Science Translational Medicine最新文献

{"title":"Interferon-induced senescent CD8+ T cells reduce anti-PD1 immunotherapy efficacy in early triple-negative breast cancer","authors":"Tong Fu,&nbsp;Xi Jin,&nbsp;Min He,&nbsp;Yi-Yu Chen,&nbsp;Yun-Song Yang,&nbsp;Li Chen,&nbsp;Hu-Yun-Long Zhang,&nbsp;Lei Fan,&nbsp;Jiong Wu,&nbsp;Zhong-Hua Wang,&nbsp;Yi-Wei Chu,&nbsp;Rong-Hua Liu,&nbsp;Yi-Zhou Jiang,&nbsp;Zhi-Ming Shao","doi":"10.1126/scitranslmed.adj7808","DOIUrl":"10.1126/scitranslmed.adj7808","url":null,"abstract":"<div >Triple-negative breast cancers (TNBCs) lack predictive biomarkers to guide immunotherapy, especially during early-stage disease. To address this issue, we used single-cell RNA sequencing, bulk transcriptomics, and pathology assays on samples from 171 patients with early-stage TNBC receiving chemotherapy with or without immunotherapy. Our investigation identified an enriched subset of interferon (IFN)–induced CD8⁺ T cells in early TNBC samples, which predict immunotherapy nonresponsiveness. Mechanistically, IFN produced by HLA-DR⁺ monocytes triggered cellular senescence in CD8⁺ T cells, which was marked by excessive NAD⁺ consumption, reduced cytotoxicity, and immunotherapy nonresponsiveness. Nicotinamide mononucleotide treatment restored the function of IFN-induced senescent CD8⁺ T cells and enhanced immunotherapy efficacy in patient-derived organoid–T cell coculture and in mouse models. Overall, our study identifies IFN-induced T cell senescence as a driver of immunotherapy nonresponsiveness in early TNBC and provides a strategy to restore CD8⁺ T cell function for immunotherapeutic benefit.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"17 815","pages":""},"PeriodicalIF":14.6,"publicationDate":"2025-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145028491","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":"Human myelinated brain organoids with integrated microglia as a model for myelin repair and remyelinating therapies","authors":"Simona Lange,&nbsp;Martin Ebeling,&nbsp;Athéna Loye,&nbsp;Florian Wanke,&nbsp;Juliane Siebourg-Polster,&nbsp;Tania J. J. Sudharshan,&nbsp;Franziska Völlmy,&nbsp;Jakub Kralik,&nbsp;Bérengère Vidal,&nbsp;Kerstin Hahn,&nbsp;Lynette C. Foo,&nbsp;Jan Hoeber","doi":"10.1126/scitranslmed.adp7047","DOIUrl":"10.1126/scitranslmed.adp7047","url":null,"abstract":"<div >Oligodendrocytes, the myelinating cells of the central nervous system (CNS), are essential for the formation of myelin sheaths and pivotal for maintaining axonal integrity and conduction. Disruption of these cells and the myelin sheaths they produce is a hallmark of demyelinating conditions like multiple sclerosis or those resulting from certain drug side effects, leading to profound neurological impairments. In this study, we created a human brain organoid comprising neurons, astrocytes, and myelinating oligodendrocytes. By integrating induced pluripotent stem cell–derived microglia, we endowed these myelinated human brain organoids (MHBOs) with immune characteristics. MHBOs with microglia (MHBOs +MG) enabled the investigation of demyelination and remyelination—a process in which myelin sheaths are regenerated—in a human context. After toxin-induced demyelination, we observed a reduction in myelin followed by subsequent self-driven remyelination. Proteomic and transcriptomic analyses provided a molecular signature of demyelination and myelin recovery indicating a central role for microglia in the remyelination process. Furthermore, the application of the pro-remyelinating compounds clemastine, XAV939, and BQ3020 further enhanced remyelination in MHBOs +MG but was ineffective in the absence of microglia. Cross-validation of our findings in mouse cerebellar slice cultures confirmed that the pro-remyelinating compounds were effective ex vivo, suggesting the translational potential of our MHBOs +MG model.