Journal of Experimental & Clinical Cancer Research最新文献

{"title":"\"Small extracellular vesicles: messengers at the service of breast cancer agenda in the primary and distant microenvironments\".","authors":"Angela Galardi, Valentina Fogazzi, Claudia Tottone, Marta Giussani, Serenella M Pupa, Giulia Cosentino, Marilena V Iorio","doi":"10.1186/s13046-025-03471-y","DOIUrl":"10.1186/s13046-025-03471-y","url":null,"abstract":"<p><p>Breast cancer (BC) remains a leading cause of cancer-related mortality in women, with complex mechanisms driving its initiation, progression, and resistance to therapy. In recent years, the tumor microenvironment (TME) has gained attention for its critical role in shaping tumor behavior, where small extracellular vesicles (small EVs) have emerged as key mediators of intercellular communication. These vesicles carry a diverse cargo of proteins, lipids, DNA, and various non-coding RNAs-such as miR-21, miR-155, and miR-1246-mirroring the molecular status of their originating cells. This review highlights the roles of small EVs in immune modulation, stromal remodelling, and metastatic niche formation, emphasizing their contribution to therapy resistance and immune evasion. We discuss recent updates on EV biogenesis, characterisation and isolation techniques, such as ultracentrifugation, immunoaffinity and microfluidic systems. We also critically evaluate their potential for clinical application and how well they conform to the MISEV2023 guidelines. Furthermore, we examine small EVs as diagnostic tools in liquid biopsies and compare them with conventional methods such as mammography and tissue biopsies. We also discuss organotropism mediated by small EV cargo (e.g., integrins α6β4, αvβ5) and the diagnostic potential of protein and lipid signatures (e.g., PD-L1, CD63, and exosomal lipidomics). Therapeutically, we explore engineered small EVs for drug delivery, gene modulation, and immune activation, addressing challenges of targeting efficiency, in vivo stability, immunogenicity, and clinical scalability. The review discusses ongoing clinical trials involving small EVs in BC and highlights key translational gaps between preclinical advances and clinical implementation. Finally, we explores how integrating artificial intelligence, single-cell transcriptomics, and multi-omics approaches can help overcome major challenges such as small EV heterogeneity and tracking limitations. Crucially, this integration enables a more tailored understanding of each patient's tumor biology, reducing therapeutic failures by guiding more personalized and effective treatment strategies. Overall, small EVs represent a transformative tool in precision oncology, contingent on resolving key challenges in their clinical translation.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"44 1","pages":"216"},"PeriodicalIF":12.8,"publicationDate":"2025-07-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12278669/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144683463","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":"Targeting autophagy and plasminogen activator inhibitor-1 increases survival and remodels the tumor microenvironment in glioblastoma.","authors":"Sophie G Shifman, Jennifer L O'Connor, Daniel P Radin, Aryan Sharma, Laura Infante, Francesca Ferraresso, Christian J Kastrup, Daniel A Lawrence, Stella E Tsirka","doi":"10.1186/s13046-025-03473-w","DOIUrl":"10.1186/s13046-025-03473-w","url":null,"abstract":"<p><strong>Background: </strong>Glioblastoma (GBM), the most common and aggressive type of primary brain tumor, engages multiple survival mechanisms, including autophagy. GBM exploits both degradative and secretory autophagy pathways to support tumor growth and limit the efficacy of standard-of-care treatments. We have previously shown that lucanthone, a blood-brain barrier permeable autophagy inhibitor, reduces tumor burden. However, although lucanthone-treated tumors are significantly smaller in size, they are not completely obliterated, suggesting compensatory survival mechanisms. A critical factor for GBM survival is communication with the tumor microenvironment (TME), which can be programmed by glioma cells to support growth and immunosuppression. Plasminogen activator inhibitor-1 (PAI-1), a secreted serine protease inhibitor, has been implicated in the progression of several cancers, including GBM, and has been shown to be modulated by autophagy in other cancers. The role of PAI-1 in GBM, namely its relationship with intracellular autophagy dysregulation and extracellular TME as a mechanism of tumor survival, remains incompletely understood.