Clinical and Translational Medicine最新文献

{"title":"Developing risk stratification strategies and biomarkers for recurrent hepatocellular carcinoma","authors":"Jia-Hao Law,&nbsp;Huilin Shao,&nbsp;Ramanuj DasGupta,&nbsp;Daniel Q. Huang","doi":"10.1002/ctm2.70410","DOIUrl":"https://doi.org/10.1002/ctm2.70410","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <p>Hepatocellular carcinoma (HCC) remains a leading cause of cancer-related mortality, with high rates of post-resection recurrence posing significant clinical challenges. Early recurrence is largely driven by aggressive tumor biology, while late recurrence reflects de novo carcinogenesis in a cirrhotic liver. Traditional clinical and pathological predictors are insufficient for accurately identifying high-risk patients. Emerging translational advances including genomic, transcriptomic, proteomic, and metabolomic biomarkers; liquid biopsy techniques; artificial intelligence (AI)-driven histological and radiomic analyses offer new avenues to refine recurrence risk stratification and guide perioperative therapy. Simultaneously, the shifting etiological landscape from viral hepatitis to metabolic dysfunction-associated steatohepatitis (MASH) and alcohol-related liver disease underscores the need for tailored surveillance and preventive strategies. Advanced technologies such as single-cell and spatial transcriptomics provide unprecedented insights into fibrosis progression and tumor evolution. Integrating these approaches may enable personalized surveillance protocols and therapeutic interventions, optimizing outcomes for HCC patients and reducing unnecessary resource utilization.</p>\u0000 </section>\u0000 </div>","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 8","pages":""},"PeriodicalIF":6.8,"publicationDate":"2025-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70410","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144740124","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}

{"title":"Analysis of hepatitis B virus integration identifies KMT2B as a novel cancer-related gene in pancreatic cancer","authors":"Mengge Li,&nbsp;Huimin Li,&nbsp;Dejun Liu,&nbsp;Shunan Liu,&nbsp;Hui Yuan,&nbsp;Yan Wu,&nbsp;Min Du,&nbsp;Yuan Fang,&nbsp;Jin Li,&nbsp;Hui Cong,&nbsp;Dan Zhao,&nbsp;Chunsun Fan,&nbsp;Qing Wang,&nbsp;Cenkai Shen,&nbsp;Yu Gan,&nbsp;Yongwei Sun,&nbsp;Hong Tu","doi":"10.1002/ctm2.70424","DOIUrl":"https://doi.org/10.1002/ctm2.70424","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive malignancy with few well-established risk factors. Emerging epidemiological evidence suggests a link between hepatitis B virus (HBV) infection and PDAC. However, the underlying mechanisms remain unclear.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>High-throughput sequencing-based approach was employed to identify HBV integrations in tumour and para-tumour tissues of PDAC. The biological functions of KMT2B were evaluated in PDAC cell lines as well as in subcutaneous and orthotopic mouse models of PDAC. Chromatin immunoprecipitation sequencing and RNA sequencing were used to identify the pathway involved in PDAC development.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>HBV integration was detected in approximately one-third of HBV DNA-positive PDAC and adjacent para-tumour tissues. A total of 425 viral‒host junctions were identified, with the majority located in intergenic regions (51.29%), followed by introns (43.29%) and exons (2.35%) of the human genome. Lysine methyltransferase 2B (<i>KMT2B</i>, also known as <i>MLL4</i>), a gene frequently targeted by HBV integration in hepatocellular carcinoma, was also found to be interrupted by HBV in PDAC. KMT2B was significantly upregulated in PDAC and promoted malignant behaviours both in vitro and in vivo. Mechanistically, KMT2B exerts its oncogenic effects by regulating the downstream target gene <i>FYN</i> through histone H3K4 trimethylation, leading to the activation of the PI3K/Akt signalling pathway.