Pub Date : 2026-01-07DOI: 10.1126/scitranslmed.aed6475
Manish C. Choudhary, Jonathan Z. Li
HIV can take several mutational pathways to become resistant to lenacapavir, each with distinct resistance and fitness profiles (Pennetzdorfer et al., this issue).
{"title":"When HIV pays the price: Fitness costs behind lenacapavir resistance","authors":"Manish C. Choudhary, Jonathan Z. Li","doi":"10.1126/scitranslmed.aed6475","DOIUrl":"10.1126/scitranslmed.aed6475","url":null,"abstract":"<div >HIV can take several mutational pathways to become resistant to lenacapavir, each with distinct resistance and fitness profiles (Pennetzdorfer <i>et al.</i>, this issue).</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"18 831","pages":""},"PeriodicalIF":14.6,"publicationDate":"2026-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145908257","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}
Brain stimulation therapies have been increasingly applied to treat patients with drug-resistant epilepsy or other neuropsychiatric disorders, but identifying effective stimulation targets appropriate for individual patients remains challenging. Using intracranial electrophysiological recordings, we found that fast ripple (FR) activity was tightly correlated with the severity of consciousness impairment during seizures in patients with drug-resistant, consciousness-staged epilepsy. Epileptic network analysis based on FR coincidence across brain regions revealed hubs of ictal FR activity, defined as highly connected nodes, specific to individual patients. A small, exploratory study on eight patients with drug-resistant epilepsy showed that stimulating these hubs reduced FRs, ameliorated consciousness impairments, and reduced seizures during a poststimulation time window of up to 11 days. Moreover, FR hub stimulation showed a lower risk of evoking seizures than stimulating seizure onset zones, a now approved treatment option. These results suggest a potentially safe and effective strategy to alleviate epileptic seizures by stimulating patient-specific FR network hubs.
{"title":"Targeting brain hubs of ictal fast ripple activity to reduce seizures in patients with drug-resistant epilepsy","authors":"Shanshan Liang, Lukang Wang, Kaifeng Shen, Zhiji Wang, Xin Zheng, Qingtian Duan, Xianjun Shi, Lei Zhang, Yang Dai, Yuanxi Zou, Jing Deng, Xinyue Zhang, Hongbo Jia, Shiyong Liu, Hui Yang, Ying Mao, Xiang Liao, Chunqing Zhang, Xiaowei Chen","doi":"10.1126/scitranslmed.adq4423","DOIUrl":"10.1126/scitranslmed.adq4423","url":null,"abstract":"<div >Brain stimulation therapies have been increasingly applied to treat patients with drug-resistant epilepsy or other neuropsychiatric disorders, but identifying effective stimulation targets appropriate for individual patients remains challenging. Using intracranial electrophysiological recordings, we found that fast ripple (FR) activity was tightly correlated with the severity of consciousness impairment during seizures in patients with drug-resistant, consciousness-staged epilepsy. Epileptic network analysis based on FR coincidence across brain regions revealed hubs of ictal FR activity, defined as highly connected nodes, specific to individual patients. A small, exploratory study on eight patients with drug-resistant epilepsy showed that stimulating these hubs reduced FRs, ameliorated consciousness impairments, and reduced seizures during a poststimulation time window of up to 11 days. Moreover, FR hub stimulation showed a lower risk of evoking seizures than stimulating seizure onset zones, a now approved treatment option. These results suggest a potentially safe and effective strategy to alleviate epileptic seizures by stimulating patient-specific FR network hubs.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"17 830","pages":""},"PeriodicalIF":14.6,"publicationDate":"2025-12-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145813644","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-24DOI: 10.1126/scitranslmed.ads0594
Yifan Zhang, Dongsheng Wen, Chiakang Ho, Yangdan Liu, Xin Wang, Zhiyuan Zhou, Ya Gao, Qingfeng Li
Skin repair after injury is a complex multistage process. Reepithelialization is a vital component of skin wound healing and involves intricate molecular regulations that are still not fully understood. Here, using a combination of human tissue and animal models, we identified histone deacetylase 5 (HDAC5) as a key mediator of reepithelialization through a mechanism involving nucleocytoplasmic shuttling to regulate deacetylation of a nonhistone protein. We conducted functional validation through a conditional gene knockout mouse model. In addition, parallel studies using ex vivo human skin confirmed that HDAC5 cytoplasmic localization is necessary for efficient wound closure. Liquid chromatography–mass spectrometry of mouse wounds revealed that cytoplasmic HDAC5 interacts with alpha-actinin-4 (ACTN4). Site-directed mutagenesis, immunofluorescence, and luciferase assays demonstrated that HDAC5 deacetylates ACTN4 at the K417 site, allowing nuclear translocation of ACTN4 and subsequent modulation of transcriptional activity of Y-box–binding protein 1 (YBX1). Single-cell transcriptome analysis of mouse wounds revealed cystatin A as a key factor downstream of the HDAC5/ACTN4/YBX1 axis that enhanced reepithelialization and wound healing. We further identified an HDAC5-selective activator, G194-0712, and showed that it improved wound healing in three mouse models of chronic wounds: diabetic wounds, ischemic wounds, and radiation injury. Together, these results highlight a previously unappreciated mechanism involved in skin repair and suggest that HDAC5 activation may hold promise for the treatment of nonhealing skin wounds.
