EMBO Molecular Medicine最新文献_第2页

Generalization of neoantigen-based tumor vaccine by delivering peptide-MHC complex via oncolytic virus. 通过溶瘤病毒传递肽- mhc复合物的新抗原肿瘤疫苗推广。

IF 9 1区医学

EMBO Molecular Medicine Pub Date : 2025-05-01 Epub Date: 2025-04-07 DOI: 10.1038/s44321-025-00225-3

Chenyi Wang, Yingjun Shi, Da Zhang, Yupeng Sun, Junjie Xie, Bingchen Wu, Cuilin Zhang, Xiaolong Liu

{"title":"Generalization of neoantigen-based tumor vaccine by delivering peptide-MHC complex via oncolytic virus.","authors":"Chenyi Wang, Yingjun Shi, Da Zhang, Yupeng Sun, Junjie Xie, Bingchen Wu, Cuilin Zhang, Xiaolong Liu","doi":"10.1038/s44321-025-00225-3","DOIUrl":"10.1038/s44321-025-00225-3","url":null,"abstract":"Neoantigen vaccine is a promising breakthrough in tumor immunotherapy. However, the application of this highly personalized strategy in the treatment of solid tumors is hindered by several obstacles, including very costly and time-consuming preparation steps, uncertainty in prediction algorithms and tumor heterogeneity. Universalization of neoantigen vaccine is an ideal yet currently unattainable solution to such limitations. To overcome these limitations, we engineered oncolytic viruses co-expressing neoantigens and neoantigen-binding major histocompatibility complex (MHC) molecules to force ectopic delivery of peptide-MHC ligands to T cell receptors (TCRs), enabling specific targeting by neoantigen vaccine-primed host immunity. When integrated with neoantigen vaccination, the engineered viruses exhibited potent cytolytic activity in a variety of tumor models irrespective of the neoantigen expression profiles, eliciting robust systemic antitumor immunity to reject tumor rechallenge and inhibit abscopal tumor growth with a favorable safety profile. Thus, this study provides a powerful approach to enhance the universality and efficacy of neoantigen vaccines, meeting the urgent need for universal neoantigen vaccines in the clinic to facilitate the further development of tumor immunotherapy.","PeriodicalId":11597,"journal":{"name":"EMBO Molecular Medicine","volume":" ","pages":"1118-1152"},"PeriodicalIF":9.0,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12081622/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143802706","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

Bile acid 7α-dehydroxylating bacteria accelerate injury-induced mucosal healing in the colon. 胆汁酸7α-去羟基化细菌加速结肠损伤诱导的粘膜愈合。

IF 9 1区医学

EMBO Molecular Medicine Pub Date : 2025-05-01 Epub Date: 2025-03-10 DOI: 10.1038/s44321-025-00202-w

Antoine Jalil, Alessia Perino, Yuan Dong, Jéromine Imbach, Colin Volet, Eduard Vico-Oton, Hadrien Demagny, Lucie Plantade, Hector Gallart-Ayala, Julijana Ivanisevic, Rizlan Bernier-Latmani, Siegfried Hapfelmeier, Kristina Schoonjans

{"title":"Bile acid 7α-dehydroxylating bacteria accelerate injury-induced mucosal healing in the colon.","authors":"Antoine Jalil, Alessia Perino, Yuan Dong, Jéromine Imbach, Colin Volet, Eduard Vico-Oton, Hadrien Demagny, Lucie Plantade, Hector Gallart-Ayala, Julijana Ivanisevic, Rizlan Bernier-Latmani, Siegfried Hapfelmeier, Kristina Schoonjans","doi":"10.1038/s44321-025-00202-w","DOIUrl":"10.1038/s44321-025-00202-w","url":null,"abstract":"Host-microbiome communication is frequently perturbed in gut pathologies due to microbiome dysbiosis, leading to altered production of bacterial metabolites. Among these, 7α-dehydroxylated bile acids are notably diminished in inflammatory bowel disease patients. Herein, we investigated whether restoration of 7α-dehydroxylated bile acids levels by Clostridium scindens, a human-derived 7α-dehydroxylating bacterium, can reestablish intestinal epithelium homeostasis following colon injury. Gnotobiotic and conventional mice were subjected to chemically-induced experimental colitis following administration of Clostridium scindens. Colonization enhanced the production of 7α-dehydroxylated bile acids and conferred prophylactic and therapeutic protection against colon injury through epithelial regeneration and specification. Computational analysis of human datasets confirmed defects in intestinal cell renewal and differentiation in ulcerative colitis patients while expression of genes involved in those pathways showed a robust positive correlation with 7α-dehydroxylated bile acid levels. Clostridium scindens administration could therefore be a promising biotherapeutic strategy to foster mucosal healing following colon injury by restoring bile acid homeostasis.","PeriodicalId":11597,"journal":{"name":"EMBO Molecular Medicine","volume":" ","pages":"889-908"},"PeriodicalIF":9.0,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12081655/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143596604","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