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>HBV integration is a common event in HBV-related PDAC and <i>KMT2B</i> has been identified as a novel PDAC-related gene.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Key points</h3>\u0000 \u0000 <div>\u0000 <ul>\u0000 \u0000 <li>Hepatitis B virus (HBV) integrates in both tumour and adjacent para-tumour tissues of pancreatic ductal adenocarcinoma (PDAC).</li>\u0000 \u0000 <li><i>KMT2B</i>, a target gene of HBV integration, promotes PDAC proliferation and metastasis in vivo and in vitro experiments.</li>\u0000 \u0000 <li>KMT2B exerts its oncogenic effects by regulating the downstream target gene <i>FYN</i> via histone H3K4 trimethylation, activating the PI3K/Akt signalling pathway.</li>\u0000 </ul>\u0000 </div>\u0000 </section>\u0000 </div>","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 8","pages":""},"PeriodicalIF":6.8,"publicationDate":"2025-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70424","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144740123","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}

{"title":"Bispecific antibody targeting CD40 and HER2 potentiates therapeutic efficacy by reprogramming macrophages within the tumour microenvironment","authors":"Na Li,&nbsp;Ruonan Li,&nbsp;Qiongqiong Ma,&nbsp;Xiaoqi Zhang,&nbsp;Wenxuan Ma,&nbsp;Yi Wang,&nbsp;Baoxin Duan,&nbsp;Kailu Yang,&nbsp;Dongping Zhang,&nbsp;Jiashuo Zhang,&nbsp;Manping Gu,&nbsp;Yaxing Wu,&nbsp;Jiajin Sun,&nbsp;Huawei Wang,&nbsp;Anqi Li,&nbsp;Fuquan Chen,&nbsp;Yiyang Bai,&nbsp;Yujie Tian,&nbsp;Xin Li,&nbsp;Yingbin Yan,&nbsp;Wei Wang,&nbsp;Hongkai Zhang,&nbsp;Yuan Wang","doi":"10.1002/ctm2.70428","DOIUrl":"https://doi.org/10.1002/ctm2.70428","url":null,"abstract":"&lt;p&gt;Dear Editor,&lt;/p&gt;&lt;p&gt;CD40, a stimulatory receptor that is highly expressed primarily on antigen-presenting cells (APCs) plays a pivotal function in mediating immune system activation.&lt;span&gt;&lt;sup&gt;1, 2&lt;/sup&gt;&lt;/span&gt; Although agonistic CD40 antibodies have demonstrated some efficacy in early-phase clinical trials, they have been hampered by both dependency of FcγR-mediated crosslinking and systemic toxicity.&lt;span&gt;&lt;sup&gt;3, 4&lt;/sup&gt;&lt;/span&gt; TAA-CD40 bispecific antibodies (BsAbs) represent a promising strategy to overcome these limitations,&lt;span&gt;&lt;sup&gt;5, 6&lt;/sup&gt;&lt;/span&gt; but their in vivo therapeutic mechanisms remain poorly understood. In this study, we developed a CD40‒HER2 BsAb that demonstrated potent antitumour efficacy while evading the toxicity limitations commonly associated with CD40 agonists. Mechanistically, CD40‒HER2 BsAb treatment primarily reprogrammed macrophages to boost the immune response in vivo.&lt;/p&gt;&lt;p&gt;To achieve tumour-localised CD40 stimulation without systemic FcγR crosslinking, we designed CD40‒HER2 BsAbs with an N297A Fc mutation, which eliminates FcγR binding to prevent antibody-dependent cellular cytotoxicity against CD40-positive APCs and HER2-independent CD40 activation (Figure 1A).&lt;span&gt;&lt;sup&gt;7-9&lt;/sup&gt;&lt;/span&gt; While BsAb-1 and BsAb-5 exhibited low production yields (Table S1). BsAb-2 to BsAb-4 derived from trastuzumab and BsAb7 with a HER2-binding Fc mutation showed the capacity to target CD40 and HER2 (Figure 1B). Further Jurkat/NF-κB-GFP-hCD40 reporter cells assay showed that BsAb-7 specifically activated reporter cells with maximal intensity in the presence of HER2-positive CHO‒HER2 cells (Figure 1C,D).