Science Translational Medicine最新文献

{"title":"Proteogenomic characterization reveals that lipid droplet formation promotes esophageal squamous cell cancer progression","authors":"Zhaoyu Qin,&nbsp;Dongxian Jiang,&nbsp;Zihan Yu,&nbsp;Lingling Li,&nbsp;Wenhao Xu,&nbsp;Chen Xu,&nbsp;Qi Song,&nbsp;Xiaogang Sun,&nbsp;Liangyuan Li,&nbsp;Wenjia Guo,&nbsp;Yan Pu,&nbsp;Jinwen Feng,&nbsp;Yang Liu,&nbsp;Haixing Wang,&nbsp;Lan Wang,&nbsp;Yuanyuan Qu,&nbsp;Fuchu He,&nbsp;Jun Qin,&nbsp;Lijie Tan,&nbsp;Jian-Yuan Zhao,&nbsp;Wenjun Yang,&nbsp;Yingyong Hou,&nbsp;Chen Ding","doi":"10.1126/scitranslmed.adt0214","DOIUrl":"10.1126/scitranslmed.adt0214","url":null,"abstract":"<div >Esophageal cancer is one of the most common cancers and a leading cause of cancer-related mortality in the world. Here, we have performed comprehensive characterization of genetic, transcriptomic, proteomic, and phosphoproteomic features in 293 patients with esophageal squamous cell carcinoma (ESCC). Chromosome 12q13.13 amplification was correlated with the up-regulation of Janus kinase–signal transducer and activator of transcription pathway and keratins at the protein level in ESCC tissues and associated with poor prognosis in patients with well-differentiated and moderately differentiated ESCC tumors. Patients with poorly differentiated ESCC tumors had infiltration of activated T cells in the tumor microenvironment, suggesting their potential responsiveness to immunotherapy. Chromosome 8q amplification was associated with lymph node metastasis in ESCC tissues, characterized by a switch from noncanonical to canonical WNT signaling. Proteomic classification revealed that the subgroup with the worst prognosis had chromosome 2p amplification and up-regulated lipid metabolism in ESCC tissues at the protein level. Lipid droplet formation induced by perilipin-2 and apolipoprotein E promoted cytokine secretion, which, in turn, recruited T cells and enhanced stromalization, thereby suppressing T cell activation and promoting malignant ESCC progression. This study provides a resource for understanding the development of ESCC and identifying potential therapeutic targets for testing.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"17 802","pages":""},"PeriodicalIF":15.8,"publicationDate":"2025-06-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144264741","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeting immune hubs to advance cancer immunotherapy","authors":"Karin Pelka","doi":"10.1126/scitranslmed.adx7698","DOIUrl":"10.1126/scitranslmed.adx7698","url":null,"abstract":"<div >Multicellular networks shape immune responses in solid tumors and inform improved immunotherapies.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"17 802","pages":""},"PeriodicalIF":15.8,"publicationDate":"2025-06-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144264742","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Germline-encoded recognition of peanut underlies development of convergent antibodies in humans","authors":"Orlee Marini-Rapoport,&nbsp;Léna Andrieux,&nbsp;Tarun Keswani,&nbsp;Guangning Zong,&nbsp;Dylan Duchen,&nbsp;Gur Yaari,&nbsp;Jungki Min,&nbsp;Isabelle R. Lytle,&nbsp;Alexander F. Rosenberg,&nbsp;Christopher Fucile,&nbsp;James J. Kobie,&nbsp;Michael S. Piepenbrink,&nbsp;Timothy Sun,&nbsp;Victoria M. Martin,&nbsp;Qian Yuan,&nbsp;Wayne G. Shreffler,&nbsp;Antti E. Seppo,&nbsp;Kirsi M. Järvinen,&nbsp;Johannes R. Loeffler,&nbsp;Andrew B. Ward,&nbsp;Steven H. Kleinstein,&nbsp;Lars C. Pedersen,&nbsp;Monica L. Fernández-Quintero,&nbsp;Geoffrey A. Mueller,&nbsp;Sarita U. Patil","doi":"10.1126/scitranslmed.adw4148","DOIUrl":"10.1126/scitranslmed.adw4148","url":null,"abstract":"<div >Humans develop immunoglobulin G (IgG) antibodies to the foods they consume. In the context of food allergy, allergen-specific IgG antibodies can sequentially