{"title":"HDAC5 deacetylates cytosolic ACTN4 during skin reepithelialization and represents a therapeutic target for chronic wound healing","authors":"Yifan Zhang, Dongsheng Wen, Chiakang Ho, Yangdan Liu, Xin Wang, Zhiyuan Zhou, Ya Gao, Qingfeng Li","doi":"10.1126/scitranslmed.ads0594","DOIUrl":"10.1126/scitranslmed.ads0594","url":null,"abstract":"<div >Skin repair after injury is a complex multistage process. Reepithelialization is a vital component of skin wound healing and involves intricate molecular regulations that are still not fully understood. Here, using a combination of human tissue and animal models, we identified histone deacetylase 5 (HDAC5) as a key mediator of reepithelialization through a mechanism involving nucleocytoplasmic shuttling to regulate deacetylation of a nonhistone protein. We conducted functional validation through a conditional gene knockout mouse model. In addition, parallel studies using ex vivo human skin confirmed that HDAC5 cytoplasmic localization is necessary for efficient wound closure. Liquid chromatography–mass spectrometry of mouse wounds revealed that cytoplasmic HDAC5 interacts with alpha-actinin-4 (ACTN4). Site-directed mutagenesis, immunofluorescence, and luciferase assays demonstrated that HDAC5 deacetylates ACTN4 at the K417 site, allowing nuclear translocation of ACTN4 and subsequent modulation of transcriptional activity of Y-box–binding protein 1 (YBX1). Single-cell transcriptome analysis of mouse wounds revealed cystatin A as a key factor downstream of the HDAC5/ACTN4/YBX1 axis that enhanced reepithelialization and wound healing. We further identified an HDAC5-selective activator, G194-0712, and showed that it improved wound healing in three mouse models of chronic wounds: diabetic wounds, ischemic wounds, and radiation injury. Together, these results highlight a previously unappreciated mechanism involved in skin repair and suggest that HDAC5 activation may hold promise for the treatment of nonhealing skin wounds.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"17 830","pages":""},"PeriodicalIF":14.6,"publicationDate":"2025-12-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145813643","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-24DOI: 10.1126/scitranslmed.aea9007
Grace A. Osborne, Lin Zhang, Feiyang Ma, Mehrnaz Gharaee-Kermani, Jessica L. Turnier, Amanda N. Victory, Amy Hurst, Bin Xu, Elisabeth A. Pedersen, Rachael Bogle, Celine C. Berthier, Vladimir Ognenovski, Mio Nakamura, Lam C. Tsoi, Allison C. Billi, Johann E. Gudjonsson, Benjamin Klein, Pei-Suen Tsou, J. Michelle Kahlenberg
Dermatomyositis is a rare yet devastating autoimmune disease characterized by inflammatory and vasculopathic changes in skin and muscle. Dermatomyositis and systemic lupus erythematosus (lupus) skin lesions have overlapping clinical and histopathological features but show disparate responses to available therapeutics, with dermatomyositis skin disease often relapsing and being recalcitrant. To investigate dermatomyositis immunopathogenesis, nonlesional skin, lesional skin, and circulating immune cells from patients with dermatomyositis were analyzed using single-cell RNA sequencing. Samples were analyzed in parallel with lesional and nonlesional lupus skin, healthy control skin, and peripheral blood from all three patient groups. We demonstrate a pervasive type I interferon signature in dermatomyositis stroma that persisted in culture and was distinguished from lupus by up-regulation of vascular endothelial growth factor and interleukin-18 signaling in dermatomyositis keratinocytes. Furthermore, endothelial cells in lesional dermatomyositis exhibited decreased proliferation, which was not observed in lupus skin. Using cell communication networks, we identified a population of dermatomyositis-specific monocytes interacting with nonproliferating endothelial cells. Coculture of monocytes from patients with dermatomyositis with endothelial cells resulted in increased endothelial cell apoptosis, which was inhibited by Janus kinase 1 (JAK1) blockade. JAK1 inhibition also resulted in reversal of dermatomyositis stromal and inflammatory signatures. Together, our data provide a comprehensive cross-disease characterization of lesional and nonlesional skin in dermatomyositis and implicate monocyte-mediated endothelial cell dysfunction in dermatomyositis vasculopathy. Moreover, these results suggest that JAK inhibition may offer a suitable therapeutic intervention for refractory skin disease.