Beyond mitotic arrest: the diverse effects of microtubule-targeting drugs on tumor vasculature. 超越有丝分裂停止：微管靶向药物对肿瘤血管系统的不同影响。

IF 9 1区医学

EMBO Molecular Medicine Pub Date : 2025-05-01 Epub Date: 2025-03-26 DOI: 10.1038/s44321-025-00223-5

April L Risinger

引用次数: 0

Liver TET1 promotes metabolic dysfunction-associated steatotic liver disease. 肝脏TET1促进代谢功能障碍相关的脂肪变性肝病。

IF 9 1区医学

EMBO Molecular Medicine Pub Date : 2025-05-01 Epub Date: 2025-03-31 DOI: 10.1038/s44321-025-00224-4

Hongze Chen, Muhammad Azhar Nisar, Joud Mulla, Xinjian Li, Kevin Cao, Shaolei Lu, Katsuya Nagaoka, Shang Wu, Peng-Sheng Ting, Tung-Sung Tseng, Hui-Yi Lin, Xiao-Ming Yin, Wenke Feng, Zhijin Wu, Zhixiang Cheng, William Mueller, Amalia Bay, Layla Schechner, Xuewei Bai, Chiung-Kuei Huang

{"title":"Liver TET1 promotes metabolic dysfunction-associated steatotic liver disease.","authors":"Hongze Chen, Muhammad Azhar Nisar, Joud Mulla, Xinjian Li, Kevin Cao, Shaolei Lu, Katsuya Nagaoka, Shang Wu, Peng-Sheng Ting, Tung-Sung Tseng, Hui-Yi Lin, Xiao-Ming Yin, Wenke Feng, Zhijin Wu, Zhixiang Cheng, William Mueller, Amalia Bay, Layla Schechner, Xuewei Bai, Chiung-Kuei Huang","doi":"10.1038/s44321-025-00224-4","DOIUrl":"10.1038/s44321-025-00224-4","url":null,"abstract":"Global hepatic DNA methylation change has been linked to human patients with metabolic dysfunction-associated steatotic liver disease (MASLD). DNA demethylation is regulated by the TET family proteins, whose enzymatic activities require 2-oxoglutarate (2-OG) and iron that both are elevated in human MASLD patients. We aimed to investigate liver TET1 in MASLD progression. Depleting TET1 using two different strategies substantially alleviated MASLD progression. Knockout (KO) of TET1 slightly improved diet induced obesity and glucose homeostasis. Intriguingly, hepatic cholesterols, triglycerides, and CD36 were significantly decreased upon TET1 depletion. Consistently, liver specific TET1 KO led to improvement of MASLD progression. Mechanistically, TET1 promoted CD36 expression through transcriptional upregulation via DNA demethylation control. Overexpression of CD36 reversed the impacts of TET1 downregulation on fatty acid uptake in hepatocytes. More importantly, targeting TET1 with a small molecule inhibitor significantly suppressed MASLD progression. Conclusively, liver TET1 plays a deleterious role in MASLD, suggesting the potential of targeting TET1 in hepatocytes to suppress MASLD.","PeriodicalId":11597,"journal":{"name":"EMBO Molecular Medicine","volume":" ","pages":"1101-1117"},"PeriodicalIF":9.0,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12081649/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143751613","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