class-switch to pathogenic IgE. However, the mechanism underlying the antigenicity of food proteins remains uncharacterized. Here, we identified convergent antibodies arising from different antibody gene rearrangements that bind to the immunodominant peanut allergen Ara h 2 and characterized allelic and junctional constraints on germline antibody specificity. Structurally, we found similar epitope-paratope interactions across multiple gene rearrangements. We demonstrate that these germline-encoded epitope-specific convergent antibodies to peanut occur commonly in the population because of the worldwide prevalence of the relevant gene rearrangements, allelic independence, and junctional malleability. As a result, serum IgG to this public epitope is prevalent among diverse cohorts of nonallergic peanut-consuming infants and peanut-allergic children and adults. This work demonstrates that IgG recognition of dietary antigens can be intrinsically programmed by the germline antibody repertoire.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"17 802","pages":""},"PeriodicalIF":15.8,"publicationDate":"2025-06-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144264734","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Nonstabilized SARS-CoV-2 spike mRNA vaccination induces broadly neutralizing antibodies in nonhuman primates","authors":"R. Dilshan Malewana,&nbsp;Victoria Stalls,&nbsp;Aaron May,&nbsp;Xiaozhi Lu,&nbsp;David R. Martinez,&nbsp;Alexandra Schäfer,&nbsp;Dapeng Li,&nbsp;Maggie Barr,&nbsp;Laura L. Sutherland,&nbsp;Esther Lee,&nbsp;Robert Parks,&nbsp;Whitney Edwards Beck,&nbsp;Amanda Newman,&nbsp;Kevin W. Bock,&nbsp;Mahnaz Minai,&nbsp;Bianca M. Nagata,&nbsp;C. Todd DeMarco,&nbsp;Thomas N. Denny,&nbsp;Thomas H. Oguin III,&nbsp;Wes Rountree,&nbsp;Yunfei Wang,&nbsp;Katayoun Mansouri,&nbsp;Robert J. Edwards,&nbsp;Lena Smith,&nbsp;Gregory D. Sempowski,&nbsp;Amanda Eaton,&nbsp;Hiromi Muramatsu,&nbsp;Rory Henderson,&nbsp;Ying Tam,&nbsp;Christopher Barbosa,&nbsp;Juanjie Tang,&nbsp;Derek W. Cain,&nbsp;Sampa Santra,&nbsp;Ian N. Moore,&nbsp;Hanne Andersen,&nbsp;Mark G. Lewis,&nbsp;Hana Golding,&nbsp;Robert Seder,&nbsp;Surender Khurana,&nbsp;David C. Montefiori,&nbsp;Norbert Pardi,&nbsp;Drew Weissman,&nbsp;Ralph S. Baric,&nbsp;Priyamvada Acharya,&nbsp;Barton F. Haynes,&nbsp;Kevin O. Saunders","doi":"10.1126/scitranslmed.adn5651","DOIUrl":"10.1126/scitranslmed.adn5651","url":null,"abstract":"<div >Immunization with messenger RNA (mRNA) or viral vectors encoding spike protein with diproline substitutions (S-2P) were shown to provide protective immunity, curbing the COVID-19 pandemic. However, in light of the emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern (VOCs) that can cause COVID-19, it is essential that we understand how immunization with spike protein elicits neutralizing antibodies (nAbs). Here, we compared immunization of macaques with mRNA vaccines expressing ancestral spike protein with or without diproline substitutions, showing that the diproline substitutions were not required for protection against SARS-CoV-2 challenge or induction of broadly neutralizing B cell lineages. One group of nAbs elicited by the ancestral spike protein lacking diproline substitutions targeted the outer face of the receptor binding domain (RBD), neutralized all tested SARS-CoV-2 VOC pseudotyped viruses including Omicron XBB.1.5 in vitro, but lacked cross-sarbecovirus neutralization. Structural analysis showed that the macaque nAbs that could broadly neutralize VOCs bound to the same epitope as a human nAb, DH1193. In contrast, vaccine-induced antibodies that targeted the RBD inner face neutralized multiple sarbecoviruses, protected mice from bat CoV RsSHC014 challenge, but lacked Omicron variant neutralization. Thus, ancestral SARS-CoV-2 spike mRNA vaccines lacking proline substitutions can induce B cell lineages binding to distinct RBD sites that either broadly neutralize animal and human sarbecoviruses or neutralize recent Omicron VOCs. Thus, the use of a nonstabilized spike protein design in some COVID-19 vaccines does not preclude the elicitation of broad sarbecovirus and broad VOC nAbs.