Cell Reports Medicine最新文献_第9页

Lysyl oxidase inhibition disrupts mitochondrial homeostasis to create vulnerability to ferroptosis in TNBC. 赖氨酸氧化酶抑制破坏线粒体稳态，使TNBC易发生铁死亡。

IF 14 1区医学

Cell Reports Medicine Pub Date : 2026-09-15 Epub Date: 2026-08-31 DOI: 10.1016/j.xcrm.2026.103015

Ozge Saatci, Burge Ulukan, Metin Cetin, Hellen Kuasne, Constanza Martinez, Elif Percin, Natalia Oleinik, Matthew T Savoca, Ali Nehme, Aldo Hernández-Corchado, Evelyn Zavacky, Kukkamudi Sreenivas, Abdol H Rezaeian, Jennifer R Bethard, Jean-Sebastien Anoma, Ozlem Sener Sahin, Adriana Aguilar-Mahecha, Marguerite Buchanan, Mertkaya Aras, Genevieve DeBlois, Mark Basik, Elizabeth G Hill, Lauren E Ball, Chintada Nageswara Rao, Campbell McInnes, Yasser Riazalhosseini, Hamed S Najafabadi, John J Lemasters, Besim Ogretmen, Morag Park, Ozgur Sahin

{"title":"Lysyl oxidase inhibition disrupts mitochondrial homeostasis to create vulnerability to ferroptosis in TNBC.","authors":"Ozge Saatci, Burge Ulukan, Metin Cetin, Hellen Kuasne, Constanza Martinez, Elif Percin, Natalia Oleinik, Matthew T Savoca, Ali Nehme, Aldo Hernández-Corchado, Evelyn Zavacky, Kukkamudi Sreenivas, Abdol H Rezaeian, Jennifer R Bethard, Jean-Sebastien Anoma, Ozlem Sener Sahin, Adriana Aguilar-Mahecha, Marguerite Buchanan, Mertkaya Aras, Genevieve DeBlois, Mark Basik, Elizabeth G Hill, Lauren E Ball, Chintada Nageswara Rao, Campbell McInnes, Yasser Riazalhosseini, Hamed S Najafabadi, John J Lemasters, Besim Ogretmen, Morag Park, Ozgur Sahin","doi":"10.1016/j.xcrm.2026.103015","DOIUrl":"10.1016/j.xcrm.2026.103015","url":null,"abstract":"High metabolic heterogeneity and plasticity of triple-negative breast cancer (TNBC) contribute to therapy resistance, necessitating identification of therapeutic vulnerabilities. Here, we identify non-canonical functions of the extracellular matrix (ECM) remodeler, lysyl oxidase (LOX), in regulating glucose metabolism and mitochondrial homeostasis and show that inhibiting LOX generates targetable vulnerability to ferroptosis. Mechanistically, LOX interacts with PARKIN and its upstream kinase PINK1, which we identified as a substrate of LOX. LOX-mediated PINK1 oxidation suppresses PARKIN phosphorylation, stabilizing hypoxia-inducible factor 1-alpha (HIF-1α) and increasing glycolysis. Concomitantly, LOX inhibits PARKIN-mediated mitophagy and maintains mitochondria-ER contacts through VDAC1 stabilization, while the LOX-HSP90 complex promotes mitochondrial Ca2+ transport and ATP production. Inhibiting LOX suppresses glycolysis, disrupts mitochondrial dynamics, reduces OXPHOS and GPX4/FSP1, and induces compensatory DHODH activity. Our \"one-two punch\" approach combining LOX inhibition with clinical DHODH inhibitor suppresses tumor growth in vivo in chemo-free setting. Notably, LOX protein correlates with HIF-1α/GLUT1/GPX4 in TNBC patient tumors, supporting its clinical relevance.","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"103015"},"PeriodicalIF":14.0,"publicationDate":"2026-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13589490/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148863705","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}

引用次数: 0

Surface display of co-stimulatory ligand B7H2 on engineered bacteria enhances tumor immunotherapy. 共刺激配体B7H2在工程细菌表面的展示增强了肿瘤免疫治疗。

