Science Translational Medicine最新文献

{"title":"Aberrant erythrocyte rigidity in JAK2V617F myeloproliferative neoplasms underlies concurrent thrombosis and hemorrhage","authors":"Aae Suzuki,&nbsp;Liang Zhao,&nbsp;Chelsea Thorsheim,&nbsp;Brittany Weiderhold,&nbsp;Changsong Yang,&nbsp;Valerie Tutwiler,&nbsp;Carla Casu,&nbsp;Jacob W. Myerson,&nbsp;Elizabeth O. Hexner,&nbsp;Narla Mohandas,&nbsp;Vladimir R. Muzykantov,&nbsp;Rustem I. Litvinov,&nbsp;Chandrasekaran Nagaswami,&nbsp;Rebecca A. Risman,&nbsp;Peng Ji,&nbsp;Timothy J. Stalker,&nbsp;Aaron R. Goldman,&nbsp;Hsin-Yao Tang,&nbsp;David W. Speicher,&nbsp;Paul A. Janmey,&nbsp;Stefano Rivella,&nbsp;Wei Tong,&nbsp;John W. Weisel,&nbsp;Tatyana M. Svitkina,&nbsp;Charles S. Abrams","doi":"10.1126/scitranslmed.adt0044","DOIUrl":"10.1126/scitranslmed.adt0044","url":null,"abstract":"<div >Thrombotic events are the leading cause of death in myeloproliferative neoplasms (MPNs) driven by the JAK2 Val⁶¹⁷→Phe (JAK2V617F) mutation. We investigated how JAK2V617F alters hemostasis and thrombosis in humans and in lineage-specific knockin mice to test whether red blood cell (RBC) mechanics contribute directly to clot pathology. <i>Jak2^F/+Vav-Cre</i> knockin mice form structurally aberrant clots characterized by extended clot formation times and unstable hemostatic plug formation. Whole-blood clot contraction in vitro was impaired in humans and mice carrying the JAK2V617F mutation, even when <i>Jak2^V617F</i> erythrocytes were resuspended in normal plasma with normal platelets. Thus, in addition to increasing the hematocrit, the JAK2V617F mutation imparted intrinsic changes in erythrocytes critical for mediating abnormal clot formation. Biophysical analysis showed that <i>Jak2^V617F</i> erythrocytes had stiffened membranes, making them less compressible during clot contraction. Proteomic and lipidomic analysis of <i>Jak2^V617F</i> erythrocytes revealed the loss of key membrane and cytoskeleton proteins, a sparse spectrin cytoskeletal network, increased membrane lipid content, and deep plasma membrane invaginations that were consistent with biaxial cytoskeletal stretching and altered lipid packing. These JAK2V617F-driven changes in erythropoiesis generated intrinsically rigid erythrocytes that impaired clot contraction and produced larger and more occlusive, yet mechanically unstable thrombi. This mechanism may explain the contradictory coexistence of thrombosis and hemorrhage in MPNs and why both complications improve when blood counts are lowered, suggesting that targeting erythrocyte mechanics may provide previously unidentified therapeutic opportunities.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"18 870","pages":""},"PeriodicalIF":15.6,"publicationDate":"2026-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/scitranslmed.adt0044","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149093344","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Immunoregulatory artificial lymph nodes restore antigen-specific tolerance in advanced multiple sclerosis","authors":"Jingsen Ji,&nbsp;Xinhuan Wang,&nbsp;Lu Liu,&nbsp;Jing Zhang,&nbsp;Jiaqing Wan,&nbsp;Gengyou Li,&nbsp;Guangting Xie,&nbsp;Jingyu Qi,&nbsp;Leyan Xuan,&nbsp;Yuying Yao,&nbsp;Fangling Liao,&nbsp;Xiaobao Cao,&nbsp;Ya Liu,&nbsp;Qi Gu,&nbsp;Xing-Jie Liang,&nbsp;Weisheng Guo","doi":"10.1126/scitranslmed.aea7960","DOIUrl":"10.1126/scitranslmed.aea7960","url":null,"abstract":"<div >Tolerogenic dendritic cell (tolDC) vaccines are a promising antigen-specific therapy for multiple sclerosis (MS), yet their efficacy is limited by poor homing to secondary lymphoid organs and rapid loss of the tolerogenic phenotype in native inflamed lymph nodes. Here, we developed a 3D-printed tolerogenic artificial