Journal of Experimental & Clinical Cancer Research最新文献

{"title":"Klf4-Tymp axis promotes inflammation-driven early tumorigenesis by enhancing kras mutation-induced acinar-to-ductal metaplasia through Pi3k/Akt and Mek/Erk pathways.","authors":"Qihang Yuan, Junhong Chen, Peng Luo, Kai Liu, Fangyue Guo, Yao Xu, Mengying Tong, Hong Xiang, Dong Shang","doi":"10.1186/s13046-026-03712-8","DOIUrl":"https://doi.org/10.1186/s13046-026-03712-8","url":null,"abstract":"<p><strong>Background: </strong>Acinar-to-ductal metaplasia (ADM) is a pivotal step in pancreatic tumorigenesis, reversible in normal contexts but progressing to PanIN and pancreatic cancer (PC) in the presence of Kras mutation and inflammation. Thus, delineating exocrine cell heterogeneity and identifying regulators of ADM are essential for understanding pancreatic tumorigenesis.</p><p><strong>Methods: </strong>We collected single-cell RNA sequencing (scRNA-seq) data of 146 human pancreatic samples, followed by comprehensive exploration of dynamic change and heterogeneity of ADM via machine learning algorithms. Multi-omics analysis integrating ATAC-seq and RNA-seq highlights the association of Klf4-Tymp axis with ADM. A dual-luciferase reporter assay was performed to evaluate the transcriptional activation of the Tymp promoter by Klf4. AAV-mediated gene silencing was performed in vivo to elucidate the roles and underlying mechanisms of the Klf4/Tymp axis during the ADM process in Pdx1-Cre; Kras^G12D/+ (KC) mice. In-vitro mouse pancreatic organoid model combined with amino acid mutation was established to investigate the role of Tymp in regulating ADM and its underlying mechanisms.</p><p><strong>Results: </strong>scRNA-seq revealed one S100A4⁺ acinar subpopulation and six ductal subpopulations (GPX1⁺, CD24⁺, TFF3⁺, MT-ATP8⁺, S100A9⁺, and HMGB2⁺) associated with poor prognosis in PC. Integrated pseudotime analysis of pancreatic acinar and ductal cells highlighted the potential involvement of TYMP in regulating the pathological process of ADM. Klf4 was identified as an upstream transcription factor regulating the Tymp gene. ATAC-seq revealed increased chromatin accessibility at the Klf4 and Tymp locus under inflammatory injury or oncogenic Kras conditions. Dual-luciferase reporter assays demonstrated that the transcription factor Klf4 binds to the promoter region of Tymp, thereby promoting its transcriptional expression. Pancreatic overexpression of Klf4 in mice upregulated Tymp expression and facilitated inflammation-induced initiation and progression of ADM. Exogenous supplementation with Tipiracil Hydrochloride suppressed the effects induced by Klf4. Knockdown of the Tymp gene suppressed inflammation-driven initiation and progression of ADM in KC mice through Pi3k/Akt and Mek/Erk pathways.</p><p><strong>Conclusions: </strong>The Klf4-Tymp axis promotes inflammation-associated early pancreatic tumorigenesis by enhancing KRAS mutation-induced ADM through activation of the Pi3k/Akt and Mek/Erk signaling pathways. These findings provide new insights into the molecular mechanisms linking inflammatory injury to ADM and early pancreatic tumorigenesis.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":" ","pages":""},"PeriodicalIF":12.8,"publicationDate":"2026-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147845493","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":"Nanocarrier-mediated targeting of NF-κB and JAK/STAT signaling pathways in hepatocellular carcinoma: mechanisms and therapeutic strategies.","authors":"Muhammad Azhar, Yang Duan, Muhammad Ahmad, Haichuan Wang","doi":"10.1186/s13046-026-03715-5","DOIUrl":"https://doi.org/10.1186/s13046-026-03715-5","url":null,"abstract":"<p><p>Hepatocellular carcinoma (HCC) remains a major global cause of cancer-related deaths. HCC development, immune evasion, and treatment resistance are significantly influenced by the aberrant activation of the NF-κB and JAK/STAT signaling pathways. The review provides a thorough and critical analysis of recent developments in nanocarrier-mediated targeting of NF-κB and JAK/STAT pathways in HCC. It demonstrates the molecular interactions between various pathways and their implications for inflammation, angiogenesis, hepatocarcinogenesis, and resistance to both immunotherapy and chemotherapy. A variety of nanoplatforms, such as polymeric nanoparticles, lipid-based systems, inorganic nanomaterials, and biomimetic carriers, are designed to enhance the delivery of small-molecule inhibitors, nucleic acids, and combination therapies, improving pharmacokinetic and pharmacodynamic profiles. The review highlights ligand-functionalized and stimulus-responsive nanocarriers designed for controlled drug release and targeted therapy in the liver environment. Co-modulation of NF-κB and JAK/STAT signaling via nanotechnology enhances antitumor efficacy and decreases systemic toxicity, as supported by preclinical and recent translational data. Lastly, important issues such as scalability, biosafety, and regulatory concerns are discussed. Future directions for integrating precision cancer techniques with nanomedicine are proposed. This analysis emphasizes the therapeutic potential of targeting the NF-κB and JAK/STAT pathways with nanotechnology to enhance outcomes in HCC.