IF 14 1区医学

Cell Reports Medicine Pub Date : 2026-09-15 Epub Date: 2026-09-03 DOI: 10.1016/j.xcrm.2026.103016

Qiliner Feng, Chen Wang, Zexi Li, Dingran Sheng, Si Shi, Jie Liu, Baizhu Chen

{"title":"Surface display of co-stimulatory ligand B7H2 on engineered bacteria enhances tumor immunotherapy.","authors":"Qiliner Feng, Chen Wang, Zexi Li, Dingran Sheng, Si Shi, Jie Liu, Baizhu Chen","doi":"10.1016/j.xcrm.2026.103016","DOIUrl":"10.1016/j.xcrm.2026.103016","url":null,"abstract":"Bacteria-based living therapeutics exhibit outstanding potential for tumor immunotherapy when combined with functional materials or rewired with rationally designed gene circuits. To stimulate T cells precisely and effectively, herein, we report the surface-engineered bacteria as the living therapeutic for tumor immunotherapy. Escherichia coli cells are genetically programmed to display surface-anchored B7H2 to provide immunological co-stimulation signal of T cells and Histag to coordinate with ZnS quantum dots. In tumors, B7H2 induces the co-stimulatory ICOS-B7H2 signal at the molecular level and triggers the stimulation of cytotoxic T cells, the polarization of helper T cells, the release of cytokines, and long term antitumor immunological memory. Meanwhile, the coordinated ZnS quantum dots image tumors and synergize with B7H2 to enhance immune effects by activating the cGAS/STING pathway. With functional domains displaying on the bacterial surface, we establish an efficient living therapeutic approach for tumor immunotherapy.","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"103016"},"PeriodicalIF":14.0,"publicationDate":"2026-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13589496/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148886480","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}

引用次数: 0

Development and validation of a serum peptidomic signature for early detection of asymptomatic ovarian cancer: A multi-center prospective study. 开发和验证无症状卵巢癌早期检测的血清肽特征：一项多中心前瞻性研究。

IF 14 1区医学

Cell Reports Medicine Pub Date : 2026-09-15 Epub Date: 2026-08-28 DOI: 10.1016/j.xcrm.2026.103014

Zhen Li, Hua Zhang, Ruomeng Bi, Yue Zhang, Wenpei Shi, Huijuan Yang, Shanshan Cheng, Chao Wang, Yaqian Zhao, Yi Li, Xinyu Lu, Xiaobin Chen, Yuanpeng Zhou, Bowen Dong, Renhao Xue, Yu Wang

{"title":"Development and validation of a serum peptidomic signature for early detection of asymptomatic ovarian cancer: A multi-center prospective study.","authors":"Zhen Li, Hua Zhang, Ruomeng Bi, Yue Zhang, Wenpei Shi, Huijuan Yang, Shanshan Cheng, Chao Wang, Yaqian Zhao, Yi Li, Xinyu Lu, Xiaobin Chen, Yuanpeng Zhou, Bowen Dong, Renhao Xue, Yu Wang","doi":"10.1016/j.xcrm.2026.103014","DOIUrl":"10.1016/j.xcrm.2026.103014","url":null,"abstract":"Early detection of asymptomatic ovarian cancer (asym-OC) remains a critical challenge, the failure of which underlies its high mortality. Performing serum peptidomic profiling of 843 participants in the cohort SOCFCP, we distill 1,081 initial features into a 7-marker panel for asym-OC detection via a biology-informed machine-learning (ML)-based feature selection strategy. Three markers significantly revert toward non-OC levels after surgery. Integrating the panel with age, CA125, and HE4, we develop and externally validate (n = 159) a LightGBM model, ProMS+. For early-stage OC detection, ProMS+ shows a specificity of 92.6% at 95.0% sensitivity, outperforming CA125 (44.7%), HE4 (11.2%), and Risk of Ovarian Malignancy Algorithm (ROMA) (24.0%), with an area under the curve (AUC) of 0.993. In a simulated high-risk population (n = 100,000; OC prevalence = 1%), ProMS+ yields a high AUC (0.983) and a higher positive predictive value than CA125, HE4, and Age + CA125 + HE4 combined model (0.201 vs. 0.027, 0.090, and 0.064). ProMS+ offers a promising, non-invasive, and interpretable approach for the early detection of asym-OC.","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"103014"},"PeriodicalIF":14.0,"publicationDate":"2026-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13589509/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148849748","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}

