Cell Reports MedicinePub Date : 2026-10-20Epub Date: 2026-09-11DOI: 10.1016/j.xcrm.2026.103048
Tue B Bennike, Alec L Plotkin, Jensen Pak, Arthur Viode, Christoph N Schlaffner, Casey P Shannon, Olubukola T Idoko, Rebecca Ford, Anita H J van den Biggelaar, Oludare A Odumade, Dylan Nicholas Tabang, Rym Ben-Othman, Peter C Richmond, Joann Diray-Arce, Al Ozonoff, Judith A Steen, Amy H Y Lee, William S Pomat, Beate Kampmann, Ofer Levy, Tobias R Kollmann, Kinga K Smolen, Hanno Steen
{"title":"Bi-hourly plasma proteomics during the first 48 h of life in an African cohort reveals distinct periods and sex-dependent immune development.","authors":"Tue B Bennike, Alec L Plotkin, Jensen Pak, Arthur Viode, Christoph N Schlaffner, Casey P Shannon, Olubukola T Idoko, Rebecca Ford, Anita H J van den Biggelaar, Oludare A Odumade, Dylan Nicholas Tabang, Rym Ben-Othman, Peter C Richmond, Joann Diray-Arce, Al Ozonoff, Judith A Steen, Amy H Y Lee, William S Pomat, Beate Kampmann, Ofer Levy, Tobias R Kollmann, Kinga K Smolen, Hanno Steen","doi":"10.1016/j.xcrm.2026.103048","DOIUrl":"10.1016/j.xcrm.2026.103048","url":null,"abstract":"<p><p>Birth marks a sudden transition from a sterile intrauterine environment to one rich in pathogens, requiring rapid immune adaptation. Using mass spectrometry and immunoassays, we profile 324 plasma proteins, cytokines, and chemokines in 906 peripheral blood samples from 679 healthy, term, vaginally born Gambian neonates and an independent smaller validation cohort from Papua New Guinea. This proteomic analysis provides insights into plasma protein dynamics during the first 48 h of life at a bi-hourly resolution. The temporal analysis reveals non-linear trajectories, layering of immune system development, and distinct periods, all of which are inadequately described at the conventional day of life resolution. Significant sex-dependent immune system development is noticeable during the first 16 h after birth, which is also supported by a neonatal immuno-molecular clock for the earliest postnatal period. This study provides molecular insights into normal plasma protein ontogenies and developmental processes during the first two days of life.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"103048"},"PeriodicalIF":14.0,"publicationDate":"2026-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148944285","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}
Cell Reports MedicinePub Date : 2026-10-20Epub Date: 2026-09-22DOI: 10.1016/j.xcrm.2026.103056
Jie Zhang, Chun-Ming Li, Lei Fang, Xiao-Tong Lin, Ke Min, Di Wu, De-Hong Tan, Zhi-Yu Chen, Lei-Da Zhang, Chuan-Ming Xie
{"title":"Targeting RPL4 improves the therapeutic efficacy of PD-L1 blockade in liver fibrosis.","authors":"Jie Zhang, Chun-Ming Li, Lei Fang, Xiao-Tong Lin, Ke Min, Di Wu, De-Hong Tan, Zhi-Yu Chen, Lei-Da Zhang, Chuan-Ming Xie","doi":"10.1016/j.xcrm.2026.103056","DOIUrl":"10.1016/j.xcrm.2026.103056","url":null,"abstract":"<p><p>Activation and progressive accumulation of hepatic stellate cells (HSCs) are pivotal events in the progression of liver fibrosis, and no effective treatments are available to date. Hepatic FBXL6 promotes hepatocarcinogenesis, but the function of FBXL6 in tissue stromal cells remains unknown. Here, FBXL6 is highly expressed in the activated HSCs in human fibrotic livers. HSC-specific FBXL6 overexpression or deletion is achieved by crossbreeding Fbxl6<sup>CKI/+</sup> or Fbxl6<sup>CKO-fl/+</sup> mice with Pdgfrβ-Cre mice. FBXL6 drives liver fibrosis in mice, whereas FBXL6 deletion attenuates chemical- or MASH-induced liver fibrosis. Mechanistically, FBXL6 promotes the polyubiquitination and activation of a previously uncharacterized substrate, RPL4, which requires JNK2-mediated phosphorylation at Ser295. Activated RPL4 upregulates YY1, increases PD-L1, and then activates the AKT/mTOR pathway, leading to extracellular matrix production and liver fibrosis. Furthermore, the knockdown of RPL4 enhances the efficacy of anti-PD-L1 immunotherapy in FBXL6-driven liver fibrosis in mice, which provides a promising therapeutic strategy for liver fibrosis treatment.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"103056"},"PeriodicalIF":14.0,"publicationDate":"2026-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149024012","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}