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":" ","pages":""},"PeriodicalIF":12.8,"publicationDate":"2026-05-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147845540","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":"Transforming tumor microenvironments: nanotechnology and gene therapy in cellular signaling and epigenetic insight into chemo-resistance.","authors":"Prashant Sharma, Nguyen Phuong Thuy, Israrul H Ansari, Ravi Mani Tripathi, Mrinalini Kala, Mostafa H Elberry, Neelesh Sharma, Sung-Jin Lee","doi":"10.1186/s13046-026-03720-8","DOIUrl":"https://doi.org/10.1186/s13046-026-03720-8","url":null,"abstract":"<p><p>Chemoresistance remains the primary cause of cancer treatment failure, yet current understanding remains fragmented across isolated mechanistic studies. This review provides a unified framework linking tumor microenvironment (TME) signaling, epigenetic reprogramming, and nanotherapeutic intervention as an integrated axis driving and potentially reversing chemoresistance. We systematically examine how TME components: hypoxia (HIF-1α pathway), acidosis, cancer-associated fibroblasts (TGF-β/PDGF signaling), and immune cells (NF-κB-mediated immunosuppression) activate signaling cascades that directly interface with epigenetic machinery. These TME-activated pathways recruit DNA methyltransferases, histone-modifying enzymes, and regulate microRNA (miRNA) networks, establishing stable resistant phenotypes including epithelial-mesenchymal transition, cancer stem cells, and metabolic adaptation. Critically, miRNA dysregulation serves as a central integrator, creating bidirectional crosstalk between signaling pathways and epigenetic modifications through self-reinforcing circuits. Unlike previous reviews focusing on isolated resistance mechanisms, we demonstrate how this integrated TME-epigenetic axis creates specific therapeutic vulnerabilities exploitable through rationally designed nanotechnology platforms delivering epigenetic modulators (DNMT inhibitors, HDAC inhibitors, EZH2 inhibitors) and gene therapy tools (CRISPR-Cas9 epigenetic editors, miRNA mimics/antagomirs). We critically evaluate clinical translation challenges, including EPR effect heterogeneity, delivery barriers, and biomarker gaps, providing a balanced perspective on both potential and obstacles. This mechanistic framework guides the development of next-generation combination therapies targeting multiple nodes within the TME-epigenetic-nanotherapy axis.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":" ","pages":""},"PeriodicalIF":12.8,"publicationDate":"2026-05-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147845545","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":"IgG2a-formatted 4-1BB agonism combined with S100A9 inhibition enhances T cell activation and tumor control in a preclinical model of multiple myeloma.","authors":"Hatice Satilmis, Adrien Denis, Emma Verheye, Arne Van der Vreken, Dewen Zhan, Evan Calliauw, Marie Törngren, Helena Eriksson, Sylvia Faict, Elke De Bruyne, Eline Menu, Karin Vanderkerken, Kim De Veirman","doi":"10.1186/s13046-026-03716-4","DOIUrl":"https://doi.org/10.1186/s13046-026-03716-4","url":null,"abstract":"<p><strong>Background: </strong>Immunotherapy has emerged as a promising strategy for multiple myeloma (MM), yet relapse remains frequent due to the immunosuppressive bone marrow (BM) microenvironment, characterized by T cell dysfunction and accumulation of immunosuppressive myeloid cells. The co-stimulatory receptor 4-1BB (CD137, TNFRSF9) can enhance T and NK cell effector functions, but its therapeutic utility in MM is not well established. Tasquinimod (TQ), a clinical-stage S100A9 inhibitor, offers a complementary approach by limiting the recruitment and activity of suppressive myeloid cells.