&lt;/p&gt;&lt;p&gt;We next investigated the impact of affinity and epitope on CD40‒HER2 BsAb activities. Affinity maturation significantly enhanced the binding affinity and agonistic activity of CD40 mAb-H compared to its parental CD40 mAb (Figures 1E and S1A). Four formats of CD40‒HER2 BsAbs with high CD40 affinity demonstrated binding to both CD40 and HER2 (Figures 1F and S1B). Increased affinity enhanced the activity of the CD40‒HER2 BsAbs, and the Fc mutation with HER2-binding ability format (BsAb-11) had the highest agonistic capacity (Figure 1G). However, after epitope exchange with APX005M and pertuzumab (Figure S1C‒E),&lt;span&gt;&lt;sup&gt;10&lt;/sup&gt;&lt;/span&gt; APX005M-derived BsAb-15 and pertuzumab-derived BsAb-12 to BsAb-14 did not further enhance the agonistic activity compared to CD40 mAb-H-derived BsAb-11 (Figure S1F). Additionally, CD40‒HER2 BsAb-11 significantly activated the reporter cells upon incubation with HER2-high-expressing SKBR3 and BT474 cells, but not with HER2-low-expressing T47D and MDA-MB-231 cells (Figure S1G,H). These results indicating that affinity is an important variable to take into account in the development of BsAb.&lt;/p&gt;&lt;p&gt;CD40‒HER2 BsAb-11 exhibited binding affinities (&lt;i&gt;K&lt;/i&gt;&lt;sub&gt;D&lt;/sub&gt;) of 37.5 nM for CD40 and 167.1 nM for HER2, with EC50 values of 2 and 30 nM for cell surface binding, respectively (Figure S2A,B). It s","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 8","pages":""},"PeriodicalIF":7.9,"publicationDate":"2025-07-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70428","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144716933","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}

{"title":"From iPSCs to myotubes: Identifying potential biomarkers for human FSHD by single-cell transcriptomics","authors":"Wenwen Liu,&nbsp;Hao Chen,&nbsp;Jiao Jiao,&nbsp;Qinxin Zhang,&nbsp;Dong Liang,&nbsp;Haiqin Huo,&nbsp;Xiuqing Ji,&nbsp;Mingtao Huang,&nbsp;Xiaojing Hou,&nbsp;Yan Cao,&nbsp;Sihui Wu,&nbsp;Yan Wang,&nbsp;Jun Zhang,&nbsp;Zhengfeng Xu,&nbsp;Ping Hu","doi":"10.1002/ctm2.70423","DOIUrl":"https://doi.org/10.1002/ctm2.70423","url":null,"abstract":"&lt;p&gt;Dear Editor,&lt;/p&gt;&lt;p&gt;Facioscapulohumeral muscular dystrophy (FSHD), an autosomal dominant neuromuscular disorder, exists as two molecular subtypes: FSHD1 (95% of cases), defined by pathogenic contraction of the 4q35-located D4Z4 macrosatellite repeat,&lt;span&gt;&lt;sup&gt;1&lt;/sup&gt;&lt;/span&gt; and FSHD2 (5%), caused by loss-of-function mutations in chromatin-modifying suppressors (e.g., &lt;i&gt;SMCHD1&lt;/i&gt;, &lt;i&gt;DNMT3B&lt;/i&gt; and &lt;i&gt;LRIF1&lt;/i&gt;).&lt;span&gt;&lt;sup&gt;2&lt;/sup&gt;&lt;/span&gt; Both subtypes converge on D4Z4 hypomethylation-mediated epigenetic derepression of &lt;i&gt;DUX4&lt;/i&gt; gene, whose aberrant expression drives myocyte apoptosis and inflammatory cascades in terminally differentiated muscle.&lt;span&gt;&lt;sup&gt;3&lt;/sup&gt;&lt;/span&gt; The scarcity of DUX4 expression and limited accessibility to viable muscle biopsies underscore the utility of patient-derived induced pluripotent stem cells (iPSCs), which maintain donor-specific genetic/epigenetic profiles, as physiologically relevant in vitro models for FSHD pathomechanistic studies. Here, we employed iPSC-derived myotubes to investigate the pathogenesis of FSHD via single-cell transcriptomic analysis, with the aim of identifying novel biomarkers.&lt;/p&gt;&lt;p&gt;We established in vitro FSHD models by differentiating iPSCs from healthy controls (HCs) and FSHD1 patients into myogenic progenitors and myotubes via Wnt activation and BMP inhibition (Figure 1A), utilising an established differentiation protocol.