Cell Reports Medicine最新文献

{"title":"Dendritic cell centric nanoengineering couples antigen acquisition and STING activation for cancer immunotherapy.","authors":"Shuting Xiang, Shanshan Ma, Tuzhi Xu, Wenwen Yu, Jiefu Wang, Xin You, Mengjia Chai, Xiaohu Wang, Xiaoliang Wang, Junmei Zhang, Junjia Liu, Xiubao Ren, Weijie Song, Tingting Qin, Suxin Li, Jian Wang","doi":"10.1016/j.xcrm.2026.103025","DOIUrl":"10.1016/j.xcrm.2026.103025","url":null,"abstract":"<p><p>Stimulator of interferon genes (STING) agonists have shown limited antitumor efficacy, in part because STING activation is not preferentially focused on dendritic cells (DCs), which specialize in cross-priming. We present a DC-centric strategy that synergistically licenses DCs by coordinating CD47-SIRPα checkpoint relief and STING activation via dual ultra-pH-sensitive gating. Mild tumor acidity first unmasks the αCD47 cue to prime antigen acquisition. Following DC-biased uptake, a second acidic gate releases cGAMP to engage STING in antigen-bearing DCs. Functionally, efficacy requires Batf3-dependent cDC1s and CD8⁺ T cells, yet is preserved after macrophage depletion. In murine models, this strategy suppresses tumor growth and metastasis with good tolerability, and it retains activity in a humanized cell-line-derived xenograft model established in NSG-SGM3 hosts, supporting activity in a partially reconstituted human immune setting. Together, this work presents a mechanism-guided combination strategy to optimize STING agonist therapy.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"103025"},"PeriodicalIF":14.0,"publicationDate":"2026-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148905264","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":"L013 promotes NRF2 degradation in NRFA-subtype esophageal squamous cell carcinoma.","authors":"Xiao Yu, Yue Wu, Xiuyun Sun, Rui Han, Yi Cai, Wei Zeng, Yang Li, Yuhao Wang, Yahui Zhao, Yu Rao, Zhihua Liu","doi":"10.1016/j.xcrm.2026.103046","DOIUrl":"10.1016/j.xcrm.2026.103046","url":null,"abstract":"<p><p>NRF2 oncogenic activation (NRFA)-subtype esophageal squamous cell carcinoma (ESCC) patients exhibit poor prognosis and limited response to conventional therapies due to excessive NRF2 protein accumulation. Here, we identify L013, an NRF2 degrader, through high-content screening of 725 cereblon (CRBN) ligand-based degraders. Our results indicate that L013 effectively reduces NRF2 abundance and decreases NFE2L2 mRNA expression in ESCC cells. Mechanistically, L013 promotes NRF2 ubiquitination through a ubiquitin-proteasome system (UPS)-associated process involving Cullin-dependent E3 ligase activity, while its A51-derived scaffold independently contributes to NRF2 suppression, at least in part, by impairing NFE2L2 transcriptional output. In preclinical models, L013 reduces NRF2 levels and suppresses tumor growth in patient-derived organoids (PDOs) of ESCC and lung squamous cell carcinoma (LUSC), as well as ESCC xenograft models. No overt systemic toxicity occurs under the tested dosing regimen. Our findings establish L013 as a promising therapeutic candidate for NRFA-subtype ESCC patients, offering a potential strategy to target NRF2-driven oncogenesis.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"103046"},"PeriodicalIF":14.0,"publicationDate":"2026-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148944308","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":"Class visualizations and activation atlases for computational pathology.","authors":"Marco Gustav, Fabian Wolf, Christina Glasner, Nic G Reitsam, Stefan Schulz, Kira Aschenbroich, Bruno Märkl, Sebastian Foersch, Jakob Nikolas Kather","doi":"10.1016/j.xcrm.2026.103054","DOIUrl":"10.1016/j.xcrm.2026.103054","url":null,"abstract":"<p><p>The clinical promise of computational pathology increasingly depends on foundation model-based pipelines, yet the morphological concepts encoded by these systems remain poorly understood. We address this gap with a concept-level visualization framework using class visualizations (CVs) and activation atlases (AAs) in a pathology foundation-model setting across colorectal tissue and multi-organ cancer tasks. Four pathologists annotate hematoxylin and eosin-stained image patches as well as generated visualizations, complemented by attribution- and similarity-based metrics. CVs retain class-associated morphology for distinct tissue classes, with reduced separability and higher annotator variability in morphologically overlapping cancer classes. AAs expose layer-dependent organization of encoded concepts, with coherent regions for coarse tissue and cancer groupings and increasing dispersion and overlap at finer label granularities. Together, these findings show that concept-level visualization makes representations learned by pathology foundation models inspectable across diagnostic difficulty levels, with feature separation decreasing and ambiguity increasing as morphological complexity and expert disagreement rise.