引用次数: 0

Individualized antisense oligonucleotide treatment eligibility of patients living with neurodevelopmental diseases. 神经发育性疾病患者的个体化反义寡核苷酸治疗资格。

IF 14 1区医学

Cell Reports Medicine Pub Date : 2026-09-15 Epub Date: 2026-08-13 DOI: 10.1016/j.xcrm.2026.102989

Annemieke Aartsma-Rus, Claudio Melo de Gusmao, Scott Demarest, Willeke van Roon-Mom, Holm Graessner, Lynn Wein Bush, Charlotte Kogel, Timothy Wei-Wen Yu, Matthis Synofzik, Rebecca Schuele

引用次数: 0

Prevention of myopia in a near-primate by supplemental indigo light suggests a hypothesis for the myopia boom. 通过补充靛蓝光来预防近灵长类动物的近视，这为近视激增提供了一种假设。

IF 14 1区医学

Cell Reports Medicine Pub Date : 2026-09-15 Epub Date: 2026-08-18 DOI: 10.1016/j.xcrm.2026.102999

Rafael Grytz, Mustapha El Hamdaoui, Takahiro Yamashita, Shane P D'Souza, Mahmoud Tawfik KhalafAllah, Mehlika Inanici, Richard A Lang

{"title":"Prevention of myopia in a near-primate by supplemental indigo light suggests a hypothesis for the myopia boom.","authors":"Rafael Grytz, Mustapha El Hamdaoui, Takahiro Yamashita, Shane P D'Souza, Mahmoud Tawfik KhalafAllah, Mehlika Inanici, Richard A Lang","doi":"10.1016/j.xcrm.2026.102999","DOIUrl":"10.1016/j.xcrm.2026.102999","url":null,"abstract":"Today, about 2.8 billion people worldwide suffer from myopia (nearsightedness), and projections place the 2050 burden at 4.8 billion people (the \"myopia boom\"). Myopia results from abnormal elongation of the eye, which causes images to focus in front of the retina. Building on prior work in mouse models assessing the non-visual opsin OPN5, we test the hypothesis that insufficient exposure to short-wavelength light increases myopia susceptibility. We use the tree shrew, a near-primate model for human myopia. Our findings show that indigo light in the range of 419-446 nm, when used to supplement a warm white light-emitting diode (LED), completely suppresses myopia induced by minus-lens wear. A large body of genetic and epidemiological evidence suggests that the \"myopia boom\" has an environmental cause. Our findings align with this evidence and suggest that one contributing factor is the relative absence of indigo light in built environments where we spend 86% of our time.","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"102999"},"PeriodicalIF":14.0,"publicationDate":"2026-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13589487/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148788774","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}

引用次数: 0

Preferential engagement of the anti-inflammatory ATP/adenosine axis by HIV vaccine candidate with V1-deleted envelope in male rhesus macaques. 在雄性恒河猴中，带有v1缺失包膜的HIV候选疫苗优先参与抗炎ATP/腺苷轴

IF 14 1区医学

Cell Reports Medicine Pub Date : 2026-09-15 Epub Date: 2026-09-02 DOI: 10.1016/j.xcrm.2026.103022

Isabela Silva de Castro, Mohammad Arif Rahman, Massimiliano Bissa, Katherine C Goldfarbmuren, Luca Schifanella, Sarkis Sarkis, Kombo F N'guessan, Zhong-Min Ma, Anna Gutowska, James D Stamos, Melvin N Doster, Emmanuel K Woode, Justin C Smith, Pamela A Kozlowski, LaTonya D Williams, Katherine M McKinnon, Georgia D Tomaras, Xiaoying Shen, David C Montefiori, Sampa Santra, Dominic Paquin-Proulx, Frank Maldarelli, Timothy Cardozo, Genoveffa Franchini