&lt;span&gt;&lt;sup&gt;4&lt;/sup&gt;&lt;/span&gt; Peripheral blood mononuclear cell-derived iPSCs exhibited pluripotency markers (OCT4/NANOG; Figure 1B) and underwent sequential differentiation into PAX7&lt;sup&gt;+&lt;/sup&gt;/MYOD1&lt;sup&gt;+&lt;/sup&gt; progenitors (Figure 1C) and multinucleated myotubes expressing skeletal muscle markers (MF20/α-actinin; Figure 1D). While comparative analysis revealed comparable expression of myogenic surface markers (CD82/CD56) and myotube maturation (MF20&lt;sup&gt;+&lt;/sup&gt;) between FSHD1 and HC groups (Figure 1E‒G), FSHD1 myotubes exhibited specific upregulation of DUX4 and its transcriptional targets&lt;span&gt;&lt;sup&gt;5&lt;/sup&gt;&lt;/span&gt; (&lt;i&gt;MBD3L2&lt;/i&gt;, &lt;i&gt;ZSCAN4&lt;/i&gt; and &lt;i&gt;TRIM43&lt;/i&gt;; Figure 1H,I), recapitulating disease-specific transcriptional dysregulation within a conserved differentiation framework.&lt;/p&gt;&lt;p&gt;Single-cell RNA sequencing (scRNA-seq) was performed to resolve transcriptional dynamics during iPSC-derived myogenesis, analysing 132 482 cells (HCs: 65 266; FSHD1: 67 216) across differentiation stages (progenitors, myotubes day 3/day 5) obtained from sex-matched FSHD1 donors with distinct clinical-genetic profiles: a 26-year-old male carrying contracted D4Z4 repeats (4 units at 4q35) and a female patient diagnosed at age 6 with severe allelic contraction (2 repeat units) (Figure S1). Based on the gene signatures,&lt;span&gt;&lt;sup&gt;6, 7&lt;/sup&gt;&lt;/span&gt; we identified 13 major cell types, including muscle satellite cells-1/2 (&lt;i&gt;CDCP1&lt;/i&gt;), PAX3&lt;sup&gt;+&lt;/sup&gt; myogenic progenitors-1/2 (&lt;i&gt;PAX3&lt;/i&gt;), proliferating PAX3&lt;sup&gt;+&lt;/sup&gt; myogenic progenitors (&lt;i&gt;PAX3&lt;/i&gt;/&lt;i&gt;MKI67&lt;/i&gt;), PAX7&lt;sup&gt;+&lt;/sup&gt;","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 8","pages":""},"PeriodicalIF":7.9,"publicationDate":"2025-07-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70423","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144716934","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}

{"title":"Comparative spatial transcriptomics of pancreatic cancer with ductal and acinar origins in mouse models","authors":"Ming Cui,&nbsp;Jialu Bai,&nbsp;Xiaoyan Chang,&nbsp;Ruiling Xiao,&nbsp;Shengwei Mo,&nbsp;Kevin C Soares,&nbsp;Sen Yang,&nbsp;Lei You,&nbsp;Quan Liao,&nbsp;Jin He,&nbsp;Ya Hu,&nbsp;Yupei Zhao","doi":"10.1002/ctm2.70416","DOIUrl":"https://doi.org/10.1002/ctm2.70416","url":null,"abstract":"&lt;p&gt;Dear Editor,&lt;/p&gt;&lt;p&gt;Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy, and while both acinar and ductal cells can contribute to its origin, their roles in defining PDAC subtypes remain unclear.&lt;span&gt;&lt;sup&gt;1&lt;/sup&gt;&lt;/span&gt; Investigating the cellular origin of PDAC may provide valuable insights into the biological processes of carcinogenesis and inform novel clinical classification schemes, enabling more precise and effective diagnostic and therapeutic strategies. Acinar cell-derived PDAC, often through acinar-to-ductal metaplasia (ADM), has been well-studied using models such as &lt;i&gt;Pdx1-Cre&lt;/i&gt; or &lt;i&gt;Ptf1a-Cre&lt;/i&gt;.&lt;span&gt;&lt;sup&gt;2-4&lt;/sup&gt;&lt;/span&gt; Ductal cells can also give rise to precursor lesions, including intraductal papillary mucinous neoplasms (IPMN), which is an imaging-recognizable lesion that is helpful for the early diagnosis of PDAC.&lt;span&gt;&lt;sup&gt;5&lt;/sup&gt;&lt;/span&gt; However, models focusing on ductal cell-derived PDAC remain limited. Transcription factor Sox9, a hallmark marker of pancreatic ductal cells, enables lineage-specific gene editing via &lt;i&gt;Sox9-CreER&lt;/i&gt;.