Gut最新文献

{"title":"TPX2 serves as a novel target for expanding the utility of PARPi in pancreatic cancer through conferring synthetic lethality.","authors":"Mingming Xiao, Rong Tang, Haoqi Pan, Jing Yang, Xuhui Tong, He Xu, Yanmei Guo, Yalan Lei, Di Wu, Yubin Lei, Yamei Han, Zhilong Ma, Wei Wang, Jin Xu, Xianjun Yu, Si Shi","doi":"10.1136/gutjnl-2024-332782","DOIUrl":"https://doi.org/10.1136/gutjnl-2024-332782","url":null,"abstract":"<p><strong>Background: </strong>PARP inhibitors (PARPi) have been licensed for the maintenance therapy of patients with metastatic pancreatic cancer carrying pathogenic germline BRCA1/2 mutations. However, mutations in BRCA1/2 are notably rare in pancreatic cancer.</p><p><strong>Objective: </strong>There is a significant unmet clinical need to broaden the utility of PARPi.</p><p><strong>Design: </strong>RNA sequencing was performed to screen potential targets for PARPi sensitivity. The synthetic lethal effects were verified in patient-derived xenograft (PDX), xenograft and patient-derived organoid models. Mechanisms were explored via LC‒MS/MS, coimmunoprecipitation, laser microirradiation, immunofluorescence, the homologous recombination (HR) or non-homologous end joining (NHEJ) reporter system, in situ proximity ligation assay and live-cell time-lapse imaging analyses.</p><p><strong>Results: </strong>Targeting protein for Xenopus kinesin-like protein 2 (TPX2) is an exploitable vulnerability. TPX2 was downregulated in PDX models sensitive to PARPi, and TPX2 inhibition conferred synthetic lethality to PARPi both <i>in vitro</i> and <i>in vivo</i>. Mechanistically, TPX2 functions in a cell cycle-dependent manner. In the S/G2 phase, ATM-mediated TPX2 S634 phosphorylation promotes BRCA1 recruitment to double-strand breaks (DSBs) for HR repair, whereas non-phosphorylated TPX2 interacts with 53BP1 to recruit it for NHEJ. The balance between phosphorylated and non-phosphorylated TPX2 determines the DSB repair pathway choice. During mitosis, TPX2 phosphorylation enhances Aurora A activity, promoting mitotic progression and chromosomal stability. Targeting TPX2 S634 phosphorylation with a cell-penetrating peptide causes genomic instability and mitotic catastrophe and enhances PARPi sensitivity. Additionally, the inhibition of TPX2 or S634 phosphorylation combined with gemcitabine further sensitised pancreatic cancer to PARPi.</p><p><strong>Conclusions: </strong>Our findings revealed the dual-functional significance of TPX2 in controlling DNA DSB repair pathway choice and mitotic progression, suggesting a potential therapeutic strategy involving PARPi for patients with pancreatic cancer.</p>","PeriodicalId":12825,"journal":{"name":"Gut","volume":" ","pages":""},"PeriodicalIF":23.0,"publicationDate":"2024-11-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142582195","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":"Pharmacological activation of STAT1-GSDME pyroptotic circuitry reinforces epigenetic immunotherapy for hepatocellular carcinoma","authors":"Yalin Tu, Haoran Wu, Chengpeng Zhong, Yan Liu, Zhewen Xiong, Siyun Chen, Jing Wang, Patrick Pak-Chun Wong, Weiqin Yang, Zhixian Liang, Jiahuan Lu, Shufen Chen, Lingyun Zhang, Yu Feng, Willis Wai-Yiu Si-Tou, Baoyi Yin, Yingnan Lin, Jianxin Liang, Liying Liang, Joaquim S L Vong, Weida Ren, Tsz Tung Kwong, Howard Leung, Ka Fai To, Stephanie Ma, Man Tong, Hanyong Sun, Qiang Xia, Jingying Zhou, David Kerr, Nick La Thangue, Joseph J Y Sung, Stephen Lam Chan, Alfred Sze-Lok Cheng","doi":"10.1136/gutjnl-2024-332281","DOIUrl":"https://doi.org/10.1136/gutjnl-2024-332281","url":null,"abstract":"Background Genomic screening uncovered interferon-gamma (IFNγ) pathway defects in tumours refractory to immune checkpoint blockade (ICB). However, its non-mutational regulation and reversibility for therapeutic development remain less understood. Objective We aimed to identify ICB resistance-associated druggable histone deacetylases (HDACs) and develop a readily translatable combination approach for patients with hepatocellular carcinoma (HCC). Design We correlated the prognostic outcomes of HCC patients from a pembrolizumab trial ([NCT03419481][1]) with tumourous cell expressions of all HDAC isoforms by single-cell RNA sequencing. We investigated the therapeutic efficacy and mechanism of action