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"103054"},"PeriodicalIF":14.0,"publicationDate":"2026-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149001047","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":"Therapeutic oligonucleotides as genetic medicines: The current state and future perspective.","authors":"Bruno Miguel Da Cruz Godinho, Chantal M Ferguson, Annemieke Aartsma-Rus","doi":"10.1016/j.xcrm.2026.103058","DOIUrl":"10.1016/j.xcrm.2026.103058","url":null,"abstract":"<p><p>Antisense therapeutic oligonucleotides are entering a transformative era in clinical development, with a total of 21 oligonucleotides approved and a robust pipeline poised for the coming years. These drugs have emerged as a cornerstone of genetic medicine, providing a programmable platform to modulate gene expression and treat otherwise untreatable disorders. This review covers the different mechanisms of action of these drugs and highlights the key advances in oligonucleotide chemistry and delivery that have supported the clinical successes witnessed in the last decade. It also provides a historical account and overview of the growing number of approvals and key phase 3 studies. Finally, it offers a perspective on the future of the field, initially focused only on rare diseases and now expanding to common disorders.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"103058"},"PeriodicalIF":14.0,"publicationDate":"2026-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149023544","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":"Enhanced liver regeneration via targeted mRNA delivery for partial in vivo reprogramming.","authors":"Beom-Ki Jo, Young Seok Song, Woohyun Song, Hee-Ji Eom, Yon Jae Lee, Jumee Kim, Seunghee Hong, Seung-Woo Cho, Hyuk-Jin Cha","doi":"10.1016/j.xcrm.2026.103084","DOIUrl":"10.1016/j.xcrm.2026.103084","url":null,"abstract":"<p><p>Recent studies indicate that injury-induced dedifferentiation generates transient regenerative progenitors (TRPs), which support tissue repair across multiple organs, including the liver. In vivo partial reprogramming using Yamanaka factors (Oct4, Sox2, Klf4, and c-Myc; OSKM) produces intestinal TRPs closely resembling those arising from injury-induced dedifferentiation, but transgenic or viral approaches raise safety concerns because of prolonged expression. Here, we show that transient OSKM induction generates two distinct liver progenitor-like cell (LPLC) populations without injury and with limited activation of injury-associated immune responses. Single-nucleus RNA sequencing shows that one population resembles injury-induced LPLCs observed in acetaminophen-injured mouse and human livers. To develop a temporally controlled regenerative strategy, we establish a liver-targeted lipid nanoparticle system for OSKM mRNA delivery. OSKM mRNA-LNP treatment induces hepatocyte dedifferentiation and Sox9⁺ LPLC-like cell formation and is associated with enhanced regeneration after acetaminophen-induced injury. Together, these findings identify transient hepatic reprogramming as a strategy for inducing regenerative plasticity and support liver-targeted OSKM mRNA delivery as a potential approach for acute liver injury.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"103084"},"PeriodicalIF":14.0,"publicationDate":"2026-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149104637","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":"Proteogenomic analysis of pediatric and AYA high-grade glioma reveals age-dependent biology, female-male differences, and kinase targets.","authors":"Nicole L Tignor, Mateusz Koptyra, Shrabanti Chowdhury, Francesca Petralia, Marina A Gritsenko, Weiping Ma, Yuankun Zhu, Giacomo B Marino, Xiaoyu Song, Simona Migliozzi, Jeffrey R Whiteaker, Dmitry Rykunov, Yingwei Hu, Noshad Hosseini, Jo Lynne Rokita, Felipe da Veiga Leprevost, Komal S Rathi, Lijun Chen, Yi-Ting Wang, Karl K Weitz, Rosalie K Chu, Ronald J Moore, Azra Krek, Weijia Fu, Xuran Wang, Eden Z Deng, Chia-Feng Tsai, Tyler Sagendorf, Vladislav A Petyuk, Tujin Shi, Thomas L Fillmore, Rui Zhao, Matthew E Monroe, Marius V Dannappel, Paul Daniel, Lei Zhao, Richard G Ivey, Uliana J Voytovich, Tomer M Yaron-Barir, Emily M Huntsman, Jared L Johnson, Nakib Abedin, Yan-Chak Li, Mariarita Santi, Demetri Dupal, Jena Lilly, Adam