&lt;span&gt;&lt;sup&gt;6, 7&lt;/sup&gt;&lt;/span&gt; In this study, we induced the carcinogenesis of PDAC by conditionally activating &lt;i&gt;Kras&lt;sup&gt;G12D&lt;/sup&gt;&lt;/i&gt; and deleting &lt;i&gt;Trp53&lt;/i&gt; in ductal or acinar cells. Compared to the well-established KPPC (&lt;i&gt;Kras&lt;sup&gt;LSL-G12D/+&lt;/sup&gt;;Trp53&lt;sup&gt;fl/fl&lt;/sup&gt;;Pdx1-CreER&lt;/i&gt;) mouse model, the KPPS (&lt;i&gt;Kras&lt;sup&gt;LSL-G12D/+&lt;/sup&gt;;Trp53&lt;sup&gt;fl/fl&lt;/sup&gt;;Sox9-CreER&lt;/i&gt;) mouse model produces a substantial proportion of IPMN with varying pathological grades. Spatial transcriptomics further revealed partially shared, yet distinct, molecular and tumour microenvironment features between the KPPC and KPPS models, which were validated in human datasets.&lt;/p&gt;&lt;p&gt;We developed the KPPS mouse model and harvested pancreatic tissues between weeks 4 and 24 post-tamoxifen induction (Figure 1A,B and Figure S1A). H&amp;E staining was performed on pancreatic formalin-fixed paraffin-embedded (FFPE) tissue sections from both KPPS and KPPC models (Figure 1C and Figure S1B). Histological analysis of tissues collected from KPPS mice revealed progressive development of IPMN, including low-grade (LG), high-grade (HG), and IPMN-associated invasive carcinoma (IPMN-IC), which exhibited characteristic tubular adenocarcinoma features (Histological criteria are elaborated in the supplementary information; Figure 1C,D). By 24 weeks post-Tamoxifen injection, all KPPS mice had progressed to invasive carcinoma, with IPMN-IC being the predominant phenotype, accounting for more than 80% of the cases, accompanied by conventional PDAC (Figure 1C, D). Immunohistochemical analysis of mucins (MUC) revealed that IPMN lesions from KPPS mice exhibited high expression of MUC1, weak expression of MUC5AC, and minimal to no expression of MUC2 (Figure 1E and Figure S1C), suggesting a non-intestinal IPMN subtype (including gastric and pancreatobiliary types). Notably, the IPMN-IC lesions predominantly exhibited featu","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 8","pages":""},"PeriodicalIF":7.9,"publicationDate":"2025-07-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70416","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144714895","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}

{"title":"Hijacking erythropoietin: A tumour-intrinsic strategy to escape immune surveillance","authors":"David Kung-Chun Chiu,&nbsp;Edgar G Engleman","doi":"10.1002/ctm2.70427","DOIUrl":"https://doi.org/10.1002/ctm2.70427","url":null,"abstract":"&lt;p&gt;An increasingly recognised framework in cancer immunology classifies tumours into T-cell-inflamed and non-inflamed phenotypes, based on the degree of immune cell infiltration, particularly cytotoxic CD8⁺ T cells.&lt;span&gt;&lt;sup&gt;1&lt;/sup&gt;&lt;/span&gt; Early studies demonstrated that CD8⁺ T-cell infiltration is one of the most informative immune features associated with a favourable prognosis.&lt;span&gt;&lt;sup&gt;2&lt;/sup&gt;&lt;/span&gt; Building on this insight, prognostic tools such as the Immunoscore were developed to quantify the density and spatial distribution of CD3⁺ and CD8⁺ T cells within the tumour core and invasive margin. This approach has shown that CD8⁺ T-cell infiltration can serve as a robust, immune-based classifier that outperforms traditional TNM staging in predicting clinical outcomes.&lt;span&gt;&lt;sup&gt;3&lt;/sup&gt;&lt;/span&gt; The introduction of immune checkpoint inhibitors (ICI) targeting the PD-1/PD-L1 axis has transformed cancer therapy. However, response rates remain limited across many tumour types. One hypothesis is that effective responses to ICI require pre-existing anti-tumour T-cell immunity. Indeed, pioneering studies in melanoma demonstrated that patients with higher CD8⁺ T-cell densities at the invasive tumour margin were significantly more likely to respond to PD-1 blockade. Supporting this concept, a Phase II clinical trial in colorectal cancer showed that patients with a low Immunoscore did not benefit from PD-L1 blockade, whereas those with a high Immunoscore experienced a 65% reduction in disease progression risk.