{"title":"Dermatomyositis is characterized by JAK1-mediated monocyte-driven vasculopathy and inflammation","authors":"Grace A. Osborne, Lin Zhang, Feiyang Ma, Mehrnaz Gharaee-Kermani, Jessica L. Turnier, Amanda N. Victory, Amy Hurst, Bin Xu, Elisabeth A. Pedersen, Rachael Bogle, Celine C. Berthier, Vladimir Ognenovski, Mio Nakamura, Lam C. Tsoi, Allison C. Billi, Johann E. Gudjonsson, Benjamin Klein, Pei-Suen Tsou, J. Michelle Kahlenberg","doi":"10.1126/scitranslmed.aea9007","DOIUrl":"10.1126/scitranslmed.aea9007","url":null,"abstract":"<div >Dermatomyositis is a rare yet devastating autoimmune disease characterized by inflammatory and vasculopathic changes in skin and muscle. Dermatomyositis and systemic lupus erythematosus (lupus) skin lesions have overlapping clinical and histopathological features but show disparate responses to available therapeutics, with dermatomyositis skin disease often relapsing and being recalcitrant. To investigate dermatomyositis immunopathogenesis, nonlesional skin, lesional skin, and circulating immune cells from patients with dermatomyositis were analyzed using single-cell RNA sequencing. Samples were analyzed in parallel with lesional and nonlesional lupus skin, healthy control skin, and peripheral blood from all three patient groups. We demonstrate a pervasive type I interferon signature in dermatomyositis stroma that persisted in culture and was distinguished from lupus by up-regulation of vascular endothelial growth factor and interleukin-18 signaling in dermatomyositis keratinocytes. Furthermore, endothelial cells in lesional dermatomyositis exhibited decreased proliferation, which was not observed in lupus skin. Using cell communication networks, we identified a population of dermatomyositis-specific monocytes interacting with nonproliferating endothelial cells. Coculture of monocytes from patients with dermatomyositis with endothelial cells resulted in increased endothelial cell apoptosis, which was inhibited by Janus kinase 1 (JAK1) blockade. JAK1 inhibition also resulted in reversal of dermatomyositis stromal and inflammatory signatures. Together, our data provide a comprehensive cross-disease characterization of lesional and nonlesional skin in dermatomyositis and implicate monocyte-mediated endothelial cell dysfunction in dermatomyositis vasculopathy. Moreover, these results suggest that JAK inhibition may offer a suitable therapeutic intervention for refractory skin disease.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"17 830","pages":""},"PeriodicalIF":14.6,"publicationDate":"2025-12-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145813625","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}
The right vagus nerve is essential for cardiac homeostasis, and its intrathoracic resection can lead to postoperative cardiac complications. Strategies to restore vagal innervation after transection at the cardiac level remain lacking. Here, we show that early reconnection of the right vagus nerve using an implantable chitosan/poly-ε-caprolactone cuff-like nerve guidance conduit preserved cardiac mechanical function in adult male minipigs subjected to right cardiac vagotomy. Treated animals displayed improved global circumferential, longitudinal, and radial strains and reduced diastolic dyssynchrony. Histological analysis revealed partial repair with about 20% viable vagal fascicles, restoration of myocardial parasympathetic fibers, normalization of oxidative stress and aging markers, and prevention of interstitial fibrosis. These findings suggest that maintaining even limited vagal input prevents early cardiac remodeling by mitigating oxidative stress–induced premature senescence of cardiac cells. Reconnection of the right vagus nerve with chitosan/poly-ε-caprolactone cuff-like nerve guidance conduit may represent a therapeutic approach to preventing right vagotomy–induced heart failure after thoracic surgery or cardiothoracic transplantation.
