{"title":"Pharmacological rescue of mutant p53 triggers spontaneous tumor regression via immune responses.","authors":"Jiabing Li, Shuang Zhang, Baohui Wang, Yuting Dai, Jiale Wu, Dianjia Liu, Ying Liang, Shujun Xiao, Zhengyuan Wang, Jiaqi Wu, Derun Zheng, Xueqin Chen, Fangfang Shi, Kai Tan, Xianting Ding, Huaxin Song, Sujiang Zhang, Min Lu","doi":"10.1016/j.xcrm.2025.101976","DOIUrl":"https://doi.org/10.1016/j.xcrm.2025.101976","url":null,"abstract":"<p><p>Tumor suppressor p53 is the most frequently mutated protein in cancer, possessing untapped immune-modulating capabilities in anticancer treatment. Here, we investigate the efficacy and underlying mechanisms of pharmacological reactivation of mutant p53 in treating spontaneous tumors in mice. In the p53 R279W (equivalent to the human hotspot R282W) mouse model developing spontaneous tumors, arsenic trioxide (ATO) treatment through drinking water significantly prolongs the survival of mice, dependent on p53-R279W reactivation. Transient regressions of spontaneous T-lymphomas are observed in 70% of the ATO-treated mice, accompanied by interferon (IFN) response. In allograft models, the tumor-suppressive effect of reactivated p53-R279W is detectably reduced in both immunodeficient Rag1<sup>-/-</sup> and CD8<sup>+</sup> T cell-depleted mice. ATO also activates the IFN pathway in human cancer cells harboring various p53 mutations, as well as in primary samples derived from the p53-mutant patient treated with ATO. Together, p53 could serve as an alternative therapeutic target for the development of immunotherapies.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"101976"},"PeriodicalIF":11.7,"publicationDate":"2025-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143476457","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}
Christina Metoikidou, Vadim Karnaukhov, Bram Boeckx, Eleonora Timperi, Pierre-Emmanuel Bonté, Ling Wang, Marion Espenel, Benoit Albaud, Delphine Loirat, Xiaoxiao Wang, Christos Sotiriou, Philippe Aftimos, Kevin Punie, Hans Wildiers, Viktorija Labroska, Ming-Wei Wang, Joshua J Waterfall, Martine Piccart-Gebhart, Thierry Mora, Aleksandra Walczak, Olivier Lantz, Laurence Buisseret, Diether Lambrechts, Sebastian Amigorena, Emanuela Romano
{"title":"Continuous replenishment of the dysfunctional CD8 T cell axis is associated with response to chemoimmunotherapy in advanced breast cancer.","authors":"Christina Metoikidou, Vadim Karnaukhov, Bram Boeckx, Eleonora Timperi, Pierre-Emmanuel Bonté, Ling Wang, Marion Espenel, Benoit Albaud, Delphine Loirat, Xiaoxiao Wang, Christos Sotiriou, Philippe Aftimos, Kevin Punie, Hans Wildiers, Viktorija Labroska, Ming-Wei Wang, Joshua J Waterfall, Martine Piccart-Gebhart, Thierry Mora, Aleksandra Walczak, Olivier Lantz, Laurence Buisseret, Diether Lambrechts, Sebastian Amigorena, Emanuela Romano","doi":"10.1016/j.xcrm.2025.101973","DOIUrl":"https://doi.org/10.1016/j.xcrm.2025.101973","url":null,"abstract":"<p><p>Chemotherapy combined with immune checkpoint blockade has shown clinical activity in breast cancer. Response, however, occurs in only a low proportion of patients. How the immune landscape of the tumor determines the immune and clinical responses to chemoimmunotherapy is not well understood. Here, using a combination of single-cell RNA sequencing (scRNA-seq) and single-cell T cell receptor sequencing (scTCR-seq), we profile 40 biopsies from 27 patients with metastatic triple-negative breast cancer (TNBC), receiving chemotherapy and anti-PD-L1 alone or in combination with anti-CD73, in a phase 2 randomized clinical trial. Our results show an enrichment of late-dysfunctional, clonally expanded CD8<sup>+</sup> T cells in responder (R) patients. On treatment, R display an influx of newly emerging clonotypes, as well as expansion of the CD8<sup>+</sup> precursors. Collectively, our data suggest that baseline clonal expansion could be a potential predictor of response and that both clonal reinvigoration of pre-existing tumor-reactive T cells and clonal replacement on-treatment are important for a protective response to chemoimmunotherapy.