lymph node (tol-aLN) that creates a protected immune niche for durable tolerance induction. tolDCs were loaded onto a porous gelatin methacrylate scaffold engineered for sustained C-C motif chemokine ligand 21 (CCL21) release, recruiting naïve CD4⁺ T cells and shielding tolDCs from an inflammatory lymph node. Geometric optimization of an orthogonal lattice scaffold enhanced spatially confined DC–T cell interactions, promoting robust and stable induction of regulatory T cells (T_reg cells). In experimental autoimmune encephalomyelitis (EAE), tol-aLN implantation attenuated disease even at advanced stages by inducing antigen-specific Foxp3⁺ T_reg cells that trafficked to the spleen, lymph nodes, and central nervous system (CNS). Conditional T_reg cell depletion abolished therapeutic efficacy, indicating that T_reg cells are necessary mediators of tol-aLN–induced protection. Long-term studies revealed sustained remission without impairing systemic immunity. In a myelin oligodendrocyte glycoprotein (amino acids 1 to 125) (MOG_1–125)–induced EAE model, multivalent tol-aLN also efficiently suppressed inflammatory B cells and autoantibody production, reprogramming CNS B cells toward a regulatory state. Single-cell transcriptomics further revealed a global reduction in interferon-stimulated gene activity and restoration of homeostatic microglial phenotypes. Collectively, tol-aLN offers a scalable, antigen-specific platform for immune tolerance and CNS protection, with translational potential for MS and other autoimmune diseases.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"18 870","pages":""},"PeriodicalIF":15.6,"publicationDate":"2026-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149093328","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Early-life microbiota direct an epithelial S100 program required for neonatal immunity","authors":"Shikha Negi,&nbsp;Seika Hashimoto-Hill,&nbsp;Amanda Waddell,&nbsp;Laura Engleman,&nbsp;Maggie Lutz,&nbsp;Taylor Rice,&nbsp;Lee A. Denson,&nbsp;Bruce A. Vallance,&nbsp;Nurit P. Azouz,&nbsp;Philippe A. Tessier,&nbsp;Sergei I. Grivennikov,&nbsp;Hitesh Deshmukh,&nbsp;Theresa Alenghat","doi":"10.1126/scitranslmed.adx6147","DOIUrl":"10.1126/scitranslmed.adx6147","url":null,"abstract":"<div >Despite appreciation that neonatal immune responses differ markedly from those of adults, the mechanisms that enable early-life immunity remain poorly understood. Here, we find that healthy newborn mice express high concentrations of the S100 calcium-binding protein A8/A9 (S100A8/S100A9) antimicrobial heterodimer calprotectin and that this early up-regulation in the intestine is driven by initial exposure to commensal bacteria. Impaired calprotectin expression or microbiota colonization at birth increased susceptibility of neonatal mice to sepsis and death postinfection; however, calprotectin administration rescued microbiota-depleted pups from infection. Microbiota colonization induced S100A9 expression by intestinal epithelial cells (IECs), and epithelial cells represented the main source of calprotectin in the neonatal intestine. Consistent with a critical role in early-life defense, neonatal IEC-specific <i>S100A9</i> knockout pups were highly susceptible to infection, phenocopying <i>S100A8/A9</i> full knockout and antibiotic-exposed neonatal mice. IEC-intrinsic S100A9 expression mediated microbiota-sensitive defense in neonatal mice, and commensal bacteria, such as <i>Lactobacillus</i>, were sufficient to prime this epithelial defense pathway. Mechanistically, indole-3-lactic acid produced by initial colonizers directed IEC intrinsic up-regulation of S100A9 in both mice and human intestinal organoids. Thus, microbiota-epithelial dynamics that occur at birth are essential for programming early-life immunity and suggest that probiotic approaches targeting epithelial cells could prevent neonatal sepsis and death.