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"17 815","pages":""},"PeriodicalIF":14.6,"publicationDate":"2025-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145028472","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":"Type I interferon limits central nervous system autoimmunity by modulating the microRNA-21–FOXO1 axis in pathogenic T helper 17 cells","authors":"Johnna Francis Varghese,&nbsp;Mai Fujiwara,&nbsp;Amrendra K. Ajay,&nbsp;Lucien P. Garo,&nbsp;Alkeiver Cannon,&nbsp;Ryoko Kadowaki-Saga,&nbsp;Galina Gabriely,&nbsp;Fernando Pradella,&nbsp;Breno Ferrari,&nbsp;Rohit Patel,&nbsp;Shivnarayan Dhuppar,&nbsp;Rachael Rossi Cecere,&nbsp;Panagiota Kolypetri,&nbsp;Rajesh Krishnan,&nbsp;Shrishti Saxena,&nbsp;Brian Healy,&nbsp;Gauruv Bose,&nbsp;Howard L. Weiner,&nbsp;Tanuja Chitnis,&nbsp;Gopal Murugaiyan","doi":"10.1126/scitranslmed.adp5802","DOIUrl":"10.1126/scitranslmed.adp5802","url":null,"abstract":"<div >IFN-β, a type I interferon, has been used as a first-line therapy for patients with multiple sclerosis (MS) for more than 30 years; however, the cellular and molecular basis of its therapeutic efficacy remains unclear. Here, we first used experimental autoimmune encephalomyelitis (EAE), a mouse model for MS, to show that the therapeutic effects of IFN-β were associated with a down-regulation of microRNA-21 (miR-21) and pathogenic T_H17 (pT_H17) cells. In vitro experiments demonstrated that genetic knockout of miR-21 directly inhibited pathogenic T_H17 cell differentiation. Further mechanistic investigations revealed that miR-21 promoted pathogenic T_H17 differentiation by inhibiting the transcription factor <i>Forkhead box protein O1</i> (<i>Foxo1</i>). Accordingly, miR-21 loss abrogated pathogenic T_H17 differentiation and conferred resistance to EAE. Treatment of T cell monocultures with IFN-β showed that IFN-β did not directly limit miR-21 expression. Instead, IFN-β treatment inhibited the secretion of miR-21–inducing cytokines from myeloid cells, reduced miR-21 induction within cocultured T cells, and inhibited pathogenic T_H17 development. In patient samples, immunophenotypic and targeted transcriptomic analyses revealed that compared with IFN-β treatment responders, nonresponders expressed elevated miR-21–inducing cytokines within myeloid cells, alongside increased miR-21 and pathogenic T_H17 cytokines within CD4⁺ T cells. Direct miR-21 inhibition reduced pathogenic T_H17 differentiation in nonresponder CD4⁺ T cells. These results suggest that type I IFN signaling limits central nervous system autoimmunity by inhibiting miR-21–mediated pathogenic T_H17 development. miR-21 inhibition may be of potential therapeutic value specifically for the IFN-β nonresponder cohort.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"17 815","pages":""},"PeriodicalIF":14.6,"publicationDate":"2025-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/scitranslmed.adp5802","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145028486","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":"The XBB.1.5 COVID-19 vaccine elicits a durable antibody response to ancestral and XBB.1.5 SARS-CoV-2 spike proteins","authors":"Sanjeev Kumar,&nbsp;Shilpi Jain,&nbsp;Bushra Wali,&nbsp;Veronika I. Zarnitsyna,&nbsp;Devyani Joshi,&nbsp;Madison L. Ellis,&nbsp;Lilin Lai,&nbsp;Ansa A. Malik,&nbsp;Tarrant O. McPherson,&nbsp;Sucheta Godbole,&nbsp;Anamika Patel,&nbsp;Susanne Linderman,&nbsp;Daniel Solis,&nbsp;Malaya K. Sahoo,&nbsp;Kareem Bechnak,&nbsp;Isabel Paredes,&nbsp;Ralph Tanios,&nbsp;Bahaa Kazzi,&nbsp;Serena M. Dib,&nbsp;Matthew B. Litvack,&nbsp;Sonia T. Wimalasena,&nbsp;Heather Hicks,&nbsp;Azaibi Tamin,&nbsp;Nicole E. Bowen,&nbsp;Lydia Atherton,&nbsp;Clinton Paden,&nbsp;Jennifer L. Harcourt,&nbsp;David E. Wentworth,&nbsp;Caroline Ciric,&nbsp;Richard H. West,&nbsp;Christina A. Rostad,&nbsp;I-Ting Teng,&nbsp;Danyi Wang,&nbsp;Eric A. Orlund,&nbsp;Vineet D. Menachery,&nbsp;Sri Edupuganti,&nbsp;Peter