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"101973"},"PeriodicalIF":11.7,"publicationDate":"2025-02-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143472350","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":"Protective effect of ulinastatin against negative inflammatory response and organ dysfunction in acute aortic dissection surgery: The PANDA trial.","authors":"Hong Liu, Si-Chong Qian, Kai Zhu, Yi-Fei Diao, Xiu-Fan Xu, Zhi-Wei Tang, Guo-Liang Fan, Hong-Hua Yue, Jun-Quan Chen, Ji-Nong Yang, Ying-Yuan Zhang, Chao Ma, Xiang Liu, Ying Wu, Zhong Wu, Nan Liu, Ao Li, Bu-Qing Ni, Yong-Feng Shao, Sheng Zhao, Hai-Yang Li, Hong-Jia Zhang","doi":"10.1016/j.xcrm.2024.101888","DOIUrl":"https://doi.org/10.1016/j.xcrm.2024.101888","url":null,"abstract":"<p><p>Ulinastatin is a protease-inhibiting drug with anti-inflammatory and other pharmacological properties. Little is known regarding its role following acute type A aortic dissection (ATAAD) surgery. We perform a randomized controlled trial to investigate the protective effect of ulinastatin against negative inflammatory response and organ dysfunction in ATAAD surgery (PANDA). The primary outcome of mean daily Sequential Organ Failure Assessment (SOFA) score from baseline to 7 days of surgery is 8.80 (SD, 4.11) in the ulinastatin group and 8.61 (SD, 4.47) in the control group (mean difference between groups was 0.04; 95% confidence interval [CI], -0.24 to 0.33; p = 0.765). Systemic inflammatory response syndrome (SIRS) within 7 days of surgery is lower in the ulinastatin group than in the control group (p < 0.001). Additional ulinastatin to standard treatment is likely to reduce SIRS rates instead of preventing organ dysfunction, highlighting the potential importance of the benefits of anti-inflammatory pharmacotherapeutics. The trial is registered on clinicaltrials.org (NCT04711889).</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":"6 1","pages":"101888"},"PeriodicalIF":11.7,"publicationDate":"2025-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143022356","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 first-in-human clinical study of an allogenic iPSC-derived corneal endothelial cell substitute transplantation for bullous keratopathy.","authors":"Masatoshi Hirayama, Shin Hatou, Masaki Nomura, Risa Hokama, Osama Ibrahim Hirayama, Emi Inagaki, Kumi Aso, Tomoko Sayano, Hiromi Dohi, Tadaaki Hanatani, Naoko Takasu, Hideyuki Okano, Kazuno Negishi, Shigeto Shimmura","doi":"10.1016/j.xcrm.2024.101847","DOIUrl":"10.1016/j.xcrm.2024.101847","url":null,"abstract":"<p><p>A first-in-human investigator-initiated clinical study of a corneal endothelial cell substitute (CLS001) derived from a clinical-grade induced pluripotent stem cell (iPSC) line shows improvement of visual acuity and corneal stromal edema, with no adverse events for up to 1 year after surgery for the treatment of bullous keratopathy. While preclinical tests, including multiple whole-genome analysis and tumorigenicity tests adhering to the Food and Drug Administration (FDA) draft guidelines, are negative, an additional whole-genome analysis conducted on transplanted CLS001 cells reveals a de novo in-frame deletion of exon22 in the EP300 gene. No adverse events related to the mutation are observed. Our study demonstrates the feasibility of using iPSC-derived cells to replace donor transplant for bullous keratopathy, while shedding light on risk management of gene mutation in cell products. Further follow-up is required for long-term analysis of clinical safety and efficacy.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"101847"},"PeriodicalIF":11.7,"publicationDate":"2025-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142982952","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 : 2025-01-21Epub Date: 2024-12-17DOI: 10.1016/j.xcrm.2024.101874
Haifei Jiang, Rebecca Nace, Coryn Ferguson, Lianwen Zhang, Kah Whye Peng, Stephen J Russell