Kraya, Joseph M Dybas, Bo Zhang, Chuwei Zhong, Miguel A Brown, Saksham Phul, Eric Wafula, Alvin Farrel, Zhuangzhuang Geng, Ryan J Corbett, Ammar S Naqvi, Daniel P Miller, Jennifer Mason, Tatiana S Patton, Stephanie McGrory, Shannon Robins, Allison Heath, Catherine Sullivan, Noel Coleman, Allison Morgan, Luciano Garofano, Boris Reva, Eric E Schadt, Richard D Smith, Mehdi Mesri, Ana I Robles, Lewis C Cantley, Li Ding, Karin D Rodland, Bing Zhang, Alexey I Nesvizhskii, Antonio Iavarone, Marcin Cieslik, Joseph E Ippolito, Phillip B Storm, Joshua B Rubin, Ron Firestein, Avi Ma'ayan, Hui Zhang, Amanda G Paulovich, Tao Liu, Adam Resnick, Brian R Rood, Pei Wang","doi":"10.1016/j.xcrm.2026.103024","DOIUrl":"10.1016/j.xcrm.2026.103024","url":null,"abstract":"<p><p>High-grade gliomas (HGGs) in children and adolescents and young adults (AYA) exhibit distinct biology across the neurodevelopmental spectrum. To dissect tumor-intrinsic molecular characteristics independent of developmental variation, we perform comprehensive proteogenomic analyses of tumors from 112 HGG patients aged 0-40 years. Our multi-omics analysis identifies two AYA subgroups-adolescents (aged 15-26 years) and young adults (aged 26-40 years)-with distinct molecular profiles and survival outcomes. Tumor-normal comparisons and survival modeling highlight roles of oxidative phosphorylation and neuronal system biology in glioma progression. Causal network analysis and cell line studies provide a rationale for personalized therapies targeting candidate kinases, such as CDK8. Survival modeling, clustering, and immune-landscape analyses identify proteins, post-translational modifications, and immune signatures linked to outcomes and reveal clinically relevant differences between male and female patients.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"103024"},"PeriodicalIF":14.0,"publicationDate":"2026-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148988140","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":"Uncovering combination therapies for immune-mediated inflammatory diseases through systems biology analysis on longitudinal patient data.","authors":"Sergio H Martínez-Mateu, Yolanda Guillén, Edgar Angelats, María A López-Lasanta, Stefania Madonna, Laura Jiménez-Gracia, Ivan Rodriguez-Nunez, Damiana Álvarez-Errico, Adrià Aterido, Raül Tortosa, Max Ruiz, Pau Serra, Juan D Cañete, Jose M Carrascosa, Eugeni Domènech, Javier P Gisbert, Jesús Tornero, Britta Siegmund, Giampiero Girolomoni, Ernest H S Choy, Richard M Myers, Holger Heyn, Pere Santamaria, Sara Marsal, Antonio Julià","doi":"10.1016/j.xcrm.2026.103026","DOIUrl":"10.1016/j.xcrm.2026.103026","url":null,"abstract":"<p><p>While targeted therapies have reshaped the clinical management of immune-mediated inflammatory diseases (IMIDs), primary non-response remains a major obstacle for many patients. Combining two targeted therapies is an emerging strategy to overcome this therapeutic ceiling, but the number of possible drug pairs makes prioritization difficult. For this objective, we present mitigation of non-response signature (MNRS), a computational approach that uses longitudinal blood transcriptomic data from six IMIDs treated with different targeted therapies to identify the most promising drug combinations. The approach identifies complementary pairs of biologic agents and small molecules, as well as potentially incompatible pairs. In rheumatoid arthritis, anti-TNF and anti-interleukin 6 receptor therapy emerges as highly complementary; single-cell analysis localizes this effect to CD14⁺ monocytes, and a collagen-induced arthritis mouse model confirms that the combination outperforms monotherapy. These findings show that longitudinal patient data help prioritize drug combinations for clinical testing across immune-mediated diseases.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"103026"},"PeriodicalIF":14.0,"publicationDate":"2026-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148944364","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":"Allosteric modulation of YTHDFs by ellagic acid suppresses triple-negative breast cancer via non-canonical activation of the HIF-1α pathway.","authors":"Jianheng Zhou, Yuyuan Li, Xuetao Chen, Zhen Zhu, Tingting Wu, Jun Zhang, Siqi Dong, Weikun Zhang, Wenjun Tao, Jun Zhou, Ke Xu, Zhengyu Jiang","doi":"10.1016/j.xcrm.2026.103045","DOIUrl":"10.1016/j.xcrm.2026.103045","url":null,"abstract":"<p><p>Triple-negative breast cancer (TNBC) lacks effective targeted therapies, and YTHDF proteins are frequently overexpressed in this malignancy, which correlates with adverse prognosis. Through high-throughput drug