</p><p><strong>Methods: </strong>4-1BB expression was assessed during disease progression in MM mice and in newly diagnosed MM patients using single-cell RNA sequencing and flow cytometry. Therapeutic potential was evaluated in 5TGM1 tumor-bearing mice treated with two 4-1BB agonists, LOB12.3 (IgG1κ) and 3H3 (IgG2a), using isotype controls. The lead agonist was subsequently combined with TQ to investigate dual targeting of the immunosuppressive tumor microenvironment. Tumor burden was quantified via BM and spleen plasmacytosis and serum M-protein levels. Immune modulation was analyzed using multi-parameter flow cytometry. Statistical significance was determined using the Mann-Whitney U test or one-way ANOVA (p < 0.05).</p><p><strong>Results: </strong>4-1BB expression progressively increased on T and NK cells during tumor development in mice. In primary MM patient BM samples, ex vivo 4-1BB stimulation with urelumab enhanced effector responses, increasing IFN-γ⁺ and Granzyme B⁺ CD3⁺ T cells, alongside trends toward increased CD56⁺ NK cells and elevated IFN-γ⁺ NK cell activity. In vivo, 4-1BB agonist treatment promoted expansion of T cell subsets, with clone-specific effects: the IgG2a clone 3H3 significantly reduced M-protein levels and BM plasmacytosis, whereas the IgG1 clone LOB12.3 induced NK cell depletion and demonstrated limited anti-tumor activity. Combining 3H3 with TQ provided superior anti-myeloma efficacy, reducing BM plasmacytosis from 62.5% in controls to 14.1% under combination treatment. Mechanistically, the combination enhanced Granzyme B expression, effector T cell differentiation, and dendritic cell maturation (CD86 upregulation), collectively overcoming BM immunosuppression.</p><p><strong>Conclusions: </strong>These findings establish the isotype-specific efficacy of 4-1BB agonists and support 4-1BB stimulation combined with TQ as a promising strategy to enhance durable immunotherapeutic responses in MM.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":" ","pages":""},"PeriodicalIF":12.8,"publicationDate":"2026-05-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147845464","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 novel antisense lncRNA, LPCRL, functions as a molecular scaffold for the USP15/MIB1 complex to promote primary cisplatin resistance and tumor progression in lung squamous cell carcinoma.","authors":"Peng Luo, Dapeng Lu, Shuang Zhang, Wenqian Dong, Kai Fang, Shihao Yu, Bing He, Maoxin Zhu, Yuee Wang, Xianliang Jiang, Baolong Wang","doi":"10.1186/s13046-026-03721-7","DOIUrl":"https://doi.org/10.1186/s13046-026-03721-7","url":null,"abstract":"<p><strong>Background: </strong>Platinum-based chemotherapy remains the first-line treatment for advanced lung squamous cell carcinoma (LUSC), but its efficacy is often hindered by the development of chemoresistance. Although long noncoding RNAs (lncRNAs) are recognized as regulators of tumor progression and drug resistance, the functional contribution of natural antisense transcripts (NATs), a major subclass of lncRNAs involved in cisplatin resistance in LUSC, remains poorly understood.</p><p><strong>Methods: </strong>Patient-derived xenograft (PDX) models of LUSC were established and treated with cisplatin to identify cisplatin-resistant and cisplatin-sensitive tumor tissues. LncRNA microarray profiling was used to identify transcripts associated with cisplatin resistance. The functional role of a candidate lncRNA, termed LPCRL (LUSC primary cisplatin resistance-associated LncRNA), was assessed in vitro via MTT, flow cytometry, colony formation, and Transwell migration assays. Its effects on tumor growth and metastasis were further validated in vivo. Mechanistic insights were gained through RNA pull-down, silver staining, RNA immunoprecipitation (RIP), coimmunoprecipitation (Co-IP), and Western blot analyses. Finally, the therapeutic potential of LPCRL-targeting siRNA was assessed in a LUSC PDX model.</p><p><strong>Results: </strong>We found that LPCRL was significantly upregulated in primary cisplatin-resistant PDX tissues. Functionally, LPCRL promoted primary cisplatin resistance and enhanced the proliferation and migration of LUSC cells both in vitro and in vivo. Mechanistically, LPCRL functions as a molecular scaffold to facilitate the interaction between MIB1 and USP15. This complex enables USP15 to deubiquitinate MIB1, thereby increasing MIB1 stability and promoting its nuclear export. The subsequent cytoplasmic accumulation of MIB1 enhances the ubiquitination of DLL4, leading to Notch pathway activation and upregulation of the downstream effector HES1. Importantly, intratumoral administration of LPCRL-targeting siRNA in PDX models suppressed tumor growth and sensitized tumors to cisplatin in vivo.</p><p><strong>Conclusions: </strong>Our study revealed that LPCRL promotes LUSC malignancy and cisplatin resistance via the USP15/MIB1/Notch axis, highlighting LPCRL as a promising therapeutic target.