Cell Reports MedicinePub Date : 2026-10-20Epub Date: 2026-10-07DOI: 10.1016/j.xcrm.2026.103092
Siyan Zhao, Mindia Adinda Sari Haryono, Clement Wei Ming Lai, Francine Seah, Yi Ling Tang, Maybritte Lim, Eveline Febriana, Michelle H Lee, Kai Soo Tan, Jia Hui Fu, Julie K Yip, Philip M Preshaw, Rohan B H Williams, Sue-Anne Toh, Jonathan Wei Jie Lee, Charlene Enhui Goh
{"title":"Oral microbial nitrate metabolism is associated with lower prevalence of prediabetes.","authors":"Siyan Zhao, Mindia Adinda Sari Haryono, Clement Wei Ming Lai, Francine Seah, Yi Ling Tang, Maybritte Lim, Eveline Febriana, Michelle H Lee, Kai Soo Tan, Jia Hui Fu, Julie K Yip, Philip M Preshaw, Rohan B H Williams, Sue-Anne Toh, Jonathan Wei Jie Lee, Charlene Enhui Goh","doi":"10.1016/j.xcrm.2026.103092","DOIUrl":"10.1016/j.xcrm.2026.103092","url":null,"abstract":"<p><p>The oral microbiome is a key microbial interface for dietary or oral nitrate metabolism, yet its role in early glycemic dysregulation remains poorly defined. In a population-based cohort (n = 472), we perform metagenomic profiling of tongue dorsum microbiomes and identify 11 taxa and nine microbial pathways associated with prediabetes. Among these, Rothia mucilaginosa and microbial nitrate reduction emerge as the only taxon and the strongest pathway associated with lower prediabetes prevalence. Individuals without prediabetes show higher salivary nitrate and nitrite concentrations, supporting enhanced oral nitrate bioavailability. Functional characterization of an isolated Rothia mucilaginosa strain demonstrates its capacity to mediate both nitrate-nitrite-NO and nitrate-nitrite-NH<sub>4</sub><sup>+</sup> pathways under oxygen-limited conditions. Incorporating nitrate metabolism-associated microbial features into clinical risk factors improves risk stratification for progression to prediabetes. These findings support oral nitrate metabolism as a microbial pathway linking oral ecology to systemic metabolic health and suggest that tongue cleaning may modulate microbial functions involved in this pathway.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"103092"},"PeriodicalIF":14.0,"publicationDate":"2026-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149126795","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}
Cell Reports MedicinePub Date : 2026-10-20Epub Date: 2026-10-07DOI: 10.1016/j.xcrm.2026.103093
Liheng Chen, Min Yao, Honghai Tang, Jingjing Zhao, Dan Mu, Daqi Wang, Sha Yu, Luo Guo, Qi Cao, Luoying Jiang, Chong Cui, Lei Han, Yuan Yuan, Shuang Han, Sen Zhang, Xiaoyi Gu, Yicheng Zeng, Bowen Zhang, Qi Zhao, Shuyuan Li, Yiyao Chen, Ru Zhang, Huawei Li, Zhaoxin Ma, Geng-Lin Li, Yilai Shu
{"title":"A translational pipeline for classification of variants of uncertain significance to support gene therapy clinical trial in OTOF-related deafness.","authors":"Liheng Chen, Min Yao, Honghai Tang, Jingjing Zhao, Dan Mu, Daqi Wang, Sha Yu, Luo Guo, Qi Cao, Luoying Jiang, Chong Cui, Lei Han, Yuan Yuan, Shuang Han, Sen Zhang, Xiaoyi Gu, Yicheng Zeng, Bowen Zhang, Qi Zhao, Shuyuan Li, Yiyao Chen, Ru Zhang, Huawei Li, Zhaoxin Ma, Geng-Lin Li, Yilai Shu","doi":"10.1016/j.xcrm.2026.103093","DOIUrl":"10.1016/j.xcrm.2026.103093","url":null,"abstract":"<p><p>OTOF gene dysfunction causes congenital deafness. OTOF gene therapy achieves promising clinical