TFE3 fusions drive oxidative metabolism and ferroptosis resistance in translocation renal cell carcinoma. TFE3融合驱动易位性肾细胞癌的氧化代谢和铁下垂抵抗。

IF 9 1区医学

EMBO Molecular Medicine Pub Date : 2025-05-01 Epub Date: 2025-03-27 DOI: 10.1038/s44321-025-00221-7

Alexandra Helleux, Guillaume Davidson, Antonin Lallement, Fatima Al Hourani, Alexandre Haller, Isabelle Michel, Anas Fadloun, Christelle Thibault-Carpentier, Xiaoping Su, Véronique Lindner, Thibault Tricard, Hervé Lang, Nizar M Tannir, Irwin Davidson, Gabriel G Malouf

{"title":"TFE3 fusions drive oxidative metabolism and ferroptosis resistance in translocation renal cell carcinoma.","authors":"Alexandra Helleux, Guillaume Davidson, Antonin Lallement, Fatima Al Hourani, Alexandre Haller, Isabelle Michel, Anas Fadloun, Christelle Thibault-Carpentier, Xiaoping Su, Véronique Lindner, Thibault Tricard, Hervé Lang, Nizar M Tannir, Irwin Davidson, Gabriel G Malouf","doi":"10.1038/s44321-025-00221-7","DOIUrl":"10.1038/s44321-025-00221-7","url":null,"abstract":"The oncogenic mechanisms by which TFE3 fusion proteins drive translocation renal cell carcinoma (tRCC) are poorly characterized. Here, we integrated loss and gain of function experiments with multi-omics analyses in tRCC cell lines and patient tumors. High nuclear accumulation of NONO-TFE3 or PRCC-TFE3 fusion proteins promotes their broad binding across the genome at H3K27ac-marked active chromatin, engaging a core set of M/E-box-containing regulatory elements to activate specific gene expression programs as well as promiscuous binding to active promoters to stimulate mRNA synthesis. Within the core program, TFE3 fusions directly regulate genes involved in ferroptosis resistance and oxidative phosphorylation metabolism (OxPhos). Consequently, human tRCC tumors display high OxPhos scores that persist during their epithelial to mesenchymal transition (EMT). We further show that tRCC tumor aggressiveness is related to their EMT and their associated enrichment in myofibroblast cancer-associated fibroblasts (myCAFs) that are both hallmarks of poor prognostic outcomes. We define tRCC as a novel metabolic subtype of renal cancer and provide unique insights into how broad genomic binding of TFE3 fusion proteins regulates OxPhos and ferroptosis resistance.","PeriodicalId":11597,"journal":{"name":"EMBO Molecular Medicine","volume":" ","pages":"1041-1070"},"PeriodicalIF":9.0,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12081665/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143729359","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

Soluble CD27 differentially predicts resistance to anti-PD1 alone but not with anti-CTLA-4 in melanoma. 可溶性CD27在黑色素瘤中单独预测抗pd1耐药性的差异，而不是与抗ctla -4的差异。

IF 9 1区医学

EMBO Molecular Medicine Pub Date : 2025-05-01 Epub Date: 2025-03-27 DOI: 10.1038/s44321-025-00203-9

Ikuan Sam, Nadine Benhamouda, Lucie Biard, Laetitia Da Meda, Kristell Desseaux, Barouyr Baroudjan, Ines Nakouri, Marion Renaud, Aurélie Sadoux, Marina Alkatrib, Jean-François Deleuze, Maxime Battistella, Yimin Shen, Matthieu Resche-Rigon, Samia Mourah, Celeste Lebbe, Eric Tartour