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"18 870","pages":""},"PeriodicalIF":15.6,"publicationDate":"2026-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149093290","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A multiomic atlas reveals distinct immune landscapes in preterm and term chronic placental inflammation","authors":"Dustyn Levenson,&nbsp;Roberto Romero,&nbsp;Roger Pique-Regi,&nbsp;Yi Xu,&nbsp;Jose Galaz,&nbsp;Riddhishrree Badhan,&nbsp;Eva Kareus,&nbsp;Seungbaek Lee,&nbsp;Hajime Ino,&nbsp;Sarah Niesen,&nbsp;Francesco Monticolo,&nbsp;Jian Shu,&nbsp;Luke Myers,&nbsp;Kristine M. Wylie,&nbsp;Gaurav Bhatti,&nbsp;Adi L. Tarca,&nbsp;Nardhy Gomez-Lopez","doi":"10.1126/scitranslmed.aee9049","DOIUrl":"10.1126/scitranslmed.aee9049","url":null,"abstract":"<div >Chronic placental inflammation (CPI), an umbrella term encompassing chronic chorioamnionitis, chronic villitis, and chronic deciduitis, is associated with preterm birth (PTB), yet its cellular and molecular determinants across gestation remain poorly defined. Here, we constructed an integrated multiomic atlas of CPI by profiling placental and extraplacental tissues from preterm and term pregnancies using imaging mass cytometry, single-cell RNA sequencing, spatial transcriptomics, and T cell receptor (TCR) repertoire mining. CPI emerged as a gestational age–dependent immune continuum rather than a uniform inflammatory state. Preterm CPI was characterized by infiltration of cytotoxic CD8⁺ T cells, activated macrophages, and natural killer (NK) cells in the extraplacental membranes. In contrast, term CPI exhibited spatially confined immune niches enriched for homeostatic myeloid cells and regulatory T cells. Multiomic integration revealed active contributions from the developing fetal immune system in preterm CPI, including macrophages, T cells, and mast cells that reshaped maternal-fetal immune cross-talk. Cell-cell–communication analyses uncovered proinflammatory signaling states in preterm CPI and resolution-phase pathways in term CPI, whereas TCR repertoire profiling identified memory clonotypes with viral epitope similarity, consistent with antigen-agnostic activation. Overall, this atlas defines the cellular, spatial, and transcriptional architecture of CPI and provides a framework for translational biomarker discovery and therapeutic intervention development.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"18 870","pages":""},"PeriodicalIF":15.6,"publicationDate":"2026-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149093343","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Erratum for the Research Article “Multifunctional antibody responses from a primate Shigella outbreak inform vaccine design”","authors":"","doi":"10.1126/scitranslmed.aem3393","DOIUrl":"10.1126/scitranslmed.aem3393","url":null,"abstract":"","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"18 870","pages":""},"PeriodicalIF":15.6,"publicationDate":"2026-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149100872","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A single-dose topical therapy cures scabies in a human-relevant porcine model","authors":"Deepani Darshika Fernando,&nbsp;Sara Taylor,&nbsp;Gangi Rameshika Samarawickrama,&nbsp;Nirupama Abeysekara Nammunige,&nbsp;Gunter Hartel,&nbsp;Vern Bowles,&nbsp;Katja Fischer","doi":"10.1126/scitranslmed.aeg5917","DOIUrl":"10.1126/scitranslmed.aeg5917","url":null,"abstract":"<div >Scabies affects ∼400 million people annually, yet current therapies lack ovicidal activity, require repeat dosing, and are