{"title":"Preferential engagement of the anti-inflammatory ATP/adenosine axis by HIV vaccine candidate with V1-deleted envelope in male rhesus macaques.","authors":"Isabela Silva de Castro, Mohammad Arif Rahman, Massimiliano Bissa, Katherine C Goldfarbmuren, Luca Schifanella, Sarkis Sarkis, Kombo F N'guessan, Zhong-Min Ma, Anna Gutowska, James D Stamos, Melvin N Doster, Emmanuel K Woode, Justin C Smith, Pamela A Kozlowski, LaTonya D Williams, Katherine M McKinnon, Georgia D Tomaras, Xiaoying Shen, David C Montefiori, Sampa Santra, Dominic Paquin-Proulx, Frank Maldarelli, Timothy Cardozo, Genoveffa Franchini","doi":"10.1016/j.xcrm.2026.103022","DOIUrl":"10.1016/j.xcrm.2026.103022","url":null,"abstract":"We evaluate the efficacy and immunogenicity of HIV clade A/E A244 envelope (Env) immunogens with the 23 amino acids of variable region 1 deleted (ΔV1) or retained (wild-type [WT]) in macaques. Only the ΔV1 regimen significantly reduces the risk of mucosal acquisition of clade C simian/human immunodeficiency virus (SHIV)1157(QNE)Y173H versus controls, providing 81% efficacy and leaving 10 of 12 immunized animals uninfected. ΔV1 vaccination induces higher systemic antibody-dependent cellular cytotoxicity (ADCC) targeting helical-V2 and anti-inflammatory myeloid cells, which, together with IL-17+NKp44+ innate lymphoid cells (ILCs) and systemic PD-1+ helper T cells, correlated with reduced infection risk. By contrast, WT immunization induces higher IL-15, CCR2+pDC, and gp70/V1V2-biased responses, which, along with mucosal IFN-γ+NKG2A-NKp44- ILCs, were associated with increased susceptibility. Ex vivo, ΔV1 gp120 reduced CCR5 expression on CD4+ T cells relative to WT gp120, consistent with the anti-inflammatory mucosal response by ΔV1-vaccine regimens in vivo. Thus, V1 deletion promotes an anti-inflammatory mucosal landscape less permissive to HIV seeding and dissemination following virus exposure.","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"103022"},"PeriodicalIF":14.0,"publicationDate":"2026-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13589499/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148879381","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}

引用次数: 0

Global gut microbiome atlas identifies epidemiologic-stage-specific signatures in inflammatory bowel disease. 全球肠道微生物组图谱确定炎症性肠病的流行病学阶段特异性特征。

IF 14 1区医学

Cell Reports Medicine Pub Date : 2026-09-15 Epub Date: 2026-08-10 DOI: 10.1016/j.xcrm.2026.102974

Jinxia Zhai, Yingjie Li, Jiameng Liu, Xinyi Su, Runze Cui, Dianyu Zheng, Yuhan Sun, Jingsheng Yu, Cong Dai

{"title":"Global gut microbiome atlas identifies epidemiologic-stage-specific signatures in inflammatory bowel disease.","authors":"Jinxia Zhai, Yingjie Li, Jiameng Liu, Xinyi Su, Runze Cui, Dianyu Zheng, Yuhan Sun, Jingsheng Yu, Cong Dai","doi":"10.1016/j.xcrm.2026.102974","DOIUrl":"10.1016/j.xcrm.2026.102974","url":null,"abstract":"The global rise of inflammatory bowel disease (IBD) reflects environmental shifts, yet how these changes are embedded in the gut microbial ecology remains unclear. We construct a microbiome atlas comprising 245,627 profiles. By classifying countries into three epidemiologic stages, we establish a framework. As the IBD burden increases, the gut microbial alpha diversity declines, and community structures form distinct clusters. This transition is characterized by a gradient of core genera. Integrating six shotgun metagenomic cohorts, we identify the depletion of anabolic pathways in IBD patients. Strain-level analysis reveals that epidemiologic staging shapes genetic architecture within species, identifying an IBD-enriched subclade of Eisenbergiella associated with elevated fecal cholic acid. We develop a microbial inflammatory risk score (MIRS), based on 19 genera, that discriminates IBD from controls (area under the curve [AUC] = 0.92). MIRS correlates with IBD prevalence. Our study provides an atlas linking epidemiology to microbiome ecology and strain evolution, offering a foundation for population-level surveillance and interventions in IBD.","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"102974"},"PeriodicalIF":14.0,"publicationDate":"2026-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13589510/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148705630","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}