D. Kwong,&nbsp;Nadine Rouphael,&nbsp;Benjamin A. Pinsky,&nbsp;Daniel C. Douek,&nbsp;Alberto Moreno,&nbsp;Jens Wrammert,&nbsp;Mehul S. Suthar","doi":"10.1126/scitranslmed.adu8067","DOIUrl":"10.1126/scitranslmed.adu8067","url":null,"abstract":"<div >The rapid emergence of divergent SARS-CoV-2 variants led to a 2023–2024 update of the COVID-19 mRNA vaccine to a monovalent version containing the XBB.1.5 SARS-CoV-2 spike antigen. To determine the durability and breadth of the antibody responses after immunization, we analyzed antibodies and memory B cells from 24 individuals before and after a single XBB.1.5 mRNA vaccine dose for up to 6 months. Using a live virus neutralization assay, we found that the XBB.1.5 vaccine improved the magnitude and breadth of antibody neutralizing activity against the ancestral SARS-CoV-2 strain (WA1), BA.5 strain, and XBB.1.5 Omicron variants. Durable WA1 and XBB.1.5 IgG spike protein binding antibodies were induced with an estimated half-life of 703 and 531 days (at day 120), respectively. There was a greater increase of IgG1 and IgG4 binding antibodies against the XBB.1.5 spike protein compared with the WA1 spike protein postvaccination. A high proportion of antibodies were cross-reactive against both WA1 and XBB.1.5 strains, as determined by serum depletion and memory B cell analysis, and this cross-reactivity was durable. Last, we evaluated the neutralizing activity of these antibodies against more contemporary circulating Omicron strains and observed reduced cross-reactivity to KP.2 and KP.3 compared with XBB.1.5 6 months after vaccination. These data show that the XBB.1.5 COVID-19 vaccine promotes more durable binding and neutralizing antibodies than prior ancestral WA1 or bivalent vaccines. However, divergent Omicron variants with mutations in the spike protein were able to evade these neutralizing antibodies, emphasizing the need for periodic consideration of COVID-19 vaccine reformulation.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"17 814","pages":""},"PeriodicalIF":14.6,"publicationDate":"2025-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/scitranslmed.adu8067","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144935546","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":"Inhibiting SLC38A2 lowers blood pressure in rodent models of hypertension","authors":"Chunxiu Du,&nbsp;Hu Xu,&nbsp;Wenqian Zhao,&nbsp;Liping Jiao,&nbsp;Yanghui Chen,&nbsp;Xiaowan Sun,&nbsp;Mingxin Cao,&nbsp;Yufei Zhang,&nbsp;Yanlin Guo,&nbsp;Rongfang Qiao,&nbsp;Fang Ye,&nbsp;Yating Wang,&nbsp;Lan Ye,&nbsp;Lihong Chen,&nbsp;Dao Wen Wang,&nbsp;Youfei Guan,&nbsp;Xiaoyan Zhang","doi":"10.1126/scitranslmed.adt5947","DOIUrl":"10.1126/scitranslmed.adt5947","url":null,"abstract":"<div >Hypertension remains a major global health burden with limited effective treatment options. In the present study, the sodium-dependent neutral amino acid transporter SLC38A2 was identified as a regulator of blood pressure (BP) through modulating endothelial nitric oxide (NO) signaling. Here, we show that mice with global and endothelial cell (EC)–specific <i>Slc38a2</i> gene knockout (<i>Slc38a2</i>^△EC) exhibited reduced blood pressure compared with wild-type controls. Single-cell RNA sequencing analysis revealed enhanced NO biosynthesis in the ECs of the <i>Slc38a2</i>^△EC mice. Blockade of endothelial SLC38A2 by its inhibitor methylaminoisobutyric acid (MeAIB) increased NO production through activating the protein kinase B (AKT)–endothelial NO synthase (eNOS) pathway by inhibiting EC uptake of glutamine. Moreover, MeAIB lowered blood pressure in both high-salt and deoxycorticosterone acetate (DOCA)–induced hypertensive mouse and rat models. Last, in two independent population cohorts including a Chinese cohort established by our group and a European cohort from the UK Biobank, the <i>SLC38A2</i> rs1873793 variant was associated with increased risk of hypertension under a recessive model. Collectively, our findings demonstrate that targeting SLC38A2 may represent a therapeutic target for the treatment of hypertension.