. Moreover, MCH optogenetic or chemogenetic manipulation recapitulated these effects, with MCH silencing favoring cataplexy and MCH activation driving REM sleep. Last, using the skin warming condition, we combined cFos staining and retrograde labeling and identified activated monosynaptic inputs from known thermoregulatory hubs such as the median preoptic nucleus, dorsomedial hypothalamus, and the parabrachial nucleus to MCH neurons. These findings unveil an unexplored role for skin thermal dynamics and hypothalamic MCH thermosensitivity in dissociating cataplexy and REM sleep.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"18 834","pages":""},"PeriodicalIF":14.6,"publicationDate":"2026-01-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146069897","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 : 2026-01-28DOI: 10.1126/scitranslmed.adw8481
Jiayu Liu, Hao Ding, Wang Tan, Renlin Yu, Yue Li, Yuhan Liu, Mengxue Liu, Ping Zhao, Yi Liu, Fang Xu, Xiaofei Lai, Ju Cao
Invasive candidiasis is a leading cause of nosocomial bloodstream infection associated with high mortality, and there is a pressing need to develop biomarker-guided antifungal therapy to improve clinical outcomes. Meteorin-like (METRNL) is a cytokine that can act as a high-affinity ligand for the stem cell factor receptor KIT; however, the functional role of METRNL in fungal infection remains unclear. Here, we found that METRNL acts as a disease-promoting immune checkpoint to facilitate invasive Candida albicans (C. albicans) infection. Mice deficient in METRNL were refractory to a lethal systemic infection with C. albicans. Treatment with a METRNL blocking antibody protected mice from invasive C. albicans infection, whereas treatment with recombinant METRNL or overexpression of endogenous METRNL dampened fungal clearance and aggravated disease mortality but not in mice with macrophage-specific deletion of KIT. The METRNL-KIT axis decreased dectin-1 expression and impaired fungal phagocytosis and killing capacity in macrophages, which was dependent on signal transducer and activator of transcription 3 signaling, thereby negatively regulating host antifungal immunity. In two independent cohorts, patients with candidemia had elevated circulating METRNL concentrations compared with patients with bacteremia or healthy volunteers. In both cohorts, a higher circulating METRNL concentration was associated with poor survival. Therefore, our study provides mechanistic and translational insights into how METRNL orchestrates macrophage-dependent antifungal immunity, implying that a potential theranostic approach involving blood-circulating METRNL-guided patient stratification and targeted therapy of blocking METRNL may help improve the management of human fungal disease through a precision medicine strategy.
{"title":"Meteorin-like is associated with poor outcome in invasive candidiasis in mouse models and in humans","authors":"Jiayu Liu, Hao Ding, Wang Tan, Renlin Yu, Yue Li, Yuhan Liu, Mengxue Liu, Ping Zhao, Yi Liu, Fang Xu, Xiaofei Lai, Ju Cao","doi":"10.1126/scitranslmed.adw8481","DOIUrl":"10.1126/scitranslmed.adw8481","url":null,"abstract":"<div >Invasive candidiasis is a leading cause of nosocomial bloodstream infection associated with high mortality, and there is a pressing need to develop biomarker-guided antifungal therapy to improve clinical outcomes. Meteorin-like (METRNL) is a cytokine that can act as a high-affinity ligand for the stem cell factor receptor KIT; however, the functional role of METRNL in fungal infection remains unclear. Here, we found that METRNL acts as a disease-promoting immune checkpoint to facilitate invasive <i>Candida albicans</i> (<i>C. albicans</i>) infection. Mice deficient in METRNL were refractory to a lethal systemic infection with <i>C. albicans.</i> Treatment with a METRNL blocking antibody protected mice from invasive <i>C. albicans</i> infection, whereas treatment with recombinant METRNL or overexpression of endogenous METRNL dampened fungal clearance and aggravated disease mortality but not in mice with macrophage-specific deletion of KIT. The METRNL-KIT axis decreased dectin-1 expression and impaired fungal phagocytosis and killing capacity in macrophages, which was dependent on signal transducer and activator of transcription 3 signaling, thereby negatively regulating host antifungal immunity. In two independent cohorts, patients with candidemia had elevated circulating METRNL concentrations compared with patients with bacteremia or healthy volunteers. In both cohorts, a higher circulating METRNL concentration was associated with poor survival. Therefore, our study provides mechanistic and translational insights into how METRNL orchestrates macrophage-dependent antifungal immunity, implying that a potential theranostic approach involving blood-circulating METRNL-guided patient stratification and targeted therapy of blocking METRNL may help improve the management of human fungal disease through a precision medicine strategy.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"18 834","pages":""},"PeriodicalIF":14.6,"publicationDate":"2026-01-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146069898","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 : 2026-01-28DOI: 10.1126/scitranslmed.adt1211