{"title":"Soluble CD27 differentially predicts resistance to anti-PD1 alone but not with anti-CTLA-4 in melanoma.","authors":"Ikuan Sam, Nadine Benhamouda, Lucie Biard, Laetitia Da Meda, Kristell Desseaux, Barouyr Baroudjan, Ines Nakouri, Marion Renaud, Aurélie Sadoux, Marina Alkatrib, Jean-François Deleuze, Maxime Battistella, Yimin Shen, Matthieu Resche-Rigon, Samia Mourah, Celeste Lebbe, Eric Tartour","doi":"10.1038/s44321-025-00203-9","DOIUrl":"10.1038/s44321-025-00203-9","url":null,"abstract":"Metastatic melanoma can be treated with anti-PD-1 monotherapy or in combination with anti-CTLA-4 or anti-Lag3. However, combination therapy is associated with a high risk of toxicity. Recently, we reported that high plasma soluble CD27 (sCD27) levels reflect the intratumoral interaction of CD70-CD27 and dysfunctional T cells in the tumor microenvironment of renal cell carcinoma. In this study, we first characterized the intratumoral expression of CD70 and CD27 in melanoma tumors and their interaction in vivo. We then reported a significant association between baseline sCD27 and anti-PD-1 resistance as assessed by progression-free survival, overall survival, or 12-month complete response in two prospective cohorts of melanoma patients. Multivariate analysis confirmed that sCD27 was independently associated with clinical outcomes. Notably, sCD27 did not predict clinical response to combination therapy in either cohort. This differential predictive value of sCD27 for the two therapeutic options was later confirmed by propensity score analysis. Our results suggest that high plasma sCD27 levels predict poorer efficacy of anti-PD1 monotherapy in metastatic melanoma, justifying therapeutic escalation with a combination of anti-PD1 and anti-CTLA-4.","PeriodicalId":11597,"journal":{"name":"EMBO Molecular Medicine","volume":" ","pages":"909-922"},"PeriodicalIF":9.0,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12081602/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143729358","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

Getting to the heart of cardiovascular complications associated with inflammatory arthritis. 了解与炎症性关节炎相关的心血管并发症的核心。

IF 9 1区医学

EMBO Molecular Medicine Pub Date : 2025-05-01 Epub Date: 2025-04-03 DOI: 10.1038/s44321-025-00226-2

Hong Shi, Brian H Annex

引用次数: 0

PARP7 as a new target for activating anti-tumor immunity in cancer. PARP7作为激活肿瘤抗肿瘤免疫的新靶点。

IF 9 1区医学

EMBO Molecular Medicine Pub Date : 2025-05-01 Epub Date: 2025-03-24 DOI: 10.1038/s44321-025-00214-6

Katerina Popova, Johannes Benedum, Magdalena Engl, Carola Lütgendorf-Caucig, Piero Fossati, Joachim Widder, Klaus Podar, Dea Slade

{"title":"PARP7 as a new target for activating anti-tumor immunity in cancer.","authors":"Katerina Popova, Johannes Benedum, Magdalena Engl, Carola Lütgendorf-Caucig, Piero Fossati, Joachim Widder, Klaus Podar, Dea Slade","doi":"10.1038/s44321-025-00214-6","DOIUrl":"10.1038/s44321-025-00214-6","url":null,"abstract":"ADP-ribosyl transferases (ARTs) are a family of enzymes which catalyze the addition of a chain (PARylation) or a single moiety (MARylation) of ADP-ribose to their substrates. PARP7 is a mono-ADP-ribosyl transferase (mono-ART) which has recently gained attention due to its emerging role as a negative regulator of the type I interferon (IFN-I) and nuclear receptor signaling, and due to its aberrant expression in cancer, contributing to disease progression and immune evasion. PARP7-mediated ADP-ribosylation can differentially affect protein stability. On the one hand, PARP7-mediated ADP-ribosylation of the transcription factor FRA1 protects it from proteosomal degradation and thereby supports its function in negatively regulating IRF1 and the expression of apoptosis and immune signaling genes. On the other hand, PARP7-mediated ADP-ribosylation of aryl hydrocarbon receptor (AHR) and estrogen receptor (ER) marks them for proteosomal degradation. PARP7 also ADP-ribosylates the ligand-bound androgen receptor (AR), which is recognized by DTX3L-PARP9 that modulate the AR transcriptional activity. In this review, we discuss PARP7 enzymatic properties, biological functions and known substrates, its role in various cancers, and its targeting by specific inhibitors.","PeriodicalId":11597,"journal":{"name":"EMBO Molecular Medicine","volume":" ","pages":"872-888"},"PeriodicalIF":9.0,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12081928/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143699927","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