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"17 814","pages":""},"PeriodicalIF":14.6,"publicationDate":"2025-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144935544","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":"The landscape of microbial associations in human cancer","authors":"Abraham Gihawi,&nbsp;Henry M. Wood,&nbsp;Jeremy Clark,&nbsp;Justin O’Grady,&nbsp;Rosalind A. Eeles,&nbsp;David C. Wedge,&nbsp;G. Maria Jakobsdottir,&nbsp;Gkikas Magiorkinis,&nbsp;Andrew G. Schache,&nbsp;Liam Masterson,&nbsp;Matt Lechner,&nbsp;Tim R. Fenton,&nbsp;Terry M. Jones,&nbsp;Adrienne M. Flanagan,&nbsp;Solange De Noon,&nbsp;Alex Rubinsteyn,&nbsp;Rachel Hurst,&nbsp;Colin S. Cooper,&nbsp;Daniel S. Brewer","doi":"10.1126/scitranslmed.ads6166","DOIUrl":"10.1126/scitranslmed.ads6166","url":null,"abstract":"<div >Oncomicrobes are estimated to cause 15% of cancers worldwide. When cancer whole-genome sequencing (WGS) data are collected, the microbes present are also sequenced, allowing the investigation of potential etiological and clinical associations. Interrogating the microbial community for 8908 patients encompassing 22 cancer types from the Genomics England WGS dataset revealed that only colorectal tumors exhibited unmistakably distinct microbial communities that can reliably be used to distinguish anatomical site [positive predictive value (PPV) = 0.95]. This pattern was validated in two independent datasets. Potential clinical relevance uncovered by our analyses included accurate detection of alphapapillomaviruses [human papillomavirus (HPV)] in oral cancers, when compared with current clinical standards, and the detection of rare, highly pathogenic viruses such as human T-lymphotropic virus–1. Biomarker investigations demonstrated statistically significant associations (<i>P</i> &lt; 0.05) between a subset of anaerobic bacteria and survival in certain subtypes of sarcoma. Our results contradict previous claims that each cancer type has a distinct microbiological signature but highlight the potential value of microbial analysis for certain cancers as WGS of tumor samples becomes common in the clinic.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"17 814","pages":""},"PeriodicalIF":14.6,"publicationDate":"2025-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144935545","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":"Dengue disease severity in humans is augmented by waning Japanese encephalitis virus immunity","authors":"Sidharth Malhotra,&nbsp;Birendra P. Gupta,&nbsp;Surendra Uranw,&nbsp;Chinmay Kumar Mantri,&nbsp;Abhay P.S. Rathore,&nbsp;Ashley L. St. John","doi":"10.1126/scitranslmed.ads9572","DOIUrl":"10.1126/scitranslmed.ads9572","url":null,"abstract":"<div >Owing to increased global movement, vector-spread permissive climate change, and increased vaccination coverage against certain flaviviruses, the likelihood of being exposed to multiple flaviviruses in a lifetime has increased. Although many Asian countries have routine vaccination campaigns against Japanese encephalitis virus (JEV), the effect of JEV immunity on dengue disease severity is largely unknown. Here, we aimed to understand the effect of preexisting immunity against JEV on subsequent dengue disease outcomes in a prospective human cohort in Nepal, which has a high prevalence of JEV immunity and rapidly rising dengue virus (DENV) infections. A cohort consisting of 546 participants was studied over three dengue seasons and 5 years. Chymase, a serum biomarker of severe dengue across multiple patient cohorts, was assessed alongside clinical outcomes to determine whether there were associations between JEV immunity and dengue severity. We observed that midrange neutralizing antibody titers, approximately a 1:160 serum dilution capable of inhibiting JEV, were associated with heightened biomarkers of dengue disease severity and warning signs of severe disease in this cohort of patients who were mostly experiencing primary dengue infections. These results suggest that waning immunity to JEV could enhance the severity of dengue disease. This highlights the potential of maintaining strong immunity to JEV through vaccine boosters, not only to maintain protection against JEV in endemic regions but also to limit the potential of antibody-mediated enhancement of dengue disease.