&lt;span&gt;&lt;sup&gt;4&lt;/sup&gt;&lt;/span&gt; These findings have led to the now widely accepted view that non-inflamed tumours are a major cause of resistance to ICI. This realisation has catalysed two central questions in the field: What determines whether a tumour is non-inflamed? And how can we reprogram non-inflamed tumours into an inflamed, immunologically active state?&lt;/p&gt;&lt;p&gt;To investigate these questions, our laboratory utilised a collection of autochthonous mouse models of hepatocellular carcinoma (HCC), each induced by different driver mutations and characterised by a defined T-cell-inflamed or non-inflamed immune phenotype.&lt;span&gt;&lt;sup&gt;5&lt;/sup&gt;&lt;/span&gt; Compared to conventional transplantable or cell line-based models, these autochthonous models more accurately recapitulate the complex features of human tumours, including their immune tumour microenvironment and responsiveness to ICI. Through direct comparison of T-cell-inflamed and non-inflamed HCC tumours, we identified that non-inflamed tumours exhibited significantly elevated levels of erythropoietin (EPO). Forced expression of EPO in the tumour cells of T-cell-inflamed tumours was sufficient to convert the tumours into a non-inflamed phenotype, marked by a significant reduction in CD8⁺ T-cell infiltration. Conversely, genetic ablation of EPO in non-inflamed tumours restored T-cell infiltration, effectively reprogramming the tumours into an inflamed, immune-responsive state. Mechanistically, we observed tha","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 8","pages":""},"PeriodicalIF":7.9,"publicationDate":"2025-07-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70427","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144714894","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}

{"title":"A robust machine learning model based on ribosomal-subunit-derived piRNAs for diagnostic potential of nonsmall cell lung cancer across multicentre, large-scale of sequencing data","authors":"Zitong Gao,&nbsp;Masaki Nasu,&nbsp;Gehan Devendra,&nbsp;Ayman A. Abdul-Ghani,&nbsp;Anthony J. Herrera,&nbsp;Jeffrey A. Borgia,&nbsp;Christopher W. Seder,&nbsp;Donna Lee Kuehu,&nbsp;Zhuokun Feng,&nbsp;Yu Chen,&nbsp;Ting Gong,&nbsp;Zao Zhang,&nbsp;Owen Chan,&nbsp;Hua Yang,&nbsp;Jianhua Yu,&nbsp;Yuanyuan Fu,&nbsp;Lang Wu,&nbsp;Youping Deng","doi":"10.1002/ctm2.70418","DOIUrl":"https://doi.org/10.1002/ctm2.70418","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <p>Nonsmall cell lung cancer (NSCLC) is a lethal cancer and lacks robust biomarkers for noninvasive clinical diagnosis. Detecting NSCLC at the early stage can decrease the mortality rate and minimise harm caused by various treatments. We curated 2050 samples from public tissue and plasma datasets including both invasive and noninvasive types, then supplemented with in-house pooled plasma and exosome samples. Eleven independent transcriptome datasets were utilised to develop a new machine learning model by integrating PIWI-interacting RNA (piRNA) to predict NSCLC. Five piRNA signatures derived from ribosomal subunits identified to be tumour-specific exhibited robust diagnostic ability and were combined into a piRNA-Based Tumour Probability Index (pi-TPI) risk evaluation model. pi-TPI effectively distinguished NSCLC patients from healthy individuals and showed efficacy in identifying early-stage cancers with Area under the ROC Curve (AUC) values over .80. Plasma cohorts exhibited the diagnosis efficacy of pi-TPI with an AUC value of .85. Experimental exosomal data enhances the accuracy of diagnosing noncancerous, benign, and cancer cases. The pi-TPI marker in the noncancer/cancer subgroup exhibited superior predictive performance with an AUC value of .96. These findings underscore the significant clinical potential of the five piRNA signatures as a powerful diagnostic tool for NSCLC, particularly of noninvasive cancer diagnostics.