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"17 802","pages":""},"PeriodicalIF":15.8,"publicationDate":"2025-06-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144264743","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeted suppression of glioma by ultralow-dose x-ray–induced photodynamic therapy and gold-based nanoclusters in preclinical models","authors":"Shi Li,&nbsp;Shileng Chen,&nbsp;Yimin Li,&nbsp;Wenjing Sun,&nbsp;Junjun Li,&nbsp;Huaping Deng,&nbsp;Haizhen Ding,&nbsp;Zongzhang Wang,&nbsp;Luchao Zhu,&nbsp;Jun Liu,&nbsp;Minjie Wang,&nbsp;Yushuo Feng,&nbsp;Yuanyuan Xie,&nbsp;Yiru Wang,&nbsp;Yaqing Liu,&nbsp;Wenle Li,&nbsp;Qin Lin,&nbsp;Xiaobing Jiang,&nbsp;Hongmin Chen","doi":"10.1126/scitranslmed.adq5331","DOIUrl":"10.1126/scitranslmed.adq5331","url":null,"abstract":"<div >The diffuse and infiltrative nature of high-grade gliomas poses ongoing challenges in treatment and management. Radiotherapy is an important glioma treatment, with a standard radiotherapy dose of 60 gray. However, high-dose radiotherapy is associated with radiation-induced side effects on normal tissue. Scintillator-mediated low-dose x-ray–induced photodynamic therapy using kilovoltage x-rays has been shown to be effective for multiple tumor types without causing damage to healthy tissue. However, x-ray–induced photodynamic therapy is yet to be explored in glioma because of the inability of the photosensitizers to cross the blood-brain barrier. Here, we present an integrated gold clustoluminogen containing protein-protected gold nanoclusters conjugated to a photosensitizer and a cell-penetrating peptide. Using intravital imaging, we showed that gold clustoluminogen crossed the intact blood-brain barrier in healthy animals and accumulated in tumors in two murine intracranial orthotopic glioma models. Gold clustoluminogen efficiently suppressed glioma growth and prolonged animal survival under ultralow-dose x-ray treatment (total 2 gray, megavoltage x-ray) using the same protocol as that used for clinical megavoltage radiotherapy. Moreover, gold clustoluminogen potently inhibited tumor growth in an orthotopic patient-derived xenograft glioma model with prolonged animal survival under ultralow-dose x-ray treatment. Gold clustoluminogen was eliminated through hepatic and renal excretion, with no observed toxicity. These results highlight new opportunities to develop clinically relevant glioma therapies with reduced side effects.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"17 802","pages":""},"PeriodicalIF":15.8,"publicationDate":"2025-06-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144264740","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"AMPAR inhibition lowers S1P in human blood and improves murine autoimmune neuroinflammation by blocking T cell egress from lymph nodes","authors":"Beatrice Wasser,&nbsp;Manuela Ecker,&nbsp;Nicholas Hanuscheck,&nbsp;Erik Ellwardt,&nbsp;Yvonne Gärtner,&nbsp;Kira Engeroff,&nbsp;Micaela Domingues,&nbsp;Benedikt Grünewald,&nbsp;Mohammadsaleh Oshaghi,&nbsp;Philipp Wollnitzke,&nbsp;Christina B. Schroeter,&nbsp;Mirko H. H. Schmidt,&nbsp;Muthuraman Muthuraman,&nbsp;Bodo Levkau,&nbsp;Yaroslav Winter,&nbsp;Sven G. Meuth,&nbsp;Robert Nitsch,&nbsp;Jakob von Engelhardt,&nbsp;Stefan Bittner,&nbsp;Frauke Zipp","doi":"10.1126/scitranslmed.ads6434","DOIUrl":"10.1126/scitranslmed.ads6434","url":null,"abstract":"<div >Glutamatergic α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR)–mediated signaling in neurons acts through regulation of ion channels. In T cells, we uncovered a noncanonical