</p><p><strong>Methods: </strong>Murine glioma models were established using intracranial injection of GL261 cells in C57BL/6 mice, followed by autophagy inhibition with intraperitoneal lucanthone and/or PAI-1 inhibition with MDI-2268 chow, and tumors were assessed by immunohistochemistry. In culture, glioma cell lines were challenged with MDI-2268, lucanthone, mitoxantrone, or siRNA-LNPs targeting PAI-1, and assessed by MTT assay, q-RT-PCR, ELISA, invasion assay, immunoblot, and immunocytochemistry. Lysosomal markers and transient transfection with fluorescent vesicular proteins were utilized to evaluate PAI-1 intracellular localization via confocal microscopy. Synergy was analyzed using the HSA model in Combenefit, and statistical analyses included t-tests, ANOVA, and log-rank tests for survival.</p><p><strong>Results: </strong>Lucanthone treatment increased intracellular PAI-1 and autophagy markers while reducing active extracellular PAI-1. PAI-1 colocalized with lysosomal markers, suggesting impaired secretory autophagy. PAI-1 inhibition reduced glioma cell viability and invasion. Combination therapy with lucanthone and MDI-2268 drastically decreased tumor volume, prolonged survival, and promoted a pro-inflammatory state in the tumor microenvironment.</p><p><strong>Conclusions: </strong>Our findings suggest that PAI-1 may be a compensatory survival mechanism in GBM after autophagy inhibition, and that dual targeting of autophagy and PAI-1 disrupts tumor progression and enhances anti-tumor immunity, providing promising evidence for targeting this axis.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"44 1","pages":"214"},"PeriodicalIF":11.4,"publicationDate":"2025-07-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12275254/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144668841","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":"MiR-181a-driven downregulation of cholesterol biosynthesis through SREBP2 inhibition suppresses uveal melanoma metastasis.","authors":"Rui Wang, Claudia Gilbert, Houda Tahiri, Chun Yang, Solange Landreville, Pierre Hardy","doi":"10.1186/s13046-025-03459-8","DOIUrl":"10.1186/s13046-025-03459-8","url":null,"abstract":"<p><strong>Background: </strong>uveal melanoma (UM) is the most common primary intraocular tumor in adults, with metastasis being the leading cause of death. However, effective treatments for metastatic UM remain limited. Emerging evidence suggests that cholesterol metabolism plays a role in cancer progression, but its impact on UM metastasis is not well understood.</p><p><strong>Methods: </strong>we investigated the effects of miR-181a on UM metastasis using multiple UM cell lines and a suprachoroidal injection mouse model. Functional assays, including migration, invasion, and cancer stem-like cell (CSC) formation, were performed. The target of miR-181a was identified through bioinformatics, luciferase assays, and western blotting. Cholesterol levels were measured, and in vitro and in vivo studies assessed the therapeutic potential of combining miR-181a with crizotinib.</p><p><strong>Results: </strong>miR-181a significantly decreases UM cell migration, invasion, and metastasis. Mechanistically, miR-181a was found to target sterol regulatory element-binding protein 2 (SREBP2), thereby inhibiting cholesterol biosynthesis. This decrease in cholesterol levels hindered reduced epithelial-to-mesenchymal transition (EMT) and led to a decline in cancer stem-like cell (CSC) populations in UM. Furthermore, elevated cholesterol or overexpression of SREBP2 abrogated the anti-metastatic effects of miR-181a. Additionally, a combination of miR-181a and crizotinib significantly inhibited metastasis, both in vitro and in vivo.</p><p><strong>Conclusions: </strong>miR-181a inhibits UM metastasis by targeting SREBP2 and reducing cholesterol biosynthesis. Its combination with crizotinib may provide a promising therapeutic strategy for metastatic UM.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"44 1","pages":"215"},"PeriodicalIF":11.4,"publicationDate":"2025-07-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12275384/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144668838","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":"Monitoring soluble cMET and ctDNA in metastatic uveal melanoma patients to track early disease progression on immunotherapies.","authors":"Devayani Machiraju, Christian H Ziener, Elena Clementi, Francisco García-Asencio, Jennifer Hüllein, Jasmin Richter, Bénédicte Lenoir, Melanie Wiecken, Daniel Hübschmann, Dirk Jäger, Jessica C Hassel","doi":"10.1186/s13046-025-03451-2","DOIUrl":"10.1186/s13046-025-03451-2","url":null,"abstract":"<p><strong>Background: </strong>Metastatic uveal melanoma (mUM) is a rare malignancy and is different from metastatic cutaneous melanoma (mCM) in tumor characteristics and efficacy to immunotherapies. Tumor-specific biomarkers are required for mUM patients to monitor early disease progression on immunotherapies.