</p>\u0000 </section>\u0000 </div>","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 8","pages":""},"PeriodicalIF":7.9,"publicationDate":"2025-07-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70418","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144705552","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}

{"title":"Customised virus-like particles: Opening a new chapter for clinical precision gene therapy","authors":"Xingyu Zhu,&nbsp;Qingye Zhang,&nbsp;Xujiao Zhou,&nbsp;Yujia Cai,&nbsp;Jiaxu Hong","doi":"10.1002/ctm2.70395","DOIUrl":"https://doi.org/10.1002/ctm2.70395","url":null,"abstract":"&lt;p&gt;The CRISPR/Cas system, first discovered as an adaptive immune mechanism in bacteria and archaea, has evolved into a revolutionary technology capable of editing DNA loci and correcting genetic errors, offering new hope for the treatment of numerous hereditary and refractory diseases.&lt;span&gt;&lt;sup&gt;1-3&lt;/sup&gt;&lt;/span&gt; This system employs a single-guide RNA (sgRNA) to direct the endonuclease Cas9 to a specific DNA target, where it generates double-strand breaks, thereby enabling site-specific modification.&lt;span&gt;&lt;sup&gt;1&lt;/sup&gt;&lt;/span&gt; In 2023, the US FDA approved the first gene therapy utilising CRISPR/Cas9 (Casgevy) for the treatment of sickle cell disease. This remarkable milestone has inspired researchers to continuously explore and push forward the clinical application of CRISPR-based therapies.&lt;/p&gt;&lt;p&gt;The safety and efficacy of gene therapy are two critical factors that must be prioritised when applying CRISPR in vivo.&lt;span&gt;&lt;sup&gt;4&lt;/sup&gt;&lt;/span&gt; Although several clinical trials – including those involving Casgevy – have demonstrated promising results, the long-term safety and efficacy remain to be fully observed. To achieve targeted and precise delivery of CRISPR components, various engineered carrier platforms have been developed, including nanomaterials, viral particles, and exosomes.&lt;span&gt;&lt;sup&gt;5, 6&lt;/sup&gt;&lt;/span&gt; Among these, virus-like particles (VLPs), owing to their transient expression, efficient delivery, and low immunogenicity, have emerged as a highly promising delivery modality.&lt;span&gt;&lt;sup&gt;7&lt;/sup&gt;&lt;/span&gt; However, existing editing strategies based on VLPs have thus far failed to achieve cell-targeted gene editing in vivo.&lt;/p&gt;&lt;p&gt;To address this unmet need, a modular, targeted VLP platform named RIDE (RNP Integrating with Designer Envelope) was recently developed in our lab.&lt;span&gt;&lt;sup&gt;8&lt;/sup&gt;&lt;/span&gt; RIDE enables cell-selective genome editing while preserving safety and transience.&lt;/p&gt;&lt;p&gt;A key strength of the RIDE platform lies in its dual modularity: the use of engineered VLPs to deliver Cas9 ribonucleoproteins (RNPs) and the incorporation of customisable envelope proteins for cell-specific targeting. Unlike conventional delivery systems that rely on passive diffusion or broad viral tropism, RIDE has been shown to be rationally redirected to virtually any cell type, either by adapting to the local tissue environment or by employing engineered ligands such as single-chain antibodies or DARPins. This flexibility represents a conceptual shift from broadly systemic, persistent delivery toward transient, tunable, and cell-selective genome editing – an essential step toward realising personalised and tissue-specific gene therapies.