{"title":"Reconnecting the vagus nerve to the heart through nerve conduit preserves cardiac function in a minipig model of right cardiac vagotomy","authors":"Anar Dushpanova, Eugenio Redolfi-Riva, Valentina Casieri, Letizia Brogi, Chrysanthos Grigoratos, Fabio Bernini, Domiziana Terlizzi, Khatia Gabisonia, Ciro Zinno, Filippo Agnesi, Giulia Furini, Lisa Alibrandi, Aurora Paganelli, Valentina Sassu, Alessandro Carrozzo, Sabrina Marchetti, Silvia Burchielli, Jacopo Carpaneto, Micaela Sgorbini, Antonio Paolo Beltrami, Alessandro Cellerino, Giovanni Donato Aquaro, Silvestro Micera, Vincenzo Lionetti","doi":"10.1126/scitranslmed.aea4306","DOIUrl":"10.1126/scitranslmed.aea4306","url":null,"abstract":"<div >The right vagus nerve is essential for cardiac homeostasis, and its intrathoracic resection can lead to postoperative cardiac complications. Strategies to restore vagal innervation after transection at the cardiac level remain lacking. Here, we show that early reconnection of the right vagus nerve using an implantable chitosan/poly-ε-caprolactone cuff-like nerve guidance conduit preserved cardiac mechanical function in adult male minipigs subjected to right cardiac vagotomy. Treated animals displayed improved global circumferential, longitudinal, and radial strains and reduced diastolic dyssynchrony. Histological analysis revealed partial repair with about 20% viable vagal fascicles, restoration of myocardial parasympathetic fibers, normalization of oxidative stress and aging markers, and prevention of interstitial fibrosis. These findings suggest that maintaining even limited vagal input prevents early cardiac remodeling by mitigating oxidative stress–induced premature senescence of cardiac cells. Reconnection of the right vagus nerve with chitosan/poly-ε-caprolactone cuff-like nerve guidance conduit may represent a therapeutic approach to preventing right vagotomy–induced heart failure after thoracic surgery or cardiothoracic transplantation.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"17 830","pages":""},"PeriodicalIF":14.6,"publicationDate":"2025-12-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145813626","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-24DOI: 10.1126/scitranslmed.adx6797
Xiao-Ting Jiang, Mei-Kuang Chen, Jiwang Lee, Xiayu Rao, Yan Wang, Linjie Luo, Jing Wang, Kelly K. Hunt, Khandan Keyomarsi
Targeting cell cycle checkpoints has emerged as a promising strategy in cancer therapy, yet single-agent inhibitors often fail because of compensatory mechanisms. Here, we demonstrate that coinhibition of ATR (RP-3500) and PKMYT1 (RP-6306) induces synthetic lethality in Rb1-deficient breast cancers by disrupting both S-G2 and G2-M checkpoints. This leads to replication stress, premature mitotic entry, and accumulation of DNA damage. In vitro, Rb1-deficient breast cancer cells exhibited marked apoptosis and loss of clonogenic survival, whereas Rb1-proficient models remained resistant to combination treatment. Genetic manipulation confirmed this dependency: Rb1 knockdown sensitized resistant models, whereas reexpression conferred protection. In vivo, patient-derived xenograft (PDX) models recapitulated these findings. Rb1-deficient tumors regressed after ATR/PKMYT1 coinhibition, whereas Rb1-proficient tumors showed only modest responses. Combination therapy was well tolerated without weight loss or measurable toxicity. Biomarker analysis revealed increased γH2AX and reduced Ki67 staining exclusively in Rb1-deficient PDX models, underscoring the specificity of this response. Mechanistically, Rb1 loss impaired double-strand DNA repair by attenuating homologous recombination and nonhomologous end joining, leading to replication fork collapse, chromosomal instability, and mitotic catastrophe. Proteogenomic analysis identified JNK/p38 stress response pathway activation as a key driver of apoptosis after ATR/PKMYT1 inhibition in Rb1-deficient cells. Clinically, a retrospective analysis of stage IV breast cancer datasets revealed that Rb1-low tumors display reduced DNA repair pathway activity in triple-negative and CDK4/6 inhibitor–resistant luminal breast cancers. These results identify Rb1 loss as a predictive biomarker for ATR/PKMYT1-targeted therapy, offering a potential precision treatment strategy for advanced breast cancers.