of selective HDAC inhibition in 4 ICB-resistant orthotopic and spontaneous models using immune profiling, single-cell multiomics and chromatin immunoprecipitation-sequencing and verified by genetic modulations and co-culture systems. Results HCC patients showing higher HDAC1 / 2 / 3 expressions exhibited deficient IFNγ signalling and poorer survival on ICB therapy. Transient treatment of a selective class-I HDAC inhibitor CXD101 resensitised HDAC1/2/3high tumours to ICB therapies, resulting in CD8+T cell-dependent antitumour and memory T cell responses. Mechanistically, CXD101 synergised with ICB to stimulate STAT1-driven antitumour immunity through enhanced chromatin accessibility and H3K27 hyperacetylation of IFNγ-responsive genes. Intratumoural recruitment of IFNγ+GZMB+cytotoxic lymphocytes further promoted cleavage of CXD101-induced Gasdermin E (GSDME) to trigger pyroptosis in a STAT1-dependent manner. Notably, deletion of GSDME mimicked STAT1 knockout in abolishing the antitumour efficacy and survival benefit of CXD101-ICB combination therapy by thwarting both pyroptotic and IFNγ responses. Conclusion Our immunoepigenetic strategy harnesses IFNγ-mediated network to augment the cancer-immunity cycle, revealing a self-reinforcing STAT1-GSDME pyroptotic circuitry as the mechanistic basis for an ongoing phase-II trial to tackle ICB resistance ([NCT05873244][2]). Data are available on reasonable request. [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT03419481&atom=%2Fgutjnl%2Fearly%2F2024%2F11%2F01%2Fgutjnl-2024-332281.atom [2]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT05873244&atom=%2Fgutjnl%2Fearly%2F2024%2F11%2F01%2Fgutjnl-2024-332281.atom","PeriodicalId":12825,"journal":{"name":"Gut","volume":"6 1","pages":""},"PeriodicalIF":24.5,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142563069","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":"Correction: Differential inflammasome activation predisposes to acute-on-chronic liver failure in human and experimental cirrhosis with and without previous decompensation","authors":"BMJ Publishing Group Ltd and British Society of Gastroenterology","doi":"10.1136/gutjnl-2019-320170corr1","DOIUrl":"https://doi.org/10.1136/gutjnl-2019-320170corr1","url":null,"abstract":"Monteiro S, Grandt J, Uschner FE, et al . Differential inflammasome activation predisposes to acute-on-chronic liver failure in human and experimental cirrhosis with and without previous …","PeriodicalId":12825,"journal":{"name":"Gut","volume":"224 1","pages":""},"PeriodicalIF":24.5,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142383772","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":"Single-use scopes may reduce various environmental impacts of gastroscopy in some situations but probably not in routine practice of endoscopy units.","authors":"Mathieu Pioche, Guillaume Vidal, Madj Ben Rejeb, Rémi Collin, Jérémie Jacques","doi":"10.1136/gutjnl-2024-334018","DOIUrl":"https://doi.org/10.1136/gutjnl-2024-334018","url":null,"abstract":"","PeriodicalId":12825,"journal":{"name":"Gut","volume":" ","pages":""},"PeriodicalIF":23.0,"publicationDate":"2024-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142545119","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":"Evolution of the use, effectiveness and safety of bismuth-containing quadruple therapy for Helicobacter pylori infection between 2013 and 2021: results from the European registry on H. pylori management (Hp-EuReg)","authors":"Llum Olmedo, Xavier Calvet, Emili Gené, Dmitry S Bordin, Irina Voynovan, M. Castro-Fernandez, Manuel Pabón-Carrasco, Alma Keco-Huerga, Ángeles Perez-Aisa, Alfredo J Lucendo, Luís Rodrigo, Aiman S Sarsenbaeva, Igor B Khlinov, Galyna Fadieienko, Oleg Zaytsev, Ángel Lanas, Samuel J Martínez-Domínguez, Enrique Alfaro, Laimas Jonaitis, Óscar Núñez, Rinaldo Pellicano, Luis Hernández, Oleksiy Gridnyev, Juozas Kupcinskas, Antonio Gasbarrini, Doron Boltin, Yaron Niv, Gülüstan Babayeva, Ricardo Marcos-Pinto, Bojan Tepes, Marino Venerito, Veronika Papp, Frode Lerang, Mārcis Leja, Perminder S Phull, Wojciech Marlicz, Michael Doulberis, Sinead M Smith, Vladimir Milivojevic, Lumir Kunovsky, Antonio Mestrovic, Tamara Matysiak-Budnik, Halis Simsek, Anna Cano-Català, Ignasi Puig, Leticia Moreira, Pablo Parra, Olga P Nyssen, Francis