efficacy. However, OTOF variants of uncertain significance (VUS) hinder diagnosis and restrict eligibility for gene therapy in half of 135 hearing loss patients with biallelic OTOF variants in our cohort. Here, we establish a translational pipeline to reclassify VUSs and guide clinical decisions via functional analysis. We evaluate coding VUSs using an adeno-associated virus (AAV)-mediated variant delivery system into Otof<sup>-/-</sup> mice and evaluate non-coding VUSs via splicing assays. Isolated homozygous E1700Q confers normal hearing, while E1700Q consistently occurs in cis with K1992R in patients, and K1992R correlates with abnormal otoferlin subcellular localization. This pipeline reclassifies eight representative VUSs, enabling definitive molecular diagnoses for 38 patients. Seven eligible patients receive gene therapy and show auditory improvement, including one achieving near-normal hearing that was sustained for 1.5 years. This pipeline effectively expands the gene therapy eligibility for OTOF-related deafness. This study is registered with the Chinese Clinical Trial Registry: ChiCTR2200063181.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"103093"},"PeriodicalIF":14.0,"publicationDate":"2026-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149126808","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}
Cell Reports MedicinePub Date : 2026-10-20Epub Date: 2026-10-02DOI: 10.1016/j.xcrm.2026.103104
Young Cha, Kwang-Soo Kim
{"title":"From patient cells to patient therapy: Twenty years of iPSC-based translation in neurodegenerative disease.","authors":"Young Cha, Kwang-Soo Kim","doi":"10.1016/j.xcrm.2026.103104","DOIUrl":"10.1016/j.xcrm.2026.103104","url":null,"abstract":"<p><p>Twenty years after the discovery of induced pluripotent stem cells, the field has progressed from patient-specific disease modeling toward cell-based therapies for neurodegenerative disorders. Parkinson's disease has emerged as the leading model for neuronal replacement, whereas Huntington's disease, Alzheimer's disease, and amyotrophic lateral sclerosis require distinct combinations of circuit reconstruction, cellular support, immune modulation, and engineered therapeutic delivery. We discuss key determinants of clinical translation, including cell source, product identity, graft composition, graft-host interactions, manufacturing reproducibility, genomic integrity, and clinical evaluation. We propose that the interval between cell transplantation and long-term engraftment constitutes a biological \"black box\" in which graft fate and therapeutic outcome are determined. As regenerative medicine enters its third decade, future progress will depend not only on generating therapeutic cells but also on elucidating and engineering the biological processes that determine their fate after transplantation, marking a conceptual transition from stem cell biology toward transplantation biology.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"103104"},"PeriodicalIF":14.0,"publicationDate":"2026-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149104658","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}
Cell Reports MedicinePub Date : 2026-10-20Epub Date: 2026-10-09DOI: 10.1016/j.xcrm.2026.103105
Kathryn J Citrano, Vidhya Bharathi Maheswari Jawahar, Madison M Reeves, Leonardo Petrucelli, Yari Carlomagno, Mei Yue, Jorge Alaiz Noya, Lillian M Daughrity, Raul Baena Tomé, Karen Jansen-West, Bailey Rawlinson, Michael DeTure, Erica Engelberg-Cook, Alpana Singh, Neill R Graff-Radford, Gregory S Day, Bradley F Boeve, Adam L Boxer, David S Knopman, Keith A Josephs, Ronald C Petersen, Björn Oskarsson, Nicholas J Ashton, Dennis W Dickson, Tania F Gendron, Mercedes Prudencio, Yong-Jie Zhang, Leonard Petrucelli