{"title":"Oncolytic cytomegaloviruses expressing EGFR-retargeted fusogenic glycoprotein complex and drug-controllable interleukin 12.","authors":"Haifei Jiang, Rebecca Nace, Coryn Ferguson, Lianwen Zhang, Kah Whye Peng, Stephen J Russell","doi":"10.1016/j.xcrm.2024.101874","DOIUrl":"10.1016/j.xcrm.2024.101874","url":null,"abstract":"<p><p>Cytomegalovirus (CMV) infects a wide range of cell types, including tumor-associated myeloid cells and glioma cells. Clinical observations suggest a potential link between long-term glioblastoma survival and CMV reactivation. We herein present an oncolytic CMV vector, AD169r, which includes a restored pentamer complex gH/gL/pUL128-131 and the removal of UL1-UL20 and UL/b' sequences. The epidermal growth factor receptor (EGFR)-retargeted paramyxoviral glycoprotein H/F complexes are incorporated into AD169r backbone to enhance viral oncolysis. Additionally, a tet-off-controlled single-chain interleukin (IL)-12 is added to boost antitumor immune responses. The engineered oncolytic CMVs expressing EGFR-retargeted H/F complex demonstrate enhanced antitumor efficacy in human glioblastoma xenograft models. In the immunocompetent mouse CT-2A glioblastoma model, an oncolytic murine CMV (mCMV) expressing IL-12 significantly increases the abundance and cytotoxicity of CD4<sup>+</sup> T cells, CD8<sup>+</sup> T cells, and CD4<sup>-</sup>CD8<sup>-</sup> T cells in both treated and untreated tumors. Our findings highlight the potential of the AD169r-derived oncolytic viruses as CMV-based cancer viroimmunotherapy.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"101874"},"PeriodicalIF":11.7,"publicationDate":"2025-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142853165","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 : 2025-01-21Epub Date: 2025-01-06DOI: 10.1016/j.xcrm.2024.101884
Hongli Chen, Siyu Chen, Dan Liu, Yebei Liang, Huating Li, Yuqian Bao, Zhijun Zhu, Keqing Dong, Wen Li, Liang Feng, Di Cheng, Fusong Jiang, Li Wei, Xuhong Hou, Weiping Jia
{"title":"Associations between multiple metabolic biomarkers with steatotic liver disease subcategories: A 5-year Chinese cohort study.","authors":"Hongli Chen, Siyu Chen, Dan Liu, Yebei Liang, Huating Li, Yuqian Bao, Zhijun Zhu, Keqing Dong, Wen Li, Liang Feng, Di Cheng, Fusong Jiang, Li Wei, Xuhong Hou, Weiping Jia","doi":"10.1016/j.xcrm.2024.101884","DOIUrl":"https://doi.org/10.1016/j.xcrm.2024.101884","url":null,"abstract":"<p><p>The effectiveness of established biomarkers for non-alcoholic fatty liver disease (NAFLD) within the updated framework of steatotic liver disease (SLD) remains uncertain. This cohort study examines the association of four metabolic biomarkers-retinol-binding protein 4 (RBP-4), fibroblast growth factor 21 (FGF-21), adiponectin, and osteocalcin-with SLD and its subtypes: metabolic dysfunction-associated steatotic liver disease (MASLD) and metabolic dysfunction with alcohol-related liver disease (MetALD)/alcohol-related liver disease (ALD). Among 3,504 Chinese participants aged 55-70, 938 (26.8%) have developed SLD over 5 years, including 871 with MASLD and 67 with MetALD/ALD. The findings indicate that models incorporating RBP-4, FGF-21, adiponectin, and osteocalcin improve predictive accuracy for SLD beyond conventional models. Notably, adiponectin emerges as the most versatile marker, while elevated baseline levels of FGF-21 or RBP-4 indicate specific needs for metabolic or alcohol-related interventions, respectively, supporting tailored precision medicine strategies.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":"6 1","pages":"101884"},"PeriodicalIF":11.7,"publicationDate":"2025-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143022325","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":"Gut microbial GABA imbalance emerges as a metabolic signature in mild autism spectrum disorder linked to overrepresented Escherichia.","authors":"Dilong Wang, Youheng Jiang, Jian Jiang, Yihang Pan, Yanming Yang, Xiaoyi Fang, Liyang Liang, Hai Li, Zepeng Dong, Shilu Fan, Daqing Ma, Xue-Song Zhang, Huiliang Li, Yulong He, Ningning