{"title":"Rb1 deficiency induces synthetic lethality with ATR and PKMYT1 coinhibition in breast cancer cell lines and patient-derived xenografts","authors":"Xiao-Ting Jiang, Mei-Kuang Chen, Jiwang Lee, Xiayu Rao, Yan Wang, Linjie Luo, Jing Wang, Kelly K. Hunt, Khandan Keyomarsi","doi":"10.1126/scitranslmed.adx6797","DOIUrl":"10.1126/scitranslmed.adx6797","url":null,"abstract":"<div >Targeting cell cycle checkpoints has emerged as a promising strategy in cancer therapy, yet single-agent inhibitors often fail because of compensatory mechanisms. Here, we demonstrate that coinhibition of ATR (RP-3500) and PKMYT1 (RP-6306) induces synthetic lethality in Rb1-deficient breast cancers by disrupting both S-G<sub>2</sub> and G<sub>2</sub>-M checkpoints. This leads to replication stress, premature mitotic entry, and accumulation of DNA damage. In vitro, Rb1-deficient breast cancer cells exhibited marked apoptosis and loss of clonogenic survival, whereas Rb1-proficient models remained resistant to combination treatment. Genetic manipulation confirmed this dependency: Rb1 knockdown sensitized resistant models, whereas reexpression conferred protection. In vivo, patient-derived xenograft (PDX) models recapitulated these findings. Rb1-deficient tumors regressed after ATR/PKMYT1 coinhibition, whereas Rb1-proficient tumors showed only modest responses. Combination therapy was well tolerated without weight loss or measurable toxicity. Biomarker analysis revealed increased γH2AX and reduced Ki67 staining exclusively in Rb1-deficient PDX models, underscoring the specificity of this response. Mechanistically, Rb1 loss impaired double-strand DNA repair by attenuating homologous recombination and nonhomologous end joining, leading to replication fork collapse, chromosomal instability, and mitotic catastrophe. Proteogenomic analysis identified JNK/p38 stress response pathway activation as a key driver of apoptosis after ATR/PKMYT1 inhibition in Rb1-deficient cells. Clinically, a retrospective analysis of stage IV breast cancer datasets revealed that Rb1-low tumors display reduced DNA repair pathway activity in triple-negative and CDK4/6 inhibitor–resistant luminal breast cancers. These results identify Rb1 loss as a predictive biomarker for ATR/PKMYT1-targeted therapy, offering a potential precision treatment strategy for advanced breast cancers.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"17 830","pages":""},"PeriodicalIF":14.6,"publicationDate":"2025-12-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145813642","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-24DOI: 10.1126/scitranslmed.adv0313
Guangchao Qing, Yuxuan Zhang, Yongchao Wang, Xianlei Li, Ting Luo, Fuxue Zhang, Qiankun Ni, Runjing Hu, Shaobo Shan, Hong Zhang, Rui Yuan, Yaling Gan, Xing-Jie Liang, Yang Luo
Sepsis-associated secondary infection often leads to a high mortality rate. Dysfunctional macrophages are primary contributors to inadequate antimicrobial defense in patients with sepsis-associated immunosuppression. Rejuvenating macrophage antibacterial capacity is beneficial for host defense against secondary infection. Here, we developed “BATMAN” (bacteria-targeted transformable macrophage nanorejuvenator), a self-assembling peptide nanoparticle to tackle sepsis-associated secondary infection by coordinating the arrest of invasive bacteria and rejuvenation of dysfunctional macrophages. BATMAN comprises a bacteria-targeting ubiquicidin peptide domain, bacterial lipase–sensitive cholesteryl hemisuccinate, an assembly-driving FFVLK domain, and the immunoglobulin G–derived tuftsin peptide. Upon activation by bacterial lipase, the particles undergo an inside-out transformation and assembly to expose and cluster the concealed tuftsin peptides for interaction with macrophage Fcγ receptors. Interaction of tuftsin clusters with macrophage Fcγ receptors enhanced bacterial phagocytosis and drove macrophage repolarization. In a cecal slurry–induced septic mouse model with secondary pulmonary infection, BATMAN treatment improved survival rates and rejuvenated the sepsis-compromised immune response to address polymicrobial- and multidrug-resistant pathogen–induced pulmonary infections. These findings suggest that BATMAN holds promise for further development as a therapeutic alternative for sepsis-associated secondary infection.