&lt;/p&gt;&lt;p&gt;Complementing its targeting versatility, RIDE also features a transient mode of action. Traditional vectors, such as adeno-associated viruses (AAVs) or lentiviruses (LVs), rely on DNA-based delivery, which can lead to prolonged Cas9 expression and increase the risk of off-target effects and genomic instability. In contrast","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 7","pages":""},"PeriodicalIF":7.9,"publicationDate":"2025-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70395","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144695908","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}

{"title":"Erratum for the Clinical and Translational Medicine “Multi-omics integration reveals the oncogenic role of eccDNAs in diffuse large B-cell lymphoma through STING signalling” by Zijuan Wu et al.","authors":"","doi":"10.1002/ctm2.70312","DOIUrl":"https://doi.org/10.1002/ctm2.70312","url":null,"abstract":"<p>Following the publication of the original article,¹ the authors identified minor errors in Figure 1C, where the images of one group were incorrect. Because during the image acquisition, we mistakenly labelled two duplicate results from a single sample. We have made the necessary corrections to Figure 1C. More importantly, we promise that the erratum has no impact on the conclusion and description of the article.</p><p>We apologise for this error.</p><p>ORIGINAL FIGURE 1.</p><p></p><p>(C) AFM images of extracted eccDNAs in DLBCL cell lines. Scale bar, 200 nm.</p><p>UPDATED FIGURE 1.</p><p></p><p>(C) AFM images of extracted eccDNAs in DLBCL cell lines. Scale bar, 200 nm.</p><p>1. Wu Z, Zhang W, Wang L, et al. Multi-omics integration reveals the oncogenic role of eccDNAs in diffuse large B-cell lymphoma through STING signalling. <i>Clin Transl Med</i>. 2024;14(8):e1815 https://doi.org/10.1002/ctm2.1815.</p>","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 7","pages":""},"PeriodicalIF":7.9,"publicationDate":"2025-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70312","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144695854","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}

{"title":"Correction to “Inflammasome activation and metabolic remodeling in p16-positive aging cells aggravates high-fat diet-induced lung fibrosis by inhibiting NEDD4L-mediated K48-polyubiquitin-dependent degradation of SGK1”","authors":"","doi":"10.1002/ctm2.70379","DOIUrl":"https://doi.org/10.1002/ctm2.70379","url":null,"abstract":"<p>Gu X, Meng H, Peng C, et al. Inflammasome activation and metabolic remodelling in p16-positive aging cells aggravates high-fat diet-induced lung fibrosis by inhibiting NEDD4L-mediated K48-polyubiquitin-dependent degradation of SGK1. <i>Clin Transl Med</i>. 2023;13(6):1308.</p><p>In this article, the authors have just realized the wrong usages of immunoblotting bands for β-gal and p16 presented in Figure S1D and immunoblotting band for K48-polyubiquitin (Ub) presented in Figure S12K. The corrected Figures S1D and S12K are as follows. The quantitative analysis in Figure S1F has been conducted using this accurate immunoblotting result of Figures S1D.</p><p>The authors sincerely apologize for these errors. This correction does not affect the study's conclusions.</p>","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 7","pages":""},"PeriodicalIF":7.9,"publicationDate":"2025-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70379","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144695907","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}