{"title":"Anti-HDGFL2 cryptic protein antibodies provide a sensitive readout of TDP-43 pathology and clinical disease features.","authors":"Kathryn J Citrano, Vidhya Bharathi Maheswari Jawahar, Madison M Reeves, Leonardo Petrucelli, Yari Carlomagno, Mei Yue, Jorge Alaiz Noya, Lillian M Daughrity, Raul Baena Tomé, Karen Jansen-West, Bailey Rawlinson, Michael DeTure, Erica Engelberg-Cook, Alpana Singh, Neill R Graff-Radford, Gregory S Day, Bradley F Boeve, Adam L Boxer, David S Knopman, Keith A Josephs, Ronald C Petersen, Björn Oskarsson, Nicholas J Ashton, Dennis W Dickson, Tania F Gendron, Mercedes Prudencio, Yong-Jie Zhang, Leonard Petrucelli","doi":"10.1016/j.xcrm.2026.103105","DOIUrl":"10.1016/j.xcrm.2026.103105","url":null,"abstract":"<p><p>TAR DNA-binding protein (TDP-43) cytoplasmic aggregates and nuclear depletion contribute to TDP-43 dysfunction in frontotemporal lobar degeneration with TDP-43 pathology (FTLD-TDP) and forms of motor neuron disease (MND), particularly amyotrophic lateral sclerosis (ALS). TDP-43 regulates alternative splicing, but its dysfunction can engender the inclusion of cryptic exons (CEs) during splicing. Transcripts harboring an in-frame CE can generate de novo proteins. One example is the CE variant of hepatoma-derived growth factor-like protein 2 (HDGFL2-CE). To understand HDGFL2-CE as a readout of TDP-43 dysfunction, and its spatial relationship with TDP-43 pathology, we generate anti-HDGFL2-CE polyclonal and monoclonal antibodies and develop sensitive HDGFL2-CE immunoassays. With these tools, we observe that HDGFL2-CE accumulates in neurons with TDP-43 pathology, and that higher frontal cortex HDGFL2-CE in FTLD-TDP and FTLD-TDP/MND associates with greater pathological TDP-43, earlier age of onset, and shorter survival, supporting HDGFL2-CE as a marker tightly linked to TDP-43 dysfunction and clinical disease features.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"103105"},"PeriodicalIF":14.0,"publicationDate":"2026-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149147421","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}
Cell Reports MedicinePub Date : 2026-10-20Epub Date: 2026-10-09DOI: 10.1016/j.xcrm.2026.103109
John H Klich, Anahita Nejatfard, Emily L Meany, Ben S Ou, Zuzanna D Krawczyk, Julie Baillet, Eric A Appel
{"title":"Spatially tuned localization of interleukins and OX40 agonists enhances synergistic anti-tumor immunity.","authors":"John H Klich, Anahita Nejatfard, Emily L Meany, Ben S Ou, Zuzanna D Krawczyk, Julie Baillet, Eric A Appel","doi":"10.1016/j.xcrm.2026.103109","DOIUrl":"10.1016/j.xcrm.2026.103109","url":null,"abstract":"<p><p>While advances in immunotherapy have revolutionized care for cancer patients, most approaches still fail to mount a robust anti-cancer effect. To address this challenge, the field has turned to combination immunotherapies, but systemic administration of potent combination therapies has resulted in severe immune-related adverse effects. Here, we use an injectable polymer-nanoparticle (PNP) hydrogel to rationally localize immunotherapeutic cytokines (IL-12 and IL-2) intratumorally and antibodies (OX40a) peritumorally. We hypothesize that selectively altering the biodistribution of these cargo enables tolerable and synergistic anti-cancer combinations. Using in vivo imaging, we demonstrate that administration sites are critical for redistributing cargo to either the tumor or tumor-draining lymph node (tdLN). Further, we demonstrate that this approach synergistically improved treatment efficacy in the B16F10 and MC38 tumor models and alters cellular phenotypes, resulting in significant tumor clearance in both single and double tumor models.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"103109"},"PeriodicalIF":14.0,"publicationDate":"2026-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149148494","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}