引用次数: 0

Enfortumab vedotin induces immunogenic cell death and shows enhanced preclinical antitumor activity when combined with a PD-1 inhibitor. 当与PD-1抑制剂联合使用时，可诱导免疫原性细胞死亡并显示增强的临床前抗肿瘤活性。

IF 14 1区医学

Cell Reports Medicine Pub Date : 2026-09-15 Epub Date: 2026-09-02 DOI: 10.1016/j.xcrm.2026.103021

Devra J Olson, Bernard A Liu, Patrick Younan, Gabriele Blahnik-Fagan, R Greg Stacey, John Gosink, Katie Snead, Elena Tenn, Kelly Hensley, Disha Sahetya, Albina Nesterova, Margo Zaval, Anthony Cao, Christine O'Day, Ryan A Heiser, Timothy S Lewis, Shyra J Gardai, Taisuke Nakazawa, Masashi Shimazaki, Christopher Carosino, Gregory L Szeto, Sharsti Sandall

{"title":"Enfortumab vedotin induces immunogenic cell death and shows enhanced preclinical antitumor activity when combined with a PD-1 inhibitor.","authors":"Devra J Olson, Bernard A Liu, Patrick Younan, Gabriele Blahnik-Fagan, R Greg Stacey, John Gosink, Katie Snead, Elena Tenn, Kelly Hensley, Disha Sahetya, Albina Nesterova, Margo Zaval, Anthony Cao, Christine O'Day, Ryan A Heiser, Timothy S Lewis, Shyra J Gardai, Taisuke Nakazawa, Masashi Shimazaki, Christopher Carosino, Gregory L Szeto, Sharsti Sandall","doi":"10.1016/j.xcrm.2026.103021","DOIUrl":"10.1016/j.xcrm.2026.103021","url":null,"abstract":"Enfortumab vedotin is a Nectin-4-directed antibody-drug conjugate designed to deliver the microtubule-disrupting agent monomethyl auristatin E (MMAE) to tumor cells. Using preclinical models of urothelial cancer (UC), we expand the understanding of the multifaceted mechanism of action for enfortumab vedotin that includes direct cytotoxicity on Nectin-4-positive tumor cells, indirect bystander effect on neighboring Nectin-4-negative tumor cells, and MMAE-mediated induction of immunogenic cell death (ICD) and associated increase in activated immune cells in the tumor microenvironment. Importantly, vaccination with enfortumab vedotin-treated tumor cells results in protection against tumor rechallenge in mice, consistent with antitumor immunity. MMAE-mediated ICD induction modulates the tumor microenvironment in a complementary manner to immune checkpoint inhibition. Accordingly, enfortumab vedotin plus PD-1 inhibitor shows enhanced antitumor activity in vivo. These preclinical findings provide mechanistic hypotheses that may be relevant to the improved clinical outcomes observed for enfortumab vedotin plus pembrolizumab relative to chemotherapy.","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"103021"},"PeriodicalIF":14.0,"publicationDate":"2026-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13589495/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148879431","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}

引用次数: 0

Spatial proteogenomic profiling uncovers sensitization strategies for antibody-drug conjugate in HER2-positive breast cancer. 空间蛋白质基因组分析揭示了her2阳性乳腺癌中抗体-药物偶联物的致敏策略。

IF 14 1区医学

Cell Reports Medicine Pub Date : 2026-09-15 Epub Date: 2026-08-13 DOI: 10.1016/j.xcrm.2026.102987