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"17 814","pages":""},"PeriodicalIF":14.6,"publicationDate":"2025-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144935553","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":"High-throughput synthesis and specificity characterization of natively paired influenza hemagglutinin antibodies with oPool+ display","authors":"Wenhao O. Ouyang,&nbsp;Huibin Lv,&nbsp;Wenkan Liu,&nbsp;Ruipeng Lei,&nbsp;Zongjun Mou,&nbsp;Tossapol Pholcharee,&nbsp;Logan Talmage,&nbsp;Meixuan Tong,&nbsp;Wei Ji,&nbsp;Yiquan Wang,&nbsp;Katrine E. Dailey,&nbsp;Akshita B. Gopal,&nbsp;Danbi Choi,&nbsp;Madison R. Ardagh,&nbsp;Lucia A. Rodriguez,&nbsp;Jenna J. Guthmiller,&nbsp;Xinghong Dai,&nbsp;Nicholas C. Wu","doi":"10.1126/scitranslmed.adt4147","DOIUrl":"10.1126/scitranslmed.adt4147","url":null,"abstract":"<div >Antibody discovery is crucial for developing therapeutics and vaccines and for understanding adaptive immunity. However, the lack of approaches to synthesize antibodies with defined sequences in a high-throughput manner represents a major bottleneck in antibody discovery. Here, we present oPool⁺ display, a high-throughput cell-free platform that combined oligo pool synthesis and mRNA display to rapidly construct and characterize hundreds to thousands of natively paired antibodies in parallel. As a proof of concept, we applied oPool⁺ display to probe the binding specificity of more than 300 uncommon influenza hemagglutinin-specific antibodies against nine hemagglutinin variants through 16 screens. More than 5000 binding tests were performed in 3 to 5 days of hands-on time with further scaling potential. Follow-up structural and functional analysis of two antibodies revealed the versatility of the human immunoglobulin gene segment D3-3 (<i>IGHD-3-3</i>) in recognizing the hemagglutinin stem. Overall, this study established an experimental platform that not only accelerates antibody characterization but also enables unbiased discovery of recurring molecular signatures among antibodies with the same specificity.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"17 814","pages":""},"PeriodicalIF":14.6,"publicationDate":"2025-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144935552","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":"An allele-agnostic mutant-KRAS inhibitor suppresses tumor maintenance signals and reprograms tumor immunity in pancreatic cancer","authors":"Kathleen M. McAndrews,&nbsp;Francesca Paradiso,&nbsp;Clint A. Stalnecker,&nbsp;Benson S. Chellakkan,&nbsp;Fredrik I. Thege,&nbsp;David H. Peng,&nbsp;Barbara A. Moreno Diaz,&nbsp;Hikaru Sugimoto,&nbsp;Sarah I. Patel,&nbsp;Krishnan K. Mahadevan,&nbsp;Michelle L. Kirtley,&nbsp;Danielle Wills,&nbsp;Amari M. Sockwell,&nbsp;Andre Luis F. Fonseca,&nbsp;Yunhe Liu,&nbsp;Kimal I. Rajapakshe,&nbsp;Nathaniel G. Yee,&nbsp;Phuong Thao Tran,&nbsp;Huda Alchikh Omar,&nbsp;Antonio Tedeschi,&nbsp;Fiorella Schischlik-Siegl,&nbsp;Andrew S. Boghossian,&nbsp;Matthew G. Rees,&nbsp;Melissa M. Ronan,&nbsp;Jennifer A. Roth,&nbsp;Dorothea Rudolph,&nbsp;Martin Aichinger,&nbsp;Florian Ebner,&nbsp;Artem V. Artemov,&nbsp;Jesse Lipp,&nbsp;Laura Pisarsky,&nbsp;Valerie Laura Herrmann,&nbsp;John Park,&nbsp;Jörg F. Rippmann,&nbsp;Otmar Schaaf,&nbsp;Vanessa Chandler,&nbsp;Mariah Williams,&nbsp;Charles E. Deckard,&nbsp;Linghua