Zhongqiu Xie, Pawel Ł. Janczyk, Robert Cornelison, Sarah Lynch, Martyna Glowczyk-Gluc, Becky Leifer, Yiwei Wang, Philip Hahn, Johnathon D. Dooley, Adelaide Fierti, Xinrui Shi, Yiyu Zhang, Tingxuan Li, Qiong Wang, Zhi Zhang, Laine Marrah, Angela Koehler, James W. Mandell, Michael Hilinski, Hui Li
Glioblastoma (GBM) is the most common and deadliest malignancy of the brain. Despite decades of intense research, there has been little change to the overall survival of patients with GBM. Our laboratory recently identified the actin-binding protein advillin (AVIL) as being overexpressed, oncogenic, and necessary for tumorigenesis in GBM. Here, we further examined AVIL expression in GBMs and found that it was enriched across molecular subtypes and states, including GBM stem cells and temozolomide-resistant samples. In contrast, we found that AVIL was scarcely expressed in normal human brain tissue. In addition, Avil knockout in mice had no adverse effects, suggesting that there may be a wide therapeutic window for therapies targeting AVIL. Using high-throughput small-molecule screening, we identified a direct inhibitor of AVIL that bound to the protein and also blocked AVIL binding to its substrate, actin. It induced a transcriptome profile similar to that of AVIL silencing by siRNA and caused down-regulation of FOXM1 and LIN28B, two known downstream targets of AVIL. Moreover, it exhibited selectivity toward tumor cells, sparing astrocytes and neural stem cells in vitro. In vivo, we found that the compound readily crosses the blood-brain barrier and could be delivered orally. We then demonstrated efficacy in five GBM mouse models without evidence of side effects. In summary, we have identified an efficacious first-in-class compound targeting an oncogene in GBM. Further optimization of the molecule may offer an effective therapeutic intervention for GBM.
{"title":"A first-in-class small-molecule inhibitor targeting AVIL exhibits safety and antitumor efficacy in preclinical models of glioblastoma","authors":"Zhongqiu Xie, Pawel Ł. Janczyk, Robert Cornelison, Sarah Lynch, Martyna Glowczyk-Gluc, Becky Leifer, Yiwei Wang, Philip Hahn, Johnathon D. Dooley, Adelaide Fierti, Xinrui Shi, Yiyu Zhang, Tingxuan Li, Qiong Wang, Zhi Zhang, Laine Marrah, Angela Koehler, James W. Mandell, Michael Hilinski, Hui Li","doi":"10.1126/scitranslmed.adt1211","DOIUrl":"10.1126/scitranslmed.adt1211","url":null,"abstract":"<div >Glioblastoma (GBM) is the most common and deadliest malignancy of the brain. Despite decades of intense research, there has been little change to the overall survival of patients with GBM. Our laboratory recently identified the actin-binding protein advillin (AVIL) as being overexpressed, oncogenic, and necessary for tumorigenesis in GBM. Here, we further examined AVIL expression in GBMs and found that it was enriched across molecular subtypes and states, including GBM stem cells and temozolomide-resistant samples. In contrast, we found that AVIL was scarcely expressed in normal human brain tissue. In addition, <i>Avil</i> knockout in mice had no adverse effects, suggesting that there may be a wide therapeutic window for therapies targeting AVIL. Using high-throughput small-molecule screening, we identified a direct inhibitor of AVIL that bound to the protein and also blocked AVIL binding to its substrate, actin. It induced a transcriptome profile similar to that of <i>AVIL</i> silencing by siRNA and caused down-regulation of FOXM1 and LIN28B, two known downstream targets of AVIL. Moreover, it exhibited selectivity toward tumor cells, sparing astrocytes and neural stem cells in vitro. In vivo, we found that the compound readily crosses the blood-brain barrier and could be delivered orally. We then demonstrated efficacy in five GBM mouse models without evidence of side effects. In summary, we have identified an efficacious first-in-class compound targeting an oncogene in GBM. Further optimization of the molecule may offer an effective therapeutic intervention for GBM.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"18 834","pages":""},"PeriodicalIF":14.6,"publicationDate":"2026-01-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146069893","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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