Megraud, Colm O'Morain, Javier P Gisbert","doi":"10.1136/gutjnl-2024-332804","DOIUrl":"https://doi.org/10.1136/gutjnl-2024-332804","url":null,"abstract":"Background Bismuth quadruple therapies (BQTs) including bismuth, a proton pump inhibitor (PPI) and two antibiotics have been shown to be highly effective for treating Helicobacter pylori infection even in areas of high bacterial antibiotic resistance. Objective To describe the time trends of use, effectiveness and safety of BQT in Europe using the European Registry on Helicobacter pylori Management (Hp-EuReg). Design Patients registered in the Hp-EuReg from 2013 to 2021 who had received BQT were included. The regimens prescribed, the number of eradication attempts, effectiveness, adherence and safety were analysed. The effectiveness was assessed by modified intention to treat (mITT). Time-trend and multivariate analyses were performed to determine variables that predicted treatment success. Results Of the 49 690 patients included in the Hp-EuReg, 15 582 (31%) had received BQT. BQT use increased from 8.6% of all treatments in 2013 to 39% in 2021. Single-capsule BQT—containing bismuth, metronidazole and tetracycline—plus a PPI (single-capsule BQT, ScBQT) was the most frequent treatment mode (43%). Schemes that obtained an effectiveness above 90% were the 10-day ScBQT and 14-day BQT using tetracycline plus metronidazole, or amoxicillin plus either clarithromycin or metronidazole. Only ScBQT achieved above 90% cure rates in all the geographical areas studied. Using the ScBQT scheme, adherence, the use of standard or high-dose PPIs, 14-day prescriptions and the use of BQT as first-line treatment were significantly associated with higher mITT effectiveness. Conclusion The use of BQT increased notably in Europe over the study period. A 10-day ScBQT was the scheme that most consistently achieved optimal effectiveness. Trial registration number [NCT02328131][1]. All data relevant to the study are included in the article or uploaded as online supplemental information. [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT02328131&atom=%2Fgutjnl%2Fearly%2F2024%2F10%2F25%2Fgutjnl-2024-332804.atom","PeriodicalId":12825,"journal":{"name":"Gut","volume":"75 1","pages":""},"PeriodicalIF":24.5,"publicationDate":"2024-10-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142490300","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":"Safe and successful gut-restricted adsorbent strategy against cirrhosis and acute-on-chronic liver failure","authors":"Schalk Willem Van der Merwe, Maite G Fernandez-Barrena","doi":"10.1136/gutjnl-2024-332457","DOIUrl":"https://doi.org/10.1136/gutjnl-2024-332457","url":null,"abstract":"Cirrhosis marks the advanced stage of chronic liver disease characterised by sustained inflammation leading to the loss of hepatocytes and the progression of fibrosis. These structural and functional alterations profoundly impact blood flow within the hepatic microcirculation, potentially culminating in portal hypertension over time. Traditionally, the evolution of cirrhosis has been divided into two clinical phases: An initial asymptomatic stage known as compensated cirrhosis followed by decompensated cirrhosis, marked by the emergence of complications such as ascites, variceal bleeding, hepatic encephalopathy, jaundice, coagulopathy and bacterial infections. Decompensated cirrhosis typically signals a more aggressive disease course with patients susceptible to hepatic and extrahepatic organ dysfunction, complications or necessitating liver transplantation.1 It is imperative to recognise that decompensated cirrhosis transcends hepatic manifestations representing a systemic disorder. Recent observational studies in Europe, including chronic liver failure acute-on-chronic liver failure (CANONIC) and PREDICTing Acute-on-chronic liver failure (PREDICT), have further classified decompensated cirrhosis into non-acute and various forms of acute decompensation, potentially leading to acute-on-chronic liver failure (ACLF). However, the precise factors determining the trajectory towards decompensation in cirrhosis remain elusive. Accumulating evidence suggests that specific preceding events play pivotal roles in this progression. Notably, clinically significant portal hypertension, systemic inflammation and failure