Journal of Experimental & Clinical Cancer Research最新文献

{"title":"Retraction Note: Yes-associated protein (YAP) binds to HIF-1α and sustains HIF-1α protein stability to promote hepatocellular carcinoma cell glycolysis under hypoxic stress.","authors":"Xiaodong Zhang, Yan Li, Yingbo Ma, Liang Yang, Tao Wang, Xin Meng, Zhihong Zong, Xun Sun, Xiangdong Hua, Hangyu Li","doi":"10.1186/s13046-026-03728-0","DOIUrl":"10.1186/s13046-026-03728-0","url":null,"abstract":"","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"45 1","pages":""},"PeriodicalIF":12.8,"publicationDate":"2026-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13173711/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147942904","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":"Circulating extracellular vesicles from early-stage lung cancer patients trigger endothelial activation to drive pre-metastatic niche formation through synergistic miR-29a and C4A signaling.","authors":"Francesca Pontis, Patrizia Ghidotti, Nicole Ferrario, Camilla Locatelli, Mattia Boeri, Marco Gentili, Miriam Segale, Massimo Moro, Arianna Di Bernardo, Giulia Bertolini, Paola Suatoni, Michele Ferrari, Ugo Pastorino, Loris De Cecco, Marica Ficorilli, Marta Lucchetta, Silvia Brich, Luca Agnelli, Fabio Maiullari, Roberto Rizzi, Claudia Bearzi, Paola Portararo, Sabina Sangaletti, Rossella Crescitelli, Luca Roz, Gabriella Sozzi, Orazio Fortunato","doi":"10.1186/s13046-026-03732-4","DOIUrl":"10.1186/s13046-026-03732-4","url":null,"abstract":"<p><strong>Background: </strong>Metastatic recurrence represents the major clinical challenge in early-stage lung cancer after curative surgery. Here, we investigated the role of circulating extracellular vesicles and particles (EVPs) in promoting formation of pre-metastatic niches (PMNs).</p><p><strong>Methods: </strong>Plasma-derived EVPs were obtained by ultracentrifugation from pre-surgery blood samples of patients with poor prognosis. Heavy-smokers cancer free individuals were used as control. EVP were characterized following MISEV guidelines. Functional experiments were carried out in vitro in 2D and 3D-bioprinted models as well as in vivo.</p><p><strong>Results: </strong>EVPs from patients with early relapse show distinct molecular profiles, characterized by elevated levels of miR-29a and complement protein C4a. These EVPs preferentially target endothelial cells inducing a pro-inflammatory condition with upregulation of VCAM1 and CXCL1. In turn, endothelial modulation stimulated fibroblast activation and promoted neutrophils recruitment supporting PMNs formation. Mechanistically, we demonstrate that miR-29a and C4A act synergistically through SPARC down-modulation promoting cancer cell colonization. Preconditioning of mouse lungs using EVPs from patients with poor prognosis increased metastatic growth of human tumor cells, which was inhibited by miR-29a blockade.</p><p><strong>Conclusions: </strong>Circulating EVPs could be novel prognostic biomarkers and key players in PMN formation offering new targets to reduce relapses in lung cancer.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":" ","pages":""},"PeriodicalIF":14.3,"publicationDate":"2026-05-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13340091/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147935085","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":"PARP1-BCAT2 axis upregulates ABCG1 via histone lactylation to drive acquired PARP inhibitor resistance in prostate cancer.","authors":"Wangli Mei, Hang Zhou, Weiyi Li, Yongqiang Liu, Chaozhi Tang, Mengyu Wei, Zhen Zhou, Bowen Ye, Hanwen Niu, Weitian Wang, Kaiqi Yang, Yue Zhang, Liqun Huang, Yang Yu, Xiaofei Wen, Lin Ye","doi":"10.1186/s13046-026-03719-1","DOIUrl":"10.1186/s13046-026-03719-1","url":null,"abstract":"<p><strong>Background: </strong>Poly (ADP-ribose) polymerase inhibitor (PARPi) resistance poses a significant challenge in prostate cancer (PCa). Although branched-chain amino acid (BCAA) metabolism is implicated in cancer biology, its specific role in PARPi resistance remains unclear. This study aims to investigate how BCAA metabolism contributes to PARPi resistance in PCa.</p><p><strong>Methods: </strong>We compared BCAA and Branched-Chain Amino Acid Aminotransferase 2 (BCAT2) levels between PARPi-resistant and PARPi-sensitive cell lines and assessed their clinical relevance. Functional studies were conducted in vitro and in vivo using cell and mouse models. Mechanistic assays, including RNA sequencing, metabolomics, RNA-binding protein immunoprecipitation (RIP), chromatin immunoprecipitation (ChIP), and Cleavage Under Targets and Tagmentation (CUT&Tag), were used to delineate BCAT2-mediated PARPi resistance.