Yu-Wen Cai, Shu-Han Jia, Hao Wang, Hong Hu, Yan-Wu Zhang, Zhi-Ming Shao, Han-Dong Sun, Ke-Da Yu

{"title":"Spatial proteogenomic profiling uncovers sensitization strategies for antibody-drug conjugate in HER2-positive breast cancer.","authors":"Yu-Wen Cai, Shu-Han Jia, Hao Wang, Hong Hu, Yan-Wu Zhang, Zhi-Ming Shao, Han-Dong Sun, Ke-Da Yu","doi":"10.1016/j.xcrm.2026.102987","DOIUrl":"10.1016/j.xcrm.2026.102987","url":null,"abstract":"Antibody-drug conjugates (ADCs) have transformed the treatment of HER2-positive breast cancer, yet resistance remains poorly understood. Using imaging mass cytometry, we profiled 157 regions of interest comprising 912,360 single cells from 47 HER2-positive/hormone receptor-negative breast cancers treated with SHR-A1811 in the FASCINATE-N trial. Spatial proteomic analyses identified two determinants of ADC response: elevated tumor-cell H3K27ac expression was associated with improved ADC efficacy, whereas collagen-positive fibroblasts mediated resistance. Combining ADC with the histone deacetylase inhibitor chidamide or the collagen-modulating agent losartan produced synergistic antitumor effects in preclinical models. These biomarkers and therapeutic vulnerabilities were independently validated in patients with advanced HER2-positive disease receiving trastuzumab deruxtecan. Moreover, based on these spatial features, we developed a clinically applicable ADC barrier prediction model that can be implemented using multiplex immunofluorescence. Taken together, our findings reveal actionable spatial determinants of ADC efficacy and suggest potential combination therapeutic strategies.","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"102987"},"PeriodicalIF":14.0,"publicationDate":"2026-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13589474/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148761034","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}

引用次数: 0

Maternal secretor status and human milk oligosaccharides influence the infant gut resistome. 母体分泌状态和母乳低聚糖对婴儿肠道抵抗组的影响。

IF 14 1区医学

Cell Reports Medicine Pub Date : 2026-09-15 Epub Date: 2026-09-01 DOI: 10.1016/j.xcrm.2026.103007

Anna Samarra, Alejandro J Alcañiz, Narciso M Quijada, Simone Renwick, Sergio George, Trishla Sinha, Cecília Martínez-Costa, Nicola Segata, Alexandra Zhernakova, Lars Bode, Maria Carmen Collado

{"title":"Maternal secretor status and human milk oligosaccharides influence the infant gut resistome.","authors":"Anna Samarra, Alejandro J Alcañiz, Narciso M Quijada, Simone Renwick, Sergio George, Trishla Sinha, Cecília Martínez-Costa, Nicola Segata, Alexandra Zhernakova, Lars Bode, Maria Carmen Collado","doi":"10.1016/j.xcrm.2026.103007","DOIUrl":"10.1016/j.xcrm.2026.103007","url":null,"abstract":"The infant gut resistome is established early in life and is shaped by perinatal exposures, yet the mechanisms underlying its modulation remain unclear. We combined shotgun metagenomics of fecal samples from 57 one-month-old infants and paired milk samples from 50 mothers in the MAMI cohort to investigate the influence of maternal secretor status on early-life resistome development. Longitudinal follow-up at 6 and 12 months, and also further validation in the independent Lifelines NEXT (LLNEXT) cohort, support our findings. Cesarean section (C-section) was associated with increased antibiotic resistance gene (ARG) diversity, whereas exclusive breastfeeding reduced ARG abundance and diversity. Maternal secretor status further modified resistome composition among exclusively breastfed infants. Human milk oligosaccharide profiling identified specific glycans underlying these associations, with 2'-fucosyllactose and 6'-sialyllactose showing negative correlations with distinct ARG classes. These findings identify human milk composition as a key determinant of early-life resistome assembly and a potential target for modulating antimicrobial resistance.","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"103007"},"PeriodicalIF":14.0,"publicationDate":"2026-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13589485/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148873230","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}

引用次数: 0