Cell Reports MedicinePub Date : 2026-10-20Epub Date: 2026-09-18DOI: 10.1016/j.xcrm.2026.103057
Fahriye Duzagac, Nan Deng, Jinling Wang, Supriya Nagaraju, Peter Steinberger, Alexandre Reuben, Krishna M Sinha, Eduardo Vilar
{"title":"Characterization of circulating neoantigen-specific T cell responses and public T cell receptors shaping immune memory in Lynch syndrome carriers.","authors":"Fahriye Duzagac, Nan Deng, Jinling Wang, Supriya Nagaraju, Peter Steinberger, Alexandre Reuben, Krishna M Sinha, Eduardo Vilar","doi":"10.1016/j.xcrm.2026.103057","DOIUrl":"10.1016/j.xcrm.2026.103057","url":null,"abstract":"<p><p>Lynch syndrome (LS), a common inherited genetic condition predisposing to cancer, provides a unique model to study immune surveillance at the earliest stages of tumorigenesis. A hallmark of LS carcinogenesis is the generation of highly immunogenic neoantigens, yet the transcriptomic states of the T cells that recognize them remain poorly understood. Here, we characterize neoantigen-specific T cells from LS carriers using functional assays, single-cell RNA/T cell receptor (TCR) sequencing, and repertoire integration with existing large datasets. Recurrent neoantigens elicit strong immune responses, with neoantigen-specific T cells mediating cytotoxicity against tumor organoids. Single-cell analysis reveals oligoclonal expansions spanning effector and memory states with enrichment for exhausted subsets among cancer survivors and retention of polyfunctional effectors in cancer-free carriers. Cross-cohort analysis identifies public TCR clonotypes in circulation that overlap with pre-cancer and tumor tissue repertoires. Together, these findings define the architecture of circulating neoantigen-specific immune memory in LS and highlight public TCRs as candidates for immune monitoring and immunoprevention.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"103057"},"PeriodicalIF":14.0,"publicationDate":"2026-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149001075","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}
Cell Reports MedicinePub Date : 2026-10-20Epub Date: 2026-09-25DOI: 10.1016/j.xcrm.2026.103060
Shengchun Wang, Cosimo Lobello, Pradeep K Gupta, Roniya Francis, Aldana Vistarop, Bhaumik Shah, Sergio Zamora-Erazo, Fahad Ahmed, David Rushmore, Andrew Kalgren, David Nelson, Vanessa Dupoux, Johnvesly Basappa, Don A Baldwin, Henry Fung, Mowafaq Jillab, Hayan Lee, K Qi Cai, Reza Nejati, Bijan Boldajipour, Janusz Franco-Barraza, Gary Lee, Kavindra Nath, Mariusz A Wasik
{"title":"Multipronged enhancement of CART cell activity against ROR1 neoantigen by inhibition of H3K27 methyltransferase EZH2.","authors":"Shengchun Wang, Cosimo Lobello, Pradeep K Gupta, Roniya Francis, Aldana Vistarop, Bhaumik Shah, Sergio Zamora-Erazo, Fahad Ahmed, David Rushmore, Andrew Kalgren, David Nelson, Vanessa Dupoux, Johnvesly Basappa, Don A Baldwin, Henry Fung, Mowafaq Jillab, Hayan Lee, K Qi Cai, Reza Nejati, Bijan Boldajipour, Janusz Franco-Barraza, Gary Lee, Kavindra Nath, Mariusz A Wasik","doi":"10.1016/j.xcrm.2026.103060","DOIUrl":"10.1016/j.xcrm.2026.103060","url":null,"abstract":"<p><p>ROR1 is expressed across a broad spectrum of malignancies. While T lymphocytes armed with chimeric antigen receptor targeting ROR1 (CART-ROR1 cells) have reached clinical stage, the efficacy of this therapy has been limited. We report that inhibition of H3K27 methyltransferase EZH2 and, to a much lesser degree, the DNA methyltransferase DNMT1 and the H3K9 methyltransferase G9A promotes ROR1 expression by malignant cells. EZH2 inhibition also directly impairs the growth of some malignant cell populations. The combination of EZH2 inhibition and CART-ROR1 cells is much more effective than CART-ROR1 cells alone in eliminating malignant cells. While EZH2 inhibition variably enhances the expression of immune checkpoint receptors, it markedly increases the synthesis of T cell-activating soluble factors and promotes the cytotoxic phenotype of CART-ROR1 cells. These results indicate that EZH2 inhibition enhances the CART-ROR1 cell effectiveness by diverse mechanisms, including promotion of ROR1 expression by malignant cells, suggesting that the combination may prove clinically more effective than CART-ROR1 cell monotherapy.