AMPAR-mediated metabotropic G_i protein–coupled signaling pathway. Selective blockade of AMPAR ameliorated disease severity in experimental autoimmune encephalomyelitis (EAE) both in SJL mice, which typically show a relapsing-remitting disease course, and in C57BL/6 mice, representing chronic disease activity. AMPAR blockade led to a retention of T cells in lymph nodes resulting in reduced T cell numbers within the central nervous system. RNA sequencing and functional analysis of the lymphocyte AMPAR pathway revealed that the AMPAR antagonist perampanel inhibited G_i protein–coupled signaling and induced migration-modifying transcription programs, including CD69. CD69⁺ T cells showed down-regulated expression of sphingosine 1-phosphate (S1P) receptor, a key regulator of T cell egress. Reduced T cell egress from lymph nodes upon AMPAR blockade was rescued by anti-CD69 antibody treatment or addition of S1P. Perampanel treatment additionally reduced S1P blood concentrations in mice and patients with epilepsy. Combined AMPAR and S1P receptor inhibition had an additive beneficial effect on disease severity in C57BL/6 EAE, and single AMPAR treatment was sufficient to almost completely abolish disease development in SJL EAE. Our findings suggest that AMPAR blockade can counteract neuroinflammation caused by the infiltration of T cells into the central nervous system in conditions such as multiple sclerosis.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"17 802","pages":""},"PeriodicalIF":15.8,"publicationDate":"2025-06-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144264733","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"DeepHeme, a high-performance, generalizable deep ensemble for bone marrow morphometry and hematologic diagnosis","authors":"Shenghuan Sun,&nbsp;Zhanghan Yin,&nbsp;Jacob G. Van Cleave,&nbsp;Linlin Wang,&nbsp;Brenda Fried,&nbsp;Khawaja H. Bilal,&nbsp;Fabienne Lucas,&nbsp;Irem S. Isgor,&nbsp;Dylan C. Webb,&nbsp;Siddharth Singi,&nbsp;Laura Brown,&nbsp;Roni Shouval,&nbsp;Jeff Lin,&nbsp;Ethan S. Yan,&nbsp;Jacob D. Spector,&nbsp;Orly Ardon,&nbsp;Leonardo Boiocchi,&nbsp;Rohan Sardana,&nbsp;Jeeyeon Baik,&nbsp;Menglei Zhu,&nbsp;Aijazuddin Syed,&nbsp;Mariko Yabe,&nbsp;Chuanyi M. Lu,&nbsp;Mikhail Roshal,&nbsp;Chad Vanderbilt,&nbsp;Dmitry B. Goldgof,&nbsp;Ahmet Dogan,&nbsp;Sonam Prakash,&nbsp;Iain Carmichael,&nbsp;Atul J. Butte,&nbsp;Gregory M. Goldgof","doi":"10.1126/scitranslmed.adq2162","DOIUrl":"10.1126/scitranslmed.adq2162","url":null,"abstract":"<div >Cytomorphological analysis of the bone marrow aspirate (BMA) is pivotal for the diagnostic workup of a broad range of hematological disorders. However, this skill is error prone, highly complex, and time consuming. Deep learning–based models for the automatic classification of bone marrow cell morphology demonstrate the potential to improve diagnostic efficiency and accuracy. However, existing deep learning approaches in this field fall short of expert-level performance and lack generalizability beyond a single dataset. Working with multiple hematopathologists, we curated a dataset from the University of California, San Francisco, which included a training set of 30,394 images from 40 patients with morphologically normal marrows and a test set of 8507 images from 10 different patients, all derived from 400×-equivalent whole-slide images (WSIs). We then developed DeepHeme, a snapshot ensemble deep learning classifier, which outperformed previous models in accuracy while expanding the total number of differentiable cell classes. We externally validated DeepHeme using an independent dataset from the Memorial Sloan Kettering Cancer Center, which included 2694 images from 10 morphologically normal patients and 11,076 images from 655 patients with normal or diseased marrow, scanned using a different WSI system, demonstrating robust generalizability. At the level of individual cell classifications, we systematically compared DeepHeme’s diagnostic performance with that of three medical experts from different academic hospitals, demonstrating that DeepHeme achieved accuracy comparable to, or exceeding, that of human experts. Accurate and generalizable cell classification represents a step toward automated analysis of hematopathology slides and the development of quantitative, morphology-based, predictive markers.