Li","doi":"10.1016/j.xcrm.2024.101919","DOIUrl":"10.1016/j.xcrm.2024.101919","url":null,"abstract":"<p><p>Gut microbiota (GM) alterations have been implicated in autism spectrum disorder (ASD), yet the specific functional architecture remains elusive. Here, employing multi-omics approaches, we investigate stool samples from two distinct cohorts comprising 203 children with mild ASD or typical development. In our screening cohort, regression-based analysis for metabolomic profiling identifies an elevated γ-aminobutyric acid (GABA) to glutamate (Glu) ratio as a metabolic signature of ASD, independent of age and gender. In the validating cohort, we affirm the GABA/Glu ratio as an ASD diagnostic indicator after adjusting for geography, age, gender, and specific food-consuming frequency. Integrated analysis of metabolomics, 16S rRNA sequencing, and metagenomics reveals a correlation between overrepresented Escherichia and disrupted GABA metabolism. Furthermore, we observe social behavioral impairments in weaning mice transplanted with E. coli, suggesting a potential link to ASD symptomatology. Collectively, these findings provide insights into potential diagnostic and therapeutic strategies aimed at evaluating and restoring gut microbial neurotransmitter homeostasis.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"101919"},"PeriodicalIF":11.7,"publicationDate":"2025-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142982971","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 cellular plasticity state of medulloblastoma local recurrence and distant dissemination.","authors":"Hailong Liu, Jing Zhang, Ziwei Wang, Wei Wang, Dongming Han, Xuan Chen, Yu Su, Jiao Zhang, Craig Daniels, Olivier Saulnier, Zeyuan John Wang, Chunyu Gu, Fei Liu, Kaiwen Deng, Dongyang Wang, Zhaoyang Feng, Yahui Zhao, Yifei Jiang, Yu Gao, Zijia Liu, Mingxu Ma, Yanong Li, Zitong Zhao, Hongyu Yuan, Youliang Sun, Yanfeng Shi, Tao Yang, Wenxing Li, Xueling Qi, Zejun Duan, Junping Zhang, Mingshan Zhang, Chunjiang Yu, Wei Jin, Xinguang Yu, Yu Tian, Shuaicheng Li, Chunde Li, Michael D Taylor, Jiankang Li, Yong-Qiang Liu, Xiaoguang Qiu, Tao Jiang","doi":"10.1016/j.xcrm.2024.101914","DOIUrl":"10.1016/j.xcrm.2024.101914","url":null,"abstract":"<p><p>Medulloblastoma (MB), a heterogeneous pediatric brain tumor, poses challenges in the treatment of tumor recurrence and dissemination. To characterize cellular diversity and genetic features, we comprehensively analyzed single-cell/nucleus RNA sequencing (sc/snRNA-seq), single-nucleus assay for transposase-accessible chromatin sequencing (snATAC-seq), and spatial transcriptomics profiles and identified distinct cellular populations in SHH (sonic hedgehog) and Group_3 subgroups, with varying proportions in local recurrence or dissemination. Local recurrence showed higher cycling tumor cell enrichment, whereas disseminated lesions had a relatively notable presence of differentiated subsets. Chromosomal alteration evaluation revealed distinct genetic subclones during MB progression, such as chr7q gain and chr11 loss in Group_3 disseminations. A subpopulation termed \"high cellular plasticity (HCP)\" emerged during MB progression and was associated with increased dividing potential and chromatin accessibility, contributing to recurrence. Inhibiting HCP-associated markers, like protein tyrosine phosphatase receptor type Z1 (PTPRZ1), efficiently suppressed MB progression in preclinical models. These findings address critical gaps in understanding the cellular diversity, chromosomal alterations, and biological dynamics of recurrent MB, offering potential therapeutic insights.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"101914"},"PeriodicalIF":11.7,"publicationDate":"2025-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142982977","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 : 2025-01-21Epub Date: 2025-01-13DOI: 10.1016/j.xcrm.2024.101918
Nir Erez, Noa Furth, Vadim Fedyuk, Jack Wadden, Rayan Aittaleb, Tiffany Adam, Kallen Schwark, Michael Niculcea, Madeline Miclea, Rajen Mody, Andrea Franson, Hemant A Parmar, Mohannad Ibrahim, Benison Lau, Augustine Eze, Niku Nourmohammadi, Iris Fried, Javad Nazarian, Guy Ron, Sriram Venneti, Carl Koschmann, Efrat Shema