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"103060"},"PeriodicalIF":14.0,"publicationDate":"2026-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149058953","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}
Cell Reports MedicinePub Date : 2026-10-20Epub Date: 2026-09-29DOI: 10.1016/j.xcrm.2026.103080
Nicolaas Van Renne, Elisa Agostinetto, Andrea Joaquín García, Marie Morfouace, Marcin Możejko, Zoë Denis, Sophie Déglise, Bernd Bodenmiller, Henoch S Hong, David Venet, Marcela Carausu, Robin Liechti, Stéphanie Tissot, Sylvie Rusakiewicz, Mattia Rediti, Xavier Catteau, Daniel Schulz, Delphine Loirat, Daniel Herrero Saboya, Philippe Aftimos, Matteo Benelli, Angel L Guerrero-Zotano, Andrea Gombos, Hans Wildiers, Jip Van Dinter, Ariane Sickinghe, Nicolas Penel, Jean-Charles Goeminne, Júlio Oliveira, Birute Brasiuniene, Emanuela Romano, Justin M Balko, Marleen Kok, Ewa Szczurek, Christos Sotiriou, Laurence Buisseret
{"title":"A multi-omics analysis of advanced triple-negative breast cancer identifies predictors to chemo-immunotherapy and on-treatment dynamics.","authors":"Nicolaas Van Renne, Elisa Agostinetto, Andrea Joaquín García, Marie Morfouace, Marcin Możejko, Zoë Denis, Sophie Déglise, Bernd Bodenmiller, Henoch S Hong, David Venet, Marcela Carausu, Robin Liechti, Stéphanie Tissot, Sylvie Rusakiewicz, Mattia Rediti, Xavier Catteau, Daniel Schulz, Delphine Loirat, Daniel Herrero Saboya, Philippe Aftimos, Matteo Benelli, Angel L Guerrero-Zotano, Andrea Gombos, Hans Wildiers, Jip Van Dinter, Ariane Sickinghe, Nicolas Penel, Jean-Charles Goeminne, Júlio Oliveira, Birute Brasiuniene, Emanuela Romano, Justin M Balko, Marleen Kok, Ewa Szczurek, Christos Sotiriou, Laurence Buisseret","doi":"10.1016/j.xcrm.2026.103080","DOIUrl":"10.1016/j.xcrm.2026.103080","url":null,"abstract":"<p><p>No validated biomarkers beyond PD-L1 currently guide immune checkpoint inhibition (ICI) in advanced triple-negative breast cancer (TNBC), and how tumors remodel their microenvironment in response to ICI remains incompletely understood. We perform a temporal analysis of patients with advanced TNBC treated with chemo-immunotherapy in the SYNERGY trial (NCT03616886; n = 84) and the EORTC-1553-SPECTA initiative (NCT02834884; n = 38) using RNA sequencing, whole-exome sequencing, multiplex immunofluorescence, and imaging mass cytometry. A transcriptomic progression-free survival (PFS)-based risk signature stratifies outcomes and is validated across ICI-treated cohorts, while showing context-dependent behavior in non-ICI settings. Favorable outcomes are associated with immune-enriched tumors with organized lymphoid architecture, while poor outcomes are linked to fibrotic, angiogenic microenvironments with frequent PI3K alterations. Upon treatment, early progression was characterized by fibrovascular remodeling, macrophage expansion, and upregulation of alternative immunosuppressive mediators. These findings establish fibrovascular and myeloid reprogramming as a coordinated resistance program, identify actionable therapeutic targets, and support microenvironment stratification in future ICI-based trials.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"103080"},"PeriodicalIF":14.0,"publicationDate":"2026-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149079961","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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