Wang,&nbsp;Channing J. Der,&nbsp;Christopher Vellano,&nbsp;Paola A. Guerrero,&nbsp;Timothy P. Heffernan,&nbsp;Raghu Kalluri,&nbsp;Anirban Maitra","doi":"10.1126/scitranslmed.adt5511","DOIUrl":"10.1126/scitranslmed.adt5511","url":null,"abstract":"<div ><i>KRAS</i> is among the most frequently mutated oncogenes in cancer, and for decades, efforts at pharmacological blockade of its function in solid cancers have been unsuccessful. A notable advance in this endeavor is the recent development of small-molecule KRAS inhibitors, which enable direct targeting of the mutant oncoprotein. Here, we comprehensively evaluated the preclinical efficacy of BI-2493, a first-in-class allele-agnostic mutant-KRAS inhibitor (panKRASi), in pancreatic ductal adenocarcinoma (PDAC). We report effective tumor growth suppression across a broad range of models, including cell lines, patient-derived xenografts (PDXs), and syngeneic orthotopic models, and prolonged survival in genetically engineered mouse models. Overall, transcriptomic, proteomic, and phosphoproteomic profiling of panKRASi-treated models confirmed RAS pathway inhibition along with up-regulation of LKB1/AMPK (liver kinase B1/AMP-activated protein kinase) targets. In panKRASi-treated immune-replete models, we observed increased intratumoral CD8⁺ effector T cells and decreased infiltration of myeloid cells, along with remodeling of the tumor microenvironment (TME), enabling responses to immune checkpoint blockade. In the long term, emergence of resistance to panKRASi monotherapy was associated with increased YAP signaling within tumor cells and enhanced expression of immune checkpoints in the TME that impede effective T cell function. Our multifaceted approach identified potential combinatorial approaches for generating sustained responses to panKRASi.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"17 814","pages":""},"PeriodicalIF":14.6,"publicationDate":"2025-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144935539","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":"Comprehensive analysis of microbial content in whole-genome sequencing samples from The Cancer Genome Atlas project","authors":"Yuchen Ge,&nbsp;Jennifer Lu,&nbsp;Daniela Puiu,&nbsp;Mahler Revsine,&nbsp;Steven L. Salzberg","doi":"10.1126/scitranslmed.ads6335","DOIUrl":"10.1126/scitranslmed.ads6335","url":null,"abstract":"<div >In recent years, a growing number of publications have reported the presence of microbial species in human tumors and mixtures of microbes that appear to be highly specific to different cancer types. Our recent reanalysis of data from three cancer types revealed that technical errors have caused erroneous reports of numerous microbial species found in sequencing data from The Cancer Genome Atlas (TCGA) project. Here, we have expanded our analysis to cover all 5734 whole-genome sequencing (WGS) datasets currently available from TCGA, covering 25 distinct types of cancer. We analyzed the microbial content using updated computational methods and databases and compared our results to those from two major recent studies that focused on bacteria, viruses, and fungi in cancer. Our results expand upon and reinforce our recent findings, which show that the presence of microbes is far smaller than had been previously reported and that many species identified in TCGA data might not be present at all. As part of this expanded analysis and to help others avoid being misled by flawed data, we have released a dataset that contains detailed read counts for bacteria, viruses, archaea, and fungi detected in all 5734 TCGA samples, which can serve as a public reference for future investigations.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"17 814","pages":""},"PeriodicalIF":14.6,"publicationDate":"2025-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144935542","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}