increasingly compromised by treatment failure and resistance. The absence of a single-application therapy capable of eliminating both motile mites and eggs represents one important limitation to effective disease control. We developed a mechanism-informed topical therapy combining abametapir, a metalloprotease inhibitor with ovicidal activity, and flavesone, a β-triketone with rapid miticidal effects, designed to target multiple parasite life stages through distinct, non-neurotoxic mechanisms. Using a porcine model that closely recapitulates human scabies, we assessed efficacy, pruritus reduction, and pharmacologic exposure after topical administration. In severe scabies, a single 4-hour treatment eradicated all live mites and eggs and reduced pruritus, outperforming a standard two-dose oral ivermectin regimen. Skin pharmacokinetics demonstrated rapid attainment of concentrations with exposure profiles, supporting single-dose efficacy despite shorter systemic half-lives than ivermectin. Together, this promising therapeutic combination may offer a simplified and potentially resistance-resilient approach to scabies management.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"18 869","pages":""},"PeriodicalIF":15.6,"publicationDate":"2026-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149077626","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Prime editing of human hematopoietic stem cells for correction of GATA2 deficiency","authors":"Jonas H. Wolff,&nbsp;Thomas W. Skov,&nbsp;Sofie R. Dorset,&nbsp;Janni Sjelborg,&nbsp;Sujan Ravendran,&nbsp;Anne Louise S. Revenfeld,&nbsp;Didde Haslund,&nbsp;Anaïs Marie Møller,&nbsp;Mette Holm,&nbsp;Martin K. Thomsen,&nbsp;Trine H. Mogensen,&nbsp;Bjarne K. Møller,&nbsp;Rasmus O. Bak,&nbsp;Jacob Giehm Mikkelsen","doi":"10.1126/scitranslmed.aec7031","DOIUrl":"10.1126/scitranslmed.aec7031","url":null,"abstract":"<div >GATA2 (GATA binding protein 2) deficiency is a severe immunodeficiency caused by heterozygous variants in the gene encoding the transcription factor GATA2. Ex vivo gene editing of a patient’s own CD34⁺ hematopoietic stem and progenitor cells (HSPCs) could provide curative treatment. However, current methods that rely on nuclease-dependent editing face considerable challenges, including off-target effects, genotoxicity, and reduced engraftment potential. Here, we report the development of an efficient gene editing therapy for GATA2 deficiency using prime editing with a favorable safety profile in terms of off-target effects and genotoxicity. We used prime editing to correct a <i>GATA2</i> c.956_962del variant in patient-derived CD34⁺ HSPCs, reaching up to 70% prime editing efficiency and an increase in functional <i>GATA2</i> alleles from 50 to 77%. We demonstrate that prime-edited patient HSPCs showed increased engraftment potential compared with untreated cells and detected limited on-target genotoxicity and no off-target editing at the top 20 predicted sites. Short prestimulation of CD34⁺ HSPCs supported efficient prime editing while preserving stemness, mitigating p53 activation, and increasing multilineage engraftment. We report PASSIGE (prime editing–assisted site-specific integrase gene editing) in CD34⁺ HSPCs, developing a more broadly applicable, double-strand break–independent complementary DNA insertion strategy with the potential to address a large proportion of alleles causing GATA2 deficiency. Together, our results demonstrate the preclinical development of prime editing–based therapies for GATA2 deficiency in CD34⁺ HSPCs.