</p><p><strong>Results: </strong>BCAT2 expression correlated with PARPi resistance in PCa, and increased BCAA/BCAT2 levels in PARPi-resistant tissues were associated with reduced patient survival. Mechanistically, the DNA-binding domain (DBD) of PARP1 directly bound BCAT2 mRNA and regulated its stability; PARPi-induced PARP1 trapping weakened this interaction, increased BCAT2 expression, and promoted resistance. Transcriptomic and energy-metabolism analyses indicated that BCAT2 enhanced ABCG1 transcription by augmenting glycolysis and lactate secretion, thereby increasing histone H3K18la lactylation. These findings support a PARP1-BCAT2-ABCG1 axis in PARPi resistance. Combining a BCAT2 inhibitor with PARPi produced synergistic effects in cell line-derived xenografts (CDXs) and patient-derived organoids (PDOs).</p><p><strong>Conclusion: </strong>The PARP1-BCAT2/H3K18la-ABCG1 axis drives PARPi resistance in PCa. Targeted BCAT2 inhibition may enhance the therapeutic efficacy of PARPi.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":" ","pages":""},"PeriodicalIF":14.3,"publicationDate":"2026-05-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13330160/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147870080","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":"Exosomal NEAT1 from tumor stem cells induces SIRPA⁺ macrophages to enhance immune evasion and glioblastoma progression via upregulating the HSP90B1/STAT3 axis.","authors":"Nanheng Yin, Zhicheng Zhang, Feiyu Xia, Xiaopei Zhang, Zengyang Li, Tao Zhong, Jiaxin Pan, Geng Liang, Delong Huang, Xiaoxiao Dai, Jun Dong","doi":"10.1186/s13046-026-03729-z","DOIUrl":"10.1186/s13046-026-03729-z","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Background: &lt;/strong&gt;Signal Regulatory Protein Alpha (SIRPA) functions as an inhibitory receptor to suppress phagocytosis of macrophages and promote tumor immune evasion. Recent studies revealed that SIRPA deficiency reprogrammed tumor-associated macrophages toward an antitumor phenotype, and SIRPA functioned independently of CD47. However, the exact role and signaling pathways by which SIRPA&lt;sup&gt;+&lt;/sup&gt; macrophages were induced and exerted their functions in glioblastoma have not been fully elucidated.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;Public single-cell RNA sequencing datasets were analyzed to identify SIRPA&lt;sup&gt;+&lt;/sup&gt; macrophages and characterize their transcriptional states. Immunofluorescence staining was applied to compare difference in SIRPA expression between tumor and peritumoral tissues, and spatial association of SIRPA&lt;sup&gt;+&lt;/sup&gt; macrophages with glioblastoma stem cells (GSCs) was investigated. Phenotypic alterations of macrophages were assessed after coculture with glioblastoma cells or GSCs. Transwell and CCK-8 assays were performed to evaluate the effects of SIRPA&lt;sup&gt;+&lt;/sup&gt; macrophages on proliferation, migration and invasion of tumor cells. CXCL8 secretion by macrophages was quantified with ELISA. Bioinformatic analyses were performed to predict candidate upstream regulators of SIRPA, which were subsequently validated by qPCR, Western blot, RIP, Co-IP, PLA and dual-luciferase assays. Orthotopic xenografts were applied to validate the relevant molecular pathways in vivo.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results: &lt;/strong&gt;Bioinformatic analysis of single-cell datasets identified a distinct subset of SIRPA&lt;sup&gt;+&lt;/sup&gt; macrophages, enriched in tumor regions with epithelial-mesenchymal transition (EMT) signatures, correlating with poor clinical prognosis. Immunofluorescence confirmed higher abundance of SIRPA&lt;sup&gt;+&lt;/sup&gt; macrophages within tumor parenchyma and their spatial colocalization with GSC markers. GSC-derived exosomes induced SIRPA expression in macrophages and suppressed their phagocytic ability, thereby enhancing proliferation, migration, invasion and EMT of glioblastoma cells. LncRNA NEAT1 was highly expressed in GSCs and their exosomes. NEAT1 was efficiently transferred into macrophages, then stabilized HSP90B1 and strengthened its interaction with STAT3, thereby enhancing HSP90B1-dependent STAT3 phosphorylation and activating SIRPA transcription. In vivo, knockdown of NEAT1 or SIRPA in macrophages partially reversed intracranial tumor progression induced by GSC-derived exosomes and prolonged survival of tumor-bearing mice, supporting the tumor-promoting role of the NEAT1/HSP90B1/STAT3/SIRPA axis in glioblastoma.