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"17 802","pages":""},"PeriodicalIF":15.8,"publicationDate":"2025-06-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/scitranslmed.adq2162","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144264736","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 host defense peptide–mimicking prodrug activated by drug-resistant Gram-negative bacterial infections","authors":"Jiayang Xie,&nbsp;Min Zhou,&nbsp;Zihao Cong,&nbsp;Ximian Xiao,&nbsp;Longqiang Liu,&nbsp;Sheng Chen,&nbsp;Weinan Jiang,&nbsp;Yueming Wu,&nbsp;Runhui Liu","doi":"10.1126/scitranslmed.adl4870","DOIUrl":"10.1126/scitranslmed.adl4870","url":null,"abstract":"<div >The high mortality of drug-resistant Gram-negative bacterial infections and the scarcity of antibiotics against Gram-negative bacteria urgently call for effective antimicrobial agents. Antimicrobial polymers that mimic host defense peptides (HDPs) have been extensively studied, but in the complex in vivo environment, cationic polymers can interact with polyanionic macromolecules and host cells bearing polyanionic membranes, leading to undesired side effects. Here, we report an “acid-responsive antimicrobial polymer prodrug” strategy and performed a proof-of-concept treatment using HDP-mimicking poly(2-oxazoline)s. By protecting the side-chain amines with 2,3-dimethylmaleic anhydride to neutralize the positive charges, the poly(2-oxazoline) prodrug can remain stealthy under physiological conditions but expose these charges to become activated at infection sites. The poly(2-oxazoline) prodrug exhibited high biocompatibility, prolonged blood circulation time, and potent activity against drug-resistant Gram-negative bacteria and biofilms in vitro and did not develop antibacterial resistance. Moreover, the poly(2-oxazoline) prodrug showed strong therapeutic potential for both local and systemic infections. The prodrug displayed potent activity in treating Gram-negative bacteria–associated infections in multiple mouse models, including subcutaneous abscess, neutropenic thigh infection, kidney infection, lung infection, and peritonitis. These results demonstrate the effectiveness of our prodrug strategy to develop potent antibacterial agents.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"17 801","pages":""},"PeriodicalIF":15.8,"publicationDate":"2025-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144214297","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Longitudinally stable T cell function and innate immune activation distinguish healthy adult immunotypes","authors":"Megan E. Smithmyer,&nbsp;Alex Hu,&nbsp;Matthew J. Dufort,&nbsp;Anne M. Hocking,&nbsp;Alice E. Wiedeman,&nbsp;Kayla J. Fasano,&nbsp;Troy R. Torgerson,&nbsp;Peter J. Skene,&nbsp;Julian Reading,&nbsp;Xiaojun Li,&nbsp;Qiuyu Gong,&nbsp;S. Alice Long,&nbsp;Adam Lacy-Hulbert,&nbsp;Claire E. Gustafson,&nbsp;Jane H. Buckner,&nbsp;Cate Speake,&nbsp;members of the BRI Sound Life Project Team","doi":"10.1126/scitranslmed.adt4605","DOIUrl":"10.1126/scitranslmed.adt4605","url":null,"abstract":"<div >Understanding the variability of immune cell composition and responsiveness in health is critical to define changes that predict and explain immune-associated diseases like autoimmunity and cancer. Here, we comprehensively phenotyped a cohort of 100 healthy adults aged 25 to 35 and 55 to 65 years