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"18 869","pages":""},"PeriodicalIF":15.6,"publicationDate":"2026-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149077629","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Hyperosmotic niche adaptation and tissue polyamines underlie MRSA persistence in the kidney","authors":"Nobuhiro Kanazawa,&nbsp;Caroline P. Martens,&nbsp;Shinichi Makino,&nbsp;Segewkal Hawaze Heruye,&nbsp;Amy Zollman,&nbsp;Jered Myslinski,&nbsp;Annabelle White,&nbsp;Chetan Poudel,&nbsp;Jodi Yanagida,&nbsp;Farooq Syed,&nbsp;Bernhard Maier,&nbsp;Yinghua Cheng,&nbsp;Bill Bowen,&nbsp;Tarek M. El-Achkar,&nbsp;Patrick C McGuire,&nbsp;Fang Fang,&nbsp;Yunlong Liu,&nbsp;Kyle McCrocklin,&nbsp;Juexin Wang,&nbsp;Kazuya Hirakochi,&nbsp;Tomohiko Ai,&nbsp;Taeok Bae,&nbsp;Kimberly Martinod,&nbsp;Paul D. Fey,&nbsp;Pierre C. Dagher,&nbsp;Takashi Hato","doi":"10.1126/scitranslmed.aed4200","DOIUrl":"10.1126/scitranslmed.aed4200","url":null,"abstract":"<div >Methicillin-resistant <i>Staphylococcus aureus</i> (MRSA) bacteremia causes substantial morbidity, but tissue reservoirs that permit bacterial persistence remain poorly defined. Using intravenous USA300 MRSA infection in mice, multiplexed imaging, dual-species transcriptomics, host and bacterial genetics, and cell-based assays, we uncovered the renal inner medulla, the site of urine concentration, as an MRSA reservoir. In this hyperosmotic niche, MRSA evaded immune detection and co-opted tissue polyamines to sustain growth, enabling subsequent spread toward the renal cortex. Neutrophil recruitment to the inner medulla was profoundly delayed owing to osmotic inhibition of immune cell migration. Disruption of medullary osmolality with the loop diuretic furosemide accelerated neutrophil infiltration, limited bacterial spread, and improved renal outcomes. Mechanistically, polyamines promoted MRSA persistence through both extracellular and intracellular actions that depended on local osmolality and pH. In the medullary milieu, polyamines primarily associated with the bacterial surface and stabilized membranes against osmotic stress. Intracellular polyamines enhanced translation of <i>guaB</i> (inosine monophosphate dehydrogenase), the rate-limiting enzyme in bacterial de novo purine biosynthesis. The polyamine-catabolizing gene <i>speG</i> (spermidine acetyltransferase), uniquely present in epidemic USA300 MRSA strains, mitigated polyamine toxicity and conferred a selective advantage in the polyamine-rich kidney. These findings revealed the inner medulla as a physiologically immune-restricted MRSA reservoir and supported modulation of medullary osmolality and bacterial polyamine metabolism as candidate adjunctive strategies for limiting renal persistence and dissemination during MRSA bacteremia.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"18 869","pages":""},"PeriodicalIF":15.6,"publicationDate":"2026-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149077628","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cranial bone marrow–derived monocytes promote neuroinflammation in chronic traumatic brain injury","authors":"Zhichao Lu,&nbsp;Chenxing Wang,&nbsp;Peipei Gong,&nbsp;Qianqian Liu,&nbsp;Xingjia Zhu,&nbsp;Bin Yang,&nbsp;Xide Xu,&nbsp;Rui Jiang,&nbsp;Zhongzheng Jia,&nbsp;Chunfeng Sun,&nbsp;Yongqi Zhu,&nbsp;Yingcheng Wu,&nbsp;Jingwei Zhao,&nbsp;Anyi Song,&nbsp;Bin Wei,&nbsp;Kaibin Shi,&nbsp;Wei Shi","doi":"10.1126/scitranslmed.aef5898","DOIUrl":"10.1126/scitranslmed.aef5898","url":null,"abstract":"<div >Patients with chronic traumatic brain injury (cTBI) experience long-term exacerbated neurological decline, which is even more severe in older patients, yet the underlying mechanisms remain unclear. Cranial bone marrow (CBM) has recently been recognized as an adjacent immune surveillance organ of the brain that rapidly responds to acute brain injury. We investigated whether CBM-derived immune cells