of the intestinal barrier leading to bacterial product translocation through the portal circulation are key events interdependently influencing each …","PeriodicalId":12825,"journal":{"name":"Gut","volume":"30 1","pages":""},"PeriodicalIF":24.5,"publicationDate":"2024-10-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142490303","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":"ECM1 attenuates hepatic fibrosis by interfering with mediators of latent TGF-β1 activation","authors":"Frederik Link, Yujia Li, Jieling Zhao, Stefan Munker, Weiguo Fan, Zeribe C Nwosu, Ye Yao, Shanshan Wang, Chenjun Huang, Roman Liebe, Seddik Hammad, Hui Liu, Chen Shao, Chunfang Gao, Bing Sun, Natalie J Török, Huiguo Ding, Matthias PA Ebert, Honglei Weng, Peter ten Dijke, Dirk Drasdo, Steven Dooley, Sai Wang","doi":"10.1136/gutjnl-2024-333213","DOIUrl":"https://doi.org/10.1136/gutjnl-2024-333213","url":null,"abstract":"Objective Extracellular matrix protein 1 (ECM1) serves as a gatekeeper of hepatic fibrosis by maintaining transforming growth factor-β1 (TGF-β1) in its latent form. ECM1 knockout (KO) causes latent (L) TGF-β1 activation, resulting in hepatic fibrosis with rapid mortality. In chronic liver disease (CLD), ECM1 decreases with increasing CLD severity. We investigate the regulatory role of ECM1 in TGF-β1 bioavailability and its impact on CLD progression. Design RNAseq was performed to analyse hepatic gene expression. Functional assays were performed using hepatic stellate cells (HSCs), Ecm1 -KO and Fxr -KO mice, patient liver tissue and computer simulations. Results Expression of LTGF-β1 activators, including thrombospondins (TSPs), ADAMTS proteases and matrix metalloproteinases (MMPs), increased along with profibrotic gene expression in liver tissue of Ecm1 -KO mice. In HSCs, overexpression of ECM1 prevented LTGF-β1 activation mediated by TSP-1, ADAMTS1, and MMP-2/9. In vitro interaction assays demonstrated that ECM1 inhibited LTGF-β1 activation by interacting with TSP-1 and ADAMTS1 via their respective, intrinsic KRFK or KTFR amino acid sequences and by suppressing MMP-2/9 proteolytic activity. In mice, ECM1 overexpression attenuated KRFK-induced LTGF-β1 activation while KTFR treatment reversed Ecm1 -KO-mediated and Fxr -KO-mediated liver injury. In patients with CLD, ECM1 expression was inversely correlated with TSP-1, ADAMTS1, MMP-2/9 expression and LTGF-β1 activation. And, these results were complemented by a computational compartment model representing the key network of cellular phenotypes and predicted interactions in liver fibrogenesis. Conclusion Our findings underscore the hepatoprotective effect of ECM1, which interferes with mediators of LTGF-β1 activation, suggesting ECM1 or its representative peptide as potential antifibrotic therapies in CLD. Data are available in a public, open access repository. Data are available on reasonable request.","PeriodicalId":12825,"journal":{"name":"Gut","volume":"97 1","pages":""},"PeriodicalIF":24.5,"publicationDate":"2024-10-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142489447","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":"ECM1: a novel matricellular protein with promising antifibrotic potential","authors":"Isabel Fabregat, Francisco Javier Cubero","doi":"10.1136/gutjnl-2024-333455","DOIUrl":"https://doi.org/10.1136/gutjnl-2024-333455","url":null,"abstract":"Although numerous compounds that target individual or multiple cells or pathways have demonstrated antifibrotic potential, the reality is that only a small number of candidates have progressed successfully to the clinical trials phase. It seems plausible that the development of antifibrotic therapies focusing on the removal of fibrosis-causing agents and factors affecting hepatic stellate cell (HSC) activation might hold promise for reducing and preventing liver disease. Moreover, these therapies need to be safe with little or no hepatotoxicity and/or adverse effects. In liver homoeostasis, transforming growth factor-beta (TGF-β) is secreted in a biologically inactive, the so-called latent TGF-β form (LTGF-β) associated in a non-covalent complex with the extracellular matrix (ECM).1 In response to injury, local LTGF-β complexes are converted into active TGF-β. Activation of LTGF-β is mediated by several signals, including