</p><p><strong>Methods: </strong>We investigated clinical characteristics such as liver tumor burden and routine blood tumor markers, including lactate dehydrogenase (LDH) and transaminases in patients with mUM and with liver metastasized cutaneous melanoma (LmCM), treated with immune checkpoint inhibitors (ICIs) between May 2013-February 2024. In addition, we analyzed soluble cMET (scMET) in serum samples from these patients along with a cohort of mCM patients without liver metastases (nLmCM) using ELISA. Circulating tumor DNA (ctDNA) in the plasma was analyzed using digital droplet PCR (ddPCR) in mUM patients receiving immunotherapies. scMET, ctDNA, and LDH combination was used to simultaneously monitor disease progression in ICI and tebentafusp-receiving mUM patients.</p><p><strong>Results: </strong>Sixty-nine patients with mUM and seventy-six patients with LmCM were treated with either anti-PD1 monotherapy (n = 69, 48%) or ipi + nivo combination therapy (n = 76, 52%). Irrespective of the type of melanoma and type of immunotherapy, patients with liver metastasis size greater than 8cm experienced rapid disease progression. ICI-treated mUM patients with increased LDH, aspartate aminotransferase (AST), alanine transaminase (ALT), scMET, ctDNA, and rapidly growing tumors were significantly associated with treatment resistance and shorter progression-free and overall survival (p < 0.05). scMET (AUC: 0.82) outperforms LDH (AUC: 0.77) and S100 (0.68) in predicting one-year overall survival in these patients. A validation set with LmCM and nLmCM patient samples showed that increased scMET is likely a mUM-specific feature and does not predict ICI outcomes in LmCM or nLmCM patients (p > 0.05). Moreover, monitoring ctDNA and scMET in mUM patients under ICIs or tebentafusp treatment revealed the potential for early detection of disease progression.</p><p><strong>Conclusion: </strong>Soluble cMET might serve as a tumor-specific biomarker to predict clinical outcomes in mUM patients. A combinational assessment of scMET and ctDNA in mUM patients' blood offers a highly sensitive potential approach to monitor early disease progression under immunotherapies with ICI or tebentafusp.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"44 1","pages":"213"},"PeriodicalIF":11.4,"publicationDate":"2025-07-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12275281/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144668839","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":"SNRPB/CCNB1 axis promotes hepatocellular carcinoma progression and cisplatin resistance through enhancing lipid metabolism reprogramming.","authors":"Xin Jin, Xigan He, Runze Huang, Qinyu Liu, Lei Wang, Xuanci Bai, Yibin Wu, Yixiu Wang, Ziting Jiang, Yi Shi, Gautam Sethi, Lu Wang, Weiping Zhu","doi":"10.1186/s13046-025-03463-y","DOIUrl":"10.1186/s13046-025-03463-y","url":null,"abstract":"<p><strong>Background: </strong>Hepatocellular carcinoma (HCC) is a major cause of cancer-related mortality globally, significantly impacting worldwide health. Hence, identifying key molecular drivers of HCC progression is crucial for enhancing treatment options and prognostic methods. This study explores the function of Small Nuclear Ribonucleoprotein Polypeptides B and B1 (SNRPB) in HCC, unveiling critical pathways that affect the progression of the disease.</p><p><strong>Methods: </strong>Utilizing multi-dimensional data that integrates bulk RNA sequencing (bulk RNA-seq), single-cell RNA sequencing (scRNA-seq), and spatial transcriptomics (ST) from HCC patients, we have identified SNRPB as a pivotal gene associated with the spliceosome, playing a central role in both tumor initiation and progression. We also investigated the intricate process by which SNRPB influences cyclin B1 (CCNB1) expression through FOXM1-mediated activation, using a combination of bioinformatics, functional assays, Chromatin Immunoprecipitation (ChIP), and Co-Immunoprecipitation (Co-IP) studies. Complementary in vivo experiments and metabolic assays were conducted to explore the relationship between tumor growth and lipid metabolism further. Additionally, evaluations of cisplatin sensitivity were performed, providing an in-depth analysis of influence of SNRPB on HCC.</p><p><strong>Results: </strong>Across multiple cohorts, SNRPB exhibited a marked upregulation within tumors, correlating significantly with poor prognosis. Knockdown of SNRPB suppressed HCC cell proliferation and migration, while promoting apoptosis. Mechanistically, SNRPB regulated CCNB1 expression via FOXM1-mediated transcription, and SNRPB overexpression enhanced lipid metabolism and cisplatin resistance. This increase in drug sensitivity was mediated through alterations in lipid metabolism and the regulatory effects on CCNB1, providing a comprehensive insight into multifaceted role of SNRPB in HCC pathology and potential therapeutic targets. Finally, CCNB1 knockdown reversed the proliferative and tumorigenic effects of SNRPB overexpression in a preclinical HCC model.</p><p><strong>Conclusions: </strong>SNRPB promoted HCC progression by modulating the FOXM1-CCNB1 axis and lipid metabolism, and could act as a potential therapeutic target to augment chemotherapy sensitivity in HCC.