contribute to chronic neuroinflammation after cTBI by integrating clinical specimens, cell-tracing strategies, multiomics profiling, transgenic animal assays, adoptive cell transfer, and a proof-of-concept randomized clinical trial. We found that cTBI induced persistent aberrant myelopoiesis in the CBM, characterized by expansion of inflammatory monocytes/macrophages (Mo/Macs), which aggravated with aging. These CBM-derived Mo/Macs actively migrated into brain parenchyma, where they fueled chronic neuroinflammation and drove neurological deficits. Mechanistically, age-related peroxisome proliferator–activated receptor α (PPARα) deficiency caused lipid metabolism dysfunction in these Mo/Macs, enhancing H3K4me3-mediated regulation of inflammatory chromatin states and thereby promoting neuroinflammation. Activation of PPARα via fenofibrate rectified Mo/Mac lipid metabolism and reduced inflammatory Mo/Mac infiltration into the brain. In a proof-of-concept randomized clinical trial enrolling 40 older adult patients with cTBI, fenofibrate treatment reduced plasma neurofilament light chain levels and improved cognitive functions. Together, these findings demonstrate that CBM-originated inflammatory Mo/Macs may serve as key inflammatory drivers of cTBI and further show that fenofibrate represents a potential therapeutic strategy for cTBI treatment in older adults.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"18 869","pages":""},"PeriodicalIF":15.6,"publicationDate":"2026-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149077627","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"FAK inhibitor and RAF/MEK clamp avutometinib enhance KRAS G12C inhibitor efficacy in preclinical models of non–small cell lung cancer","authors":"Silvia Coma,&nbsp;Monica Musteanu,&nbsp;Cristina Caffarra Malvezzi,&nbsp;Ryan R. Jamieson,&nbsp;Enrico Patrucco,&nbsp;Alessia Mira,&nbsp;Julien Dilly,&nbsp;Ziyue Li,&nbsp;Ana Fernández-Rodríguez,&nbsp;Alejandra López-García,&nbsp;Andrew J. Aguirre,&nbsp;Mariano Barbacid,&nbsp;Chiara Ambrogio,&nbsp;Jonathan A. Pachter","doi":"10.1126/scitranslmed.aea4608","DOIUrl":"10.1126/scitranslmed.aea4608","url":null,"abstract":"<div >KRAS G12C (Gly¹²→Cys) inhibitors (G12Cis) have improved outcomes for patients with <i>KRAS</i> G12C–mutated non–small cell lung cancer (NSCLC), but their clinical benefit is limited by the emergence of resistance mechanisms. Here, we demonstrate that combining the RAF/MEK clamp avutometinib and the focal adhesion kinase (FAK) inhibitor defactinib with a G12Ci enhanced antitumor activity by deepening mitogen-activated protein kinase (MAPK) pathway suppression and simultaneously inhibiting adaptive resistance pathways induced by G12Ci and avutometinib treatment, including FAK and PI3K signaling. In <i>KRAS</i> G12C NSCLC mouse models, the triplet combination produced greater tumor growth inhibition than either sotorasib alone or the sotorasib plus avutometinib doublet. Moreover, in <i>KRAS</i> G12C NSCLC mouse models resistant to sotorasib, the addition of avutometinib and FAK inhibition restored sensitivity to sotorasib and increased both the depth and durability of antitumor responses. Collectively, these findings demonstrate that concurrent targeting of KRAS G12C, RAF/MEK, and FAK signaling can overcome multiple resistance mechanisms and provide a strong rationale for the clinical evaluation of sotorasib, avutometinib, and defactinib in patients with <i>KRAS</i> G12C–mutated NSCLC (RAMP 203; NCT05074810).</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"18 869","pages":""},"PeriodicalIF":15.6,"publicationDate":"2026-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149077630","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}