integrins, thrombospondin, proteases and reactive oxygen species.2 During liver fibrosis, TGF-β acts as a master profibrogenic cytokine in promoting activation and myofibroblastic differentiation of HSC, a central event in liver fibrogenesis and ECM production.3 Therefore, the regulation of locally activated TGF-β levels might be an excellent therapeutic target for liver fibrogenesis. ECM protein-1 (ECM1) was recently identified2 as a critical gatekeeper in the healthy liver, contributing to normal architecture and physiological homoeostasis of cell–cell communication by …","PeriodicalId":12825,"journal":{"name":"Gut","volume":"8 1","pages":""},"PeriodicalIF":24.5,"publicationDate":"2024-10-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142489443","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":"Treatment of type 2 diabetes with MASLD: new evidence for personalised medicine","authors":"Cyrielle Caussy","doi":"10.1136/gutjnl-2024-333485","DOIUrl":"https://doi.org/10.1136/gutjnl-2024-333485","url":null,"abstract":"Metabolic dysfunction-associated steatotic liver disease (MASLD), is closely linked to type 2 diabetes (T2D).1 2 This strong association is due to shared pathophysiological pathways, including insulin resistance, mitochondrial dysfunction, adipose tissue dysfunction, low-grade inflammation and dysbiosis.3 The coexistence of MASLD and T2D affects the prognosis of both diseases in a bidirectional manner that is not yet fully understood.3 Given this connection, the impact of glucose-lowering therapies on MASLD has been an important area of investigation. Among these therapies, sodium-glucose cotransporter-2 inhibitors (SGLT2i) have been associated with a decrease in liver fat content, liver enzymes and histological feature of metabolic dysfunction associated steatohepatitis (MASH) beyond their well-established cardio–renal benefits. In a study published in Gut , Mao et al performed a retrospective analysis of 399 126 patients diagnosed with T2D and MASLD, using US healthcare claims data from 2007 to 2021.4 The study used propensity score matching to compare long-term outcomes in patients treated with SGLT2i (15.7%) versus those treated …","PeriodicalId":12825,"journal":{"name":"Gut","volume":"6 1","pages":""},"PeriodicalIF":24.5,"publicationDate":"2024-10-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142489444","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":"Leveraging the tug-of-war with genomic retroelements to enhance immunotherapy of pancreatic cancer","authors":"Elisa Espinet, Gioacchino Natoli","doi":"10.1136/gutjnl-2024-333702","DOIUrl":"https://doi.org/10.1136/gutjnl-2024-333702","url":null,"abstract":"Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal malignancies, with a dismal 5-year survival rate of less than 10%.1 Despite significant advances in cancer treatment over the past decades, PDAC has stubbornly defied progress, with most patients showing limited response to standard chemotherapy regimens. Perhaps most disappointingly, the revolutionary success of immunotherapy in various cancer types has not translated to PDAC, with checkpoint inhibitors and other immunomodulatory strategies showing dismally low response rates.2 This lack of efficacy is thought to be largely due to the characteristic PDAC tumour microenvironment (TME) that contributes to make this cancer immunologically ‘cold’.3 Characterised by a dense stromal compartment, low T cell infiltration and an overall immunosuppressive microenvironment, PDACs present a formidable barrier to the immune system that ultimately explains the inefficiency of current immunotherapeutic approaches. Whether and to what extent strategies can be identified to convert these ‘cold’ tumours into ‘hot’ ones and ultimately improve immune checkpoint blockade (ICB) efficacy in PDAC remains to be determined. One such strategy leverages the impact of epigenetic regulators in the control of genomic transposable elements, which comprise retrotransposons (or retroelements, including endogenous retroviruses, ERVs) and DNA transposons.4 Indeed, one …","PeriodicalId":12825,"journal":{"name":"Gut","volume":"62 1","pages":""},"PeriodicalIF":24.5,"publicationDate":"2024-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142487503","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}