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Conclusions: &lt;/strong&gt;GSC-derived exosomal NEAT1 reprogrammed macrophages toward an immunosuppressive SIRPA&lt;sup&gt;+&lt;/sup&gt; phenotype through the HSP90B1/STAT3 axis, thereby promoting immune evasion and progression of glioblastoma, highlighting NEAT1 as a critical mediator of the crosstalk between GSCs and macr","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":" ","pages":""},"PeriodicalIF":14.3,"publicationDate":"2026-05-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13330394/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147876491","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":"Nanovaccines with ferroptosis, necroptosis and STING-activation for synergistic immunotherapy.","authors":"Jia-Rui Du, Mu-Le Tu, Yong-Xu Xia, Yuan-Qiang Lin, Rui Yang, Chang Weng, Yi Liu, Hao Zhang, Hui Wang, Wen-Jie Feng, Deng-Ke Teng","doi":"10.1186/s13046-026-03726-2","DOIUrl":"10.1186/s13046-026-03726-2","url":null,"abstract":"<p><p>Nanovaccines based on immunogenic cell death (ICD) present a promising strategy in tumor immunotherapy, serving as a bridge connecting tumor cell death to the induction of anti-tumor immunity. However, their efficacy is severely limited by the immunologically silent nature of apoptosis-dependent ICD and the immunosuppressive tumor microenvironment (TME). In this work, we designed a metal‒polyphenol network nanovaccine (SRF@FeShik-cGAMP/HA). Upon reaching the tumor tissue through specific targeting, the nanovaccines disassemble within the tumor cells, releasing the Fenton reaction catalyst ferrous iron (Fe²⁺), the system Xc- inhibitor sorafenib (SRF), and necroptosis inducer shikonin. Fe²⁺, SRF, and shikonin collectively promote the accumulation of lipid peroxide and amplify ferroptosis by providing an exogenous iron source, inhibiting glutathione biosynthesis, and boosting reactive oxygen species production, respectively. Meanwhile, shikonin induces necroptosis. The combination of ferroptosis and necroptosis overcomes the limitation of tumor immune silencing and triggers a strong ICD. Simultaneously, the immune adjuvant 2'3'-cyclic-GMP-AMP (cGAMP) activates the STING pathway, reversing the immunosuppressive TME and enhancing the anti-tumor immune response mediated by ICD. The synergistic action of ferroptosis, necroptosis, and the STING pathway produces a cascade of antitumor immune responses and establishes long-term immune memory. This nanovaccine demonstrates promising therapeutic effects in primary, orthotopic, and recurrent hepatocellular carcinoma (HCC) models. Collectively, our findings present a cancer immunotherapy strategy that exploits dual ferroptosis and necroptosis induction to trigger ICD, bypassing the limitations of apoptosis-dependent pathways. This strategy coordinates with the STING pathway to achieve potent antitumor immunity, providing a promising paradigm for HCC treatment, and offering a promising and translatable path for clinical development.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":" ","pages":""},"PeriodicalIF":14.3,"publicationDate":"2026-05-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13255514/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147876542","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":"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":"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":14.3,"publicationDate":"2026-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13474847/pdf/","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":"OA","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":"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":14.3,"publicationDate":"2026-05-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13285497/pdf/","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":"OA","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":"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":14.3,"publicationDate":"2026-05-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13322090/pdf/","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":"OA","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":"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":14.3,"publicationDate":"2026-05-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13459263/pdf/","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":"OA","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":"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":14.3,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13276959/pdf/","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":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}