who were longitudinally followed for 10 visits over 2 years. Using mass cytometry, we identified four stable immunotypes derived from cell populations that remained stable within, but differed between, individuals. We characterized these immunotypes using whole-blood RNA sequencing, Olink proteomic profiling, and whole-blood ex vivo stimulation. Although cytomegalovirus (CMV) seropositivity, age, and sex are known to influence the immune landscape, the four immunotypes were not solely determined by these factors. A CMV-dominant immunotype exhibited exaggerated traditional markers of CMV positivity but also features unrelated to CMV positivity, including lower numbers of B cells and B cell–related transcripts. Immunotype was strongly associated with response to ex vivo stimulation with lipopolysaccharide (LPS) but not serological response to influenza vaccination, suggesting that these immunotypes are most relevant in understanding variations in innate immune responsiveness among healthy individuals. Last, we identified an immunotype comprising young females with unusually high LPS responsiveness, mature neutrophil frequency, and increased inflammatory markers. Overall, our findings establish that healthy individuals can exhibit one of four shared immunotypes, defined by adaptive and innate cell populations, that are stable over time, influence the response to innate signals, associate with clinical markers of inflammation, and shed light on overall immune health.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"17 801","pages":""},"PeriodicalIF":15.8,"publicationDate":"2025-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144214300","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Methotrexate exerts antitumor immune activity and improves the clinical efficacy of immunotherapy in patients with solid tumors","authors":"Ruirui Yang,&nbsp;Bei Wang,&nbsp;Zhaoming Su,&nbsp;Ying Song,&nbsp;Yingying Zhang,&nbsp;Yadan Liu,&nbsp;Yinghui Zhang,&nbsp;Changyu He,&nbsp;Xi Yang,&nbsp;Feisheng Zhong,&nbsp;Zunyun Fu,&nbsp;Yiluan Ding,&nbsp;Naixia Zhang,&nbsp;Rui Li,&nbsp;Shuqing Chu,&nbsp;Chuanhai Xu,&nbsp;Jian Sun,&nbsp;Haiwei Shen,&nbsp;Wei Geng,&nbsp;Sulin Zhang,&nbsp;Mingyue Zheng","doi":"10.1126/scitranslmed.adn6921","DOIUrl":"10.1126/scitranslmed.adn6921","url":null,"abstract":"<div >Low-dose methotrexate (MTX) is the first-line drug for treating rheumatoid arthritis as an immunosuppressor. We have identified that low-dose MTX exhibits antitumor immune activity. MTX treatment reduced tumor metastasis and enhanced the efficacy of radiation therapy and immune checkpoint blockade therapy in mice. Mechanistically, MTX selectively induced DNA damage, cGAS-STING [cyclic guanosine monophosphate–adenosine monophosphate (cGAMP) synthase (cGAS)–stimulator of interferon genes (STING)] pathway activation, and cGAMP generation in cancer cells. Furthermore, MTX bound to the substrate-binding pocket of ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1), inhibiting ENPP1-mediated cGAMP hydrolysis and adenosine generation. Consequently, MTX reduced extracellular adenosine and enhanced host STING-mediated antitumor immunity. In addition, a preliminary clinical trial demonstrated promising efficacy and safety of low-dose MTX in combination with immunotherapy and radiotherapy for patients with unresectable or metastatic solid tumors, showing improved outcomes compared with historical controls. These results highlight the previously unrecognized immunostimulatory functions of MTX and provide a rationale for combining MTX with tumor immunotherapy and radiotherapy in clinical settings.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"17 801","pages":""},"PeriodicalIF":15.8,"publicationDate":"2025-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144214262","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}