{"title":"FcγR-targeted tuftsin clusters rejuvenate macrophages in preclinical sepsis–associated secondary infection","authors":"Guangchao Qing, Yuxuan Zhang, Yongchao Wang, Xianlei Li, Ting Luo, Fuxue Zhang, Qiankun Ni, Runjing Hu, Shaobo Shan, Hong Zhang, Rui Yuan, Yaling Gan, Xing-Jie Liang, Yang Luo","doi":"10.1126/scitranslmed.adv0313","DOIUrl":"10.1126/scitranslmed.adv0313","url":null,"abstract":"<div >Sepsis-associated secondary infection often leads to a high mortality rate. Dysfunctional macrophages are primary contributors to inadequate antimicrobial defense in patients with sepsis-associated immunosuppression. Rejuvenating macrophage antibacterial capacity is beneficial for host defense against secondary infection. Here, we developed “BATMAN” (bacteria-targeted transformable macrophage nanorejuvenator), a self-assembling peptide nanoparticle to tackle sepsis-associated secondary infection by coordinating the arrest of invasive bacteria and rejuvenation of dysfunctional macrophages. BATMAN comprises a bacteria-targeting ubiquicidin peptide domain, bacterial lipase–sensitive cholesteryl hemisuccinate, an assembly-driving FFVLK domain, and the immunoglobulin G–derived tuftsin peptide. Upon activation by bacterial lipase, the particles undergo an inside-out transformation and assembly to expose and cluster the concealed tuftsin peptides for interaction with macrophage Fcγ receptors. Interaction of tuftsin clusters with macrophage Fcγ receptors enhanced bacterial phagocytosis and drove macrophage repolarization. In a cecal slurry–induced septic mouse model with secondary pulmonary infection, BATMAN treatment improved survival rates and rejuvenated the sepsis-compromised immune response to address polymicrobial- and multidrug-resistant pathogen–induced pulmonary infections. These findings suggest that BATMAN holds promise for further development as a therapeutic alternative for sepsis-associated secondary infection.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"17 830","pages":""},"PeriodicalIF":14.6,"publicationDate":"2025-12-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145813645","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}
A comprehensive understanding of human systemic immune responses to mosquito-borne dengue virus (DENV) infection is vital for addressing challenges posed by viral heterologous serotypes and potential adverse memory immune responses. Asymptomatic DENV infection offers an opportunity to explore protective immunity because infected individuals effectively clear the virus without symptomatic manifestations. However, data on asymptomatic dengue are scarce because of limited sample availability during silent viremia. Here, we conducted single-cell RNA and immune receptor sequencing of peripheral blood mononuclear cells (PBMCs) from donors with varying disease severities including asymptomatic dengue and performed longitudinal analysis in a symptomatic dengue cohort, enabling identification of distinct immune responses. In asymptomatic dengue, we observed potential indications of enhanced viral antigen processing via MHC-I, correlating with increased CD8 effector T cell activities, distinct NK cell profiles, and enriched IGHA1+ plasmablasts. In contrast, symptomatic dengue cases exhibited indications toward antibody-mediated viral entry, elevated type I interferon responses, and IL-10–associated expansion of IGHG1+ plasmablasts with biased V(D)J gene usage and a shared B cell receptor clonotype network. Our study reports a gene expression and immune receptor repertoire resource for systemic immune responses to DENV infection and suggests distinct mechanisms for potential protection and pathogenicity in individuals with asymptomatic compared with symptomatic dengue.