screening, we identify ellagic acid (EA) as a compound that binds to YTHDF proteins and disrupts their interaction with N6-methyladenosine (m⁶A)-modified RNAs. Structural and biochemical analyses show that EA targets a conserved, histidine-dependent allosteric site shared among YTHDF paralogs. This interaction induces conformational changes that disrupt m⁶A recognition and impair RNA binding, effectively inhibiting all three YTHDF proteins without compensatory escape. Phenotypically, EA suppresses TNBC cell proliferation and migration in vitro and in vivo. Mechanistically, EA enhances global mRNA stability, while selectively suppressing translation. In TNBC, EA-induced YTHDF2 inhibition stabilizes PFKFB4 mRNA, thereby increasing PFKFB4 protein, which blocks ubiquitin-dependent degradation of HIF-1α, resulting in BNIP3 induction and ultimately triggering apoptosis and necrosis. Collectively, our work unveils EA as a natural YTHDF inhibitor with compelling therapeutic potential for TNBC.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"103045"},"PeriodicalIF":14.0,"publicationDate":"2026-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148982485","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":"Early diagnosis and molecular classification of gastric cancer peritoneal metastasis by deep learning-driven single-cell lipidomics.","authors":"Siyuan Pan, Xiaowan Chen, Wen Xu, Jiale Chen, Kexin Xu, Peng Gao, Yuan Li, Jinming Zhao, Jinlei Yang, Murong Du, Runsong Cheng, Jingya Cao, Jiayi Li, Xinyu Zhao, Tong Qiao, Tianzi Chen, Xuan Li, Chunyu Lu, Siqi Xiong, Huan Yao, Xuanzhang Huang, Sichun Zhang, Xinrong Zhang, Zhenning Wang","doi":"10.1016/j.xcrm.2026.103055","DOIUrl":"10.1016/j.xcrm.2026.103055","url":null,"abstract":"<p><p>Peritoneal metastasis is the most lethal manifestation of gastric cancer (GC), as conventional diagnostic methods cannot reliably detect occult free GC cells in the peritoneal cavity at an early stage. Here, we present a workflow for early detection and molecular classification of free GC cells using label-free metabolite-based mass cytometry for single-cell lipidomic profiling integrated with deep learning. We obtain 41,627 single-cell lipidomic profiles from 92 samples in total and identify a distinct lipidomic fingerprint that robustly discriminates between free GC cells and benign peritoneal cells. To further interpret complex lipidomic profiles, we develop a deep learning-based graph neural network classifier to identify rare free GC cells within peritoneal ecosystem. Beyond diagnostic discrimination, we propose a clinically relevant metabolic classification based on HER2 subtype-specific lipidomic heterogeneity. Our study advances the early diagnosis and molecular classification of peritoneal metastasis in GC, offering potential for metabolism-guided intervention.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"103055"},"PeriodicalIF":14.0,"publicationDate":"2026-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149015768","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":"A blood-based metabolic signature for earlier detection of lung cancer.","authors":"Ehsan Irajizad, Hamid Khoshfekr Rudsari, Sebastien Gendarme, Jody Vykoukal, Ranran Wu, Jennifer B Dennison, Nastaran Karimi, Faezeh Darbaniyan, Seyed Javad Moghaddam, Kim-Anh Do, Ziding Feng, Edwin Ostrin, Samir Hanash, Johannes F Fahrmann","doi":"10.1016/j.xcrm.2026.103059","DOIUrl":"10.1016/j.xcrm.2026.103059","url":null,"abstract":"<p><p>Metabolomic profiling was applied to 1,259 sera collected within five years of a lung cancer diagnosis and 8,470 non-case sera from ever-smoker participants in the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial to identify metabolic signatures for the earlier detection of lung cancer. We develop a panel of five lung cancer-associated metabolites (L5MetP: diacetylspermine, creatine riboside, arginine, hypoxanthine, and acylcarnitine C18:1) to assess 1-year risk of lung cancer. In the testing set, the L5MetP achieves an area under the receiver operating characteristic curve (AUC) of 0.79 (95% CI: 0.76-0.82) for 1-year risk of lung cancer. The L5MetP also complements existing clinical risk models that predict risk incident lung cancer as well as those that predict death from lung cancer. The L5MetP provides a means for identifying ever-smoker individuals who are lung cancer to inform on the need for lung cancer screening.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"103059"},"PeriodicalIF":14.0,"publicationDate":"2026-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149030061","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}