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":" ","pages":""},"PeriodicalIF":12.8,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147823005","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":"Progress and challenges in the development of advanced pancreatic cancer organoids.","authors":"Katja Detert, Alban Piotrowsky, Luigi Marongiu, Christian Leischner, Ulrich M Lauer, Sascha Venturelli, Markus Burkard","doi":"10.1186/s13046-026-03717-3","DOIUrl":"10.1186/s13046-026-03717-3","url":null,"abstract":"<p><p>Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy with poor prognosis and rising incidence. Late detection and limited responsiveness to standard treatment translates into a 5-year overall survival of less than 12%. The pathology contributes to a desmoplastic tumor microenvironment that creates a physical barrier, leading to a dense, hypoxic environment that promotes further tumorigenesis, limited immunogenicity, and chemoresistance, resulting in a still significant translational gap in PDAC research. Feasible techniques to further elucidate tumorigenesis are indispensable because of the frequently limited predictive value of current preclinical models. PDAC organoids offer a powerful tool that can be rapidly generated from resected tumors and biopsies. This review summarizes the current technical and scientific knowledge and highlights the importance of the tumor microenvironment, the use of realistic oxygen conditions, and the role of the hypoxia-inducible factors. Additionally, various protocols based on different media and scaffolds are displayed, and it is illustrated how PDAC organoids can help to improve both diagnosis and treatment options. Finally, critical bottlenecks in modeling PDAC tumor-stromal interactions are identified, and integrated co-culture platforms are proposed as a promising solution for translational applications.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":" ","pages":""},"PeriodicalIF":12.8,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147822963","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":"Gemcitabine-induced β4 integrin drives cancer progression and gemcitabine resistance in pancreatic cancer.","authors":"Yoshinobu Kariya, Haruto Suzuki, Yukiko Kariya, Michiru Nishita","doi":"10.1186/s13046-026-03718-2","DOIUrl":"https://doi.org/10.1186/s13046-026-03718-2","url":null,"abstract":"","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":" ","pages":""},"PeriodicalIF":12.8,"publicationDate":"2026-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147787816","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":"BCG-trained macrophages promote pan-anti-tumor activity through epigenetic rewiring of NOX2-ROS axis.","authors":"Rui-Ming Sun, Yi Yang, Yang-Dian Lai, Hai-Ning Wang, Xiao-Xu Yang, Ping Ji, Ying-Ying Chen, Zhao-Yuan Liu, Florent Ginhoux, Xiao-Yong Fan, Huang-Qi Duan, Hai-Bo Shen, Dan Ye, Shun Lu, Ying Wang, Zi-Ming Li","doi":"10.1186/s13046-026-03708-4","DOIUrl":"https://doi.org/10.1186/s13046-026-03708-4","url":null,"abstract":"","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":" ","pages":""},"PeriodicalIF":12.8,"publicationDate":"2026-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147787807","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":"Ferrodoxin 1 (FDX1) drives paclitaxel resistance in ovarian cancer via copper metabolism and ULK1/ATG13-mediated autophagy: overcome by pH/ROS-responsive PPD/PDP@si-FDX1 nanomicelles.","authors":"Yangmei Gong, Zhizhi Deng, Jie Wu, Yi Hu","doi":"10.1186/s13046-025-03589-z","DOIUrl":"https://doi.org/10.1186/s13046-025-03589-z","url":null,"abstract":"","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"45 1","pages":""},"PeriodicalIF":12.8,"publicationDate":"2026-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13104215/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147787802","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: Polo-like kinase 3 inhibits glucose metabolism in colorectal cancer by targeting HSP90/STAT3/HK2 signaling.","authors":"Baochi Ou, Hongze Sun, Jingkun Zhao, Zhuoqing Xu, Yuan Liu, Hao Feng, Zhihai Peng","doi":"10.1186/s13046-026-03714-6","DOIUrl":"10.1186/s13046-026-03714-6","url":null,"abstract":"","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"45 1","pages":""},"PeriodicalIF":12.8,"publicationDate":"2026-04-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13097727/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147730449","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}