{"title":"Distinct systemic immune responses in asymptomatic and symptomatic dengue virus infection","authors":"Waradon Sungnak, Natnicha Jiravejchakul, Tiraput Poonpanichakul, Chawinya Trakoolsoontorn, Sirawit Srikor, Anunya Opasawatchai, Jantarika Arora, Damita Jevapatarakul, Narita Thungsatianpun, Sarintip Nguantad, Juthamard Chantaraamporn, Pattarakul Pakchotanon, Nuntaya Punyadee, Thaneeya Duangchinda, Panisadee Avirutnan, DENFREE Thailand, Juthathip Mongkolsapaya, Kerstin B. Meyer, Oranart Matangkasombut, Varodom Charoensawan, Sarah A. Teichmann, Ponpan Matangkasombut","doi":"10.1126/scitranslmed.ads5932","DOIUrl":"10.1126/scitranslmed.ads5932","url":null,"abstract":"<div >A comprehensive understanding of human systemic immune responses to mosquito-borne dengue virus (DENV) infection is vital for addressing challenges posed by viral heterologous serotypes and potential adverse memory immune responses. Asymptomatic DENV infection offers an opportunity to explore protective immunity because infected individuals effectively clear the virus without symptomatic manifestations. However, data on asymptomatic dengue are scarce because of limited sample availability during silent viremia. Here, we conducted single-cell RNA and immune receptor sequencing of peripheral blood mononuclear cells (PBMCs) from donors with varying disease severities including asymptomatic dengue and performed longitudinal analysis in a symptomatic dengue cohort, enabling identification of distinct immune responses. In asymptomatic dengue, we observed potential indications of enhanced viral antigen processing via MHC-I, correlating with increased CD8 effector T cell activities, distinct NK cell profiles, and enriched <i>IGHA1<sup>+</sup></i> plasmablasts. In contrast, symptomatic dengue cases exhibited indications toward antibody-mediated viral entry, elevated type I interferon responses, and IL-10–associated expansion of <i>IGHG1</i><sup>+</sup> plasmablasts with biased V(D)J gene usage and a shared B cell receptor clonotype network. Our study reports a gene expression and immune receptor repertoire resource for systemic immune responses to DENV infection and suggests distinct mechanisms for potential protection and pathogenicity in individuals with asymptomatic compared with symptomatic dengue.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"17 829","pages":""},"PeriodicalIF":14.6,"publicationDate":"2025-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145766427","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-17DOI: 10.1126/scitranslmed.adp5088
Carla L. Alves, Leena Karimi, Mikkel G. Terp, Mie K. Jakobsen, Fiona H. Zhou, Benedetta Policastro, Nikoline Nissen, Lene E. Johansen, Tina Ravnsborg, Leila Eshraghi, Sana Tamboowala, Ole N. Jensen, Elgene Lim, Henrik J. Ditzel
Combined CDK4/6 inhibitor (CDK4/6i) and endocrine therapy (ET) improves outcomes in advanced estrogen receptor–positive (ER+) breast cancer, but emergence of resistance to this combination underscores the pressing need for alternative therapeutic strategies. A promising approach involves adding an inhibitor of the PI3K/AKT/mTOR pathway to the standard combined CDK4/6i and ET, but selecting the most effective inhibitors and their optimal combinations has proven to be challenging. Here, we compared the efficacy of various triple combinations using single- or dual-point PI3K/AKT/mTOR pathway inhibitors in breast cancer cell lines, cell line xenografts, patient-derived xenografts, and organoids resistant to CDK4/6i and ET and exhibiting PIK3CA, PTEN, or AKT1 mutations. PIK3CA-mutant, PTEN–wild type, CDK4/6i-resistant, and ET-resistant models required the addition of the dual PI3K/mTOR inhibitor gedatolisib to effectively impede tumor growth by blocking the HIF-1α pathway through both mTORC1 inhibition and PI3K/AKT-mediated modulation of GSK3α/β activity. Conversely, PIK3CA–wild type, PTEN-null cells benefited from triple combinations incorporating either the AKT inhibitor capivasertib or the dual mTORC1/2 inhibitor sapanisertib to block tumor growth. In addition, gedatolisib reduced viability of PIK3CA- or AKT1-mutant and PTEN–wild type CDK4/6i-resistant patient-derived organoids compared with the α-specific PI3K inhibitor alpelisib. Our data support the higher efficacy of gedatolisib over alpelisib in ER+ breast tumors harboring alterations of the PI3K/AKT/mTOR pathway including PIK3CA or AKT1 mutations.