Author Correction: Identification of PTGR2 inhibitors as a new therapeutic strategy for diabetes and obesity. 作者更正：确定 PTGR2 抑制剂作为糖尿病和肥胖症的新治疗策略。

IF 9 1区医学

EMBO Molecular Medicine Pub Date : 2025-05-01 DOI: 10.1038/s44321-025-00228-0

Yi-Cheng Chang, Meng-Lun Hsieh, Hsiao-Lin Lee, Siow-Wey Hee, Chi-Fon Chang, Hsin-Yung Yen, Yi-An Chen, Yet-Ran Chen, Ya-Wen Chou, Fu-An Li, Yi-Yu Ke, Shih-Yi Chen, Ming-Shiu Hung, Alfur Fu-Hsin Hung, Jing-Yong Huang, Chu-Hsuan Chiu, Shih-Yao Lin, Sheue-Fang Shih, Chih-Neng Hsu, Juey-Jen Hwang, Teng-Kuang Yeh, Ting-Jen Rachel Cheng, Karen Chia-Wen Liao, Daniel Laio, Shu-Wha Lin, Tzu-Yu Chen, Chun-Mei Hu, Ulla Vogel, Daniel Saar, Birthe B Kragelund, Lun Kelvin Tsou, Yu-Hua Tseng, Lee-Ming Chuang

引用次数: 0

Targeting HPK1 inhibits neutrophil responses to mitigate post-stroke lung and cerebral injuries. 靶向HPK1抑制中性粒细胞反应减轻脑卒中后肺和脑损伤。

IF 9 1区医学

EMBO Molecular Medicine Pub Date : 2025-05-01 Epub Date: 2025-04-01 DOI: 10.1038/s44321-025-00220-8

Tingting Zhang, Ying Sun, Jing Xia, Hongye Fan, Dingfang Shi, Qian Wu, Ming Huang, Xiao-Yu Hou

{"title":"Targeting HPK1 inhibits neutrophil responses to mitigate post-stroke lung and cerebral injuries.","authors":"Tingting Zhang, Ying Sun, Jing Xia, Hongye Fan, Dingfang Shi, Qian Wu, Ming Huang, Xiao-Yu Hou","doi":"10.1038/s44321-025-00220-8","DOIUrl":"10.1038/s44321-025-00220-8","url":null,"abstract":"Circulating neutrophils are responsible for poor neurological outcomes and have been implicated in respiratory morbidity after acute ischemic stroke (AIS). However, the molecular mechanisms regulating neutrophil responses and their pathological relevance in post-stroke complications remain unclear. In this study, we investigated the involvement of hematopoietic progenitor kinase 1 (HPK1) in neutrophil responses and mobilization, as well as subsequent lung and cerebral injuries following AIS. We found that lipopolysaccharide treatment triggered neutrophil activation in an HPK1-dependent manner. HPK1 enhanced intrinsic NF-κB/STAT3/p38-MAPK pathways and gasdermin D cleavage, leading to neutrophil hyperactivation. Following AIS, HPK1 promoted the mobilization of CXCR2high bone marrow neutrophils. HPK1 loss inhibited peripheral neutrophil hyperactivation, neutrophil infiltration, and aggregation of neutrophil extracellular traps, progressively alleviating systemic inflammation and impairments in mouse pulmonary and neurological functions. Furthermore, HPK1 pharmacological inhibition attenuated post-stroke pulmonary and neurological impairments in mice. Our findings revealed that HPK1 upregulates neutrophil mobilization and various responses, promoting post-stroke systemic inflammation and tissue injury. This study highlights HPK1 as a therapeutic target for improving pulmonary and neurological functions after AIS.","PeriodicalId":11597,"journal":{"name":"EMBO Molecular Medicine","volume":" ","pages":"1018-1040"},"PeriodicalIF":9.0,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12081623/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143763110","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