{"title":"Single-molecule systems for the detection and monitoring of plasma-circulating nucleosomes and oncoproteins in diffuse midline glioma.","authors":"Nir Erez, Noa Furth, Vadim Fedyuk, Jack Wadden, Rayan Aittaleb, Tiffany Adam, Kallen Schwark, Michael Niculcea, Madeline Miclea, Rajen Mody, Andrea Franson, Hemant A Parmar, Mohannad Ibrahim, Benison Lau, Augustine Eze, Niku Nourmohammadi, Iris Fried, Javad Nazarian, Guy Ron, Sriram Venneti, Carl Koschmann, Efrat Shema","doi":"10.1016/j.xcrm.2024.101918","DOIUrl":"10.1016/j.xcrm.2024.101918","url":null,"abstract":"<p><p>The analysis of cell-free tumor DNA (ctDNA) and proteins in the blood of patients with cancer potentiates a new generation of non-invasive diagnostic approaches. However, confident detection of tumor-originating markers is challenging, especially in the context of brain tumors, where these analytes in plasma are extremely scarce. Here, we apply a sensitive single-molecule technology to profile multiple histone modifications on individual nucleosomes from the plasma of patients with diffuse midline glioma (DMG). The system reveals epigenetic patterns unique to DMG, significantly differentiating this group of patients from healthy subjects or individuals diagnosed with other cancer types. We further develop a method to directly quantify the tumor-originating oncoproteins, lysine 27 to methionine substitution in histone H3 (H3-K27M) and mutant p53, from <1 mL of plasma, allowing for the accurate molecular classification of patients with DMG. We show that our strategy correlates with MRI and droplet-digital PCR (ddPCR) measurements of ctDNA, highlighting the clinical potential of single-molecule-based, multi-parametric assays for DMG diagnosis and treatment monitoring.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"101918"},"PeriodicalIF":11.7,"publicationDate":"2025-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142982980","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 : 2025-01-21Epub Date: 2025-01-13DOI: 10.1016/j.xcrm.2024.101920
Jian Zhang, Tony Pan, Jimmy Lee, Sanja Goldberg, Sarah Ann King, Erting Tang, Yifei Hu, Lifeng Chen, Alex Hoover, Linyong Zhu, Oliver S Eng, Benjamin Dekel, Jun Huang, Xiaoyang Wu
{"title":"Enabling tumor-specific drug delivery by targeting the Warburg effect of cancer.","authors":"Jian Zhang, Tony Pan, Jimmy Lee, Sanja Goldberg, Sarah Ann King, Erting Tang, Yifei Hu, Lifeng Chen, Alex Hoover, Linyong Zhu, Oliver S Eng, Benjamin Dekel, Jun Huang, Xiaoyang Wu","doi":"10.1016/j.xcrm.2024.101920","DOIUrl":"10.1016/j.xcrm.2024.101920","url":null,"abstract":"<p><p>Metabolic reprogramming of tumor cells is an emerging hallmark of cancer. Among all the changes in cancer metabolism, increased glucose uptake and the accumulation of lactate under normoxic conditions (the \"Warburg effect\") is a common feature of cancer cells. In this study, we develop a lactate-responsive drug delivery platform by targeting the Warburg effect. We design and test a gold/mesoporous silica Janus nanoparticle system as a gated drug carrier, in which the gold particles are functionalized with lactate oxidase and the silica particles are capped with α-cyclodextrin through surface arylboronate modification. In the presence of lactate, the lactate oxidase generates hydrogen peroxide, which induces the self-immolation reaction of arylboronate, leading to uncapping and drug release. Our results demonstrate greatly improved drug delivery specificity and therapeutic efficacy with this platform for the treatment of different cancers. Our findings present an effective approach for drug delivery by metabolic targeting of tumors.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"101920"},"PeriodicalIF":11.7,"publicationDate":"2025-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142982892","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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