{"title":"Dual PI3K/mTOR inhibition is required to combat resistance to CDK4/6 inhibitor and endocrine therapy in PIK3CA-mutant breast cancer","authors":"Carla L. Alves, Leena Karimi, Mikkel G. Terp, Mie K. Jakobsen, Fiona H. Zhou, Benedetta Policastro, Nikoline Nissen, Lene E. Johansen, Tina Ravnsborg, Leila Eshraghi, Sana Tamboowala, Ole N. Jensen, Elgene Lim, Henrik J. Ditzel","doi":"10.1126/scitranslmed.adp5088","DOIUrl":"10.1126/scitranslmed.adp5088","url":null,"abstract":"<div >Combined CDK4/6 inhibitor (CDK4/6i) and endocrine therapy (ET) improves outcomes in advanced estrogen receptor–positive (ER<sup>+</sup>) breast cancer, but emergence of resistance to this combination underscores the pressing need for alternative therapeutic strategies. A promising approach involves adding an inhibitor of the PI3K/AKT/mTOR pathway to the standard combined CDK4/6i and ET, but selecting the most effective inhibitors and their optimal combinations has proven to be challenging. Here, we compared the efficacy of various triple combinations using single- or dual-point PI3K/AKT/mTOR pathway inhibitors in breast cancer cell lines, cell line xenografts, patient-derived xenografts, and organoids resistant to CDK4/6i and ET and exhibiting <i>PIK3CA</i>, <i>PTEN</i>, or <i>AKT1</i> mutations. <i>PIK3CA</i>-mutant, <i>PTEN</i>–wild type, CDK4/6i-resistant, and ET-resistant models required the addition of the dual PI3K/mTOR inhibitor gedatolisib to effectively impede tumor growth by blocking the HIF-1α pathway through both mTORC1 inhibition and PI3K/AKT-mediated modulation of GSK3α/β activity. Conversely, <i>PIK3CA</i>–wild type, <i>PTEN</i>-null cells benefited from triple combinations incorporating either the AKT inhibitor capivasertib or the dual mTORC1/2 inhibitor sapanisertib to block tumor growth. In addition, gedatolisib reduced viability of <i>PIK3CA</i>- or <i>AKT1</i>-mutant and <i>PTEN</i>–wild type CDK4/6i-resistant patient-derived organoids compared with the α-specific PI3K inhibitor alpelisib. Our data support the higher efficacy of gedatolisib over alpelisib in ER<sup>+</sup> breast tumors harboring alterations of the PI3K/AKT/mTOR pathway including <i>PIK3CA</i> or <i>AKT1</i> mutations.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"17 829","pages":""},"PeriodicalIF":14.6,"publicationDate":"2025-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145765538","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}
Monoclonal antibodies have transformed the therapeutic landscape across oncology, immunology, and infectious diseases by enabling high-affinity, antigen-specific targeting to neutralize soluble molecules, block cellular interactions, or deplete cells. Although high specificity is critical for safety, it may confer an inherent susceptibility to even minor variations in the target epitope. Here, we investigated the impact of natural single-nucleotide variants on antigen recognition by therapeutic monoclonal antibodies, both approved and in clinical development. For almost every antibody analyzed, we identified protein variants in or near the antibody-antigen interface, a subset of which were predicted to disrupt antigen recognition. Experimental studies corroborated the impact of select variants for four different antigens, revealing complete loss of antibody binding in some cases. For example, a human breast cancer cell line overexpressing human epidermal growth factor receptor 2 (HER-2), but engineered to carry the HER-2P594H variant, was completely resistant to killing even by highly potent clinical antibody-drug conjugates. These findings suggest that natural variants can confer primary resistance to antibody-based therapies, with critical implications for treatment outcomes, patient management, and safety, particularly in the context of potent modalities such as antibody-drug conjugates. Individual resistance-associated variants, although globally rare, are enriched in specific populations, underscoring the importance of accounting for genetic diversity in both drug development and clinical decision-making.
{"title":"Single–amino acid variants in target epitopes can confer resistance to antibody-based therapies","authors":"Romina Marone, Erblin Asllanaj, Giuseppina Capoferri, Torsten Schwede, Lukas T. Jeker, Rosalba Lepore","doi":"10.1126/scitranslmed.ady4877","DOIUrl":"10.1126/scitranslmed.ady4877","url":null,"abstract":"<div >Monoclonal antibodies have transformed the therapeutic landscape across oncology, immunology, and infectious diseases by enabling high-affinity, antigen-specific targeting to neutralize soluble molecules, block cellular interactions, or deplete cells. Although high specificity is critical for safety, it may confer an inherent susceptibility to even minor variations in the target epitope. Here, we investigated the impact of natural single-nucleotide variants on antigen recognition by therapeutic monoclonal antibodies, both approved and in clinical development. For almost every antibody analyzed, we identified protein variants in or near the antibody-antigen interface, a subset of which were predicted to disrupt antigen recognition. Experimental studies corroborated the impact of select variants for four different antigens, revealing complete loss of antibody binding in some cases. For example, a human breast cancer cell line overexpressing human epidermal growth factor receptor 2 (HER-2), but engineered to carry the HER-2<sup>P594H</sup> variant, was completely resistant to killing even by highly potent clinical antibody-drug conjugates. These findings suggest that natural variants can confer primary resistance to antibody-based therapies, with critical implications for treatment outcomes, patient management, and safety, particularly in the context of potent modalities such as antibody-drug conjugates. Individual resistance-associated variants, although globally rare, are enriched in specific populations, underscoring the importance of accounting for genetic diversity in both drug development and clinical decision-making.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"17 829","pages":""},"PeriodicalIF":14.6,"publicationDate":"2025-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145765542","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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