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"44 1","pages":"211"},"PeriodicalIF":11.4,"publicationDate":"2025-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12273286/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144668840","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":"Integrated multi-omics profiling reveals the role of the DNA methylation landscape in shaping biological heterogeneity and clinical behaviour of metastatic melanoma.","authors":"Andrea Anichini, Francesca P Caruso, Vincenzo Lagano, Teresa M R Noviello, Rossella Tufano, Gabriella Nicolini, Alessandra Molla, Ilaria Bersani, Francesco Sgambelluri, Alessia Covre, Maria F Lofiego, Sandra Coral, Anna Maria Di Giacomo, Elena Simonetti, Barbara Valeri, Mara Cossa, Filippo Ugolini, Sara Simi, Daniela Massi, Massimo Milione, Andrea Maurichi, Roberto Patuzzo, Mario Santinami, Michele Maio, Michele Ceccarelli, Roberta Mortarini","doi":"10.1186/s13046-025-03474-9","DOIUrl":"10.1186/s13046-025-03474-9","url":null,"abstract":"<p><strong>Background: </strong>We developed an integrated multi-omics analysis in metastatic melanoma (MM) cohorts to associate DNA methylation profiles with tumor progression, survival, response to adjuvant immunotherapy, structure of the tumor immune microenvironment and transcriptional programs of immunity and melanoma differentiation.</p><p><strong>Methods: </strong>Lesions (n = 191) from a fully annotated, retrospective cohort of 165 AJCC 8th Stage III and IV melanoma patients (EPICA cohort) were characterized by reduced representation bisulfite sequencing, RNA sequencing, whole exome sequencing, quantitative immunohistochemistry and multiplex immunofluorescence analysis. The TCGA melanoma datasets were used for validation. Pre-therapy lesions (n = 28) from a cohort of MM patients treated with adjuvant immune checkpoint blockade were characterized for the DNA methylation profile. Impact of a DNMT inhibitor on DNA methylation and transcriptomic profiles of melanoma cell lines was investigated by EPIC arrays and Clariom S arrays.</p><p><strong>Results: </strong>Four tumor subsets (i.e. DEMethylated, LOW, INTermediate and CIMP) with progressively increasing levels of DNA methylation were identified in EPICA, TCGA MM and TCGA primary melanoma cohorts. EPICA patients with LOW methylation tumors exhibited a significantly longer survival and a lower progression rate to more advanced AJCC stages, compared to patients with CIMP tumors. In an adjuvant immune checkpoint blockade cohort, patients with DEM/LOW pre-therapy lesions showed significantly longer relapse-free survival compared to those with INT/CIMP lesions. RNA-seq data analysis revealed that LOW and CIMP EPICA tumors showed opposite activation of master molecules influencing prognostic target genes, and differential expression of immunotherapy response and melanoma differentiation signatures. Compared to CIMP tumors, LOW lesions showed enrichment for CD8⁺ TCF-1⁺ PD-1⁺ TIM-3^- pre-exhausted and CD8⁺ TCF-1^- PD-1⁺ TIM-3⁺ exhausted T cells, more frequent retention of HLA Class I antigens and a de-differentiated melanoma phenotype. The differentiation and immune-related transcriptional features associated with LOW vs CIMP lesions were tumor-intrinsic programs retained in-vitro by melanoma cell lines. Consistently, treatment of differentiated melanoma cell lines with a DNMT inhibitor induced global DNA de-methylation, promoted de-differentiation and upregulated viral mimicry and IFNG predictive signatures of immunotherapy response.</p><p><strong>Conclusions: </strong>These results reveal the biological, prognostic and therapeutic relevance of DNA methylation classes in MM and support methylome targeting strategies for precision immunotherapy.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"44 1","pages":"212"},"PeriodicalIF":11.4,"publicationDate":"2025-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12273276/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144668837","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: Intravesical instillation-based mTOR-STAT3 dual targeting for bladder cancer treatment.","authors":"Dae Hoon Lee, Jung Ki Yoo, Ki Hwan Um, Wootae Ha, Soo Min Lee, Junseong Park, Min Jeong Kye, Jungyo Suh, Jin Woo Choi","doi":"10.1186/s13046-025-03469-6","DOIUrl":"10.1186/s13046-025-03469-6","url":null,"abstract":"","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"44 1","pages":"210"},"PeriodicalIF":11.4,"publicationDate":"2025-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12269282/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144660937","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":"CC48 a new CB2R agonist/FAAH inhibitor dual drug blocks gastric cancer progression and overcomes paclitaxel resistance.","authors":"Annalisa Schirizzi, Natasha Renna, Giampiero De Leonardis, Rosangela Montanaro, Francesco Mastropasqua, Giovanni Graziano, Chiara Riganti, Isabella Pisano, Antonio Laghezza, Carmen Abate, Angela Stefanachi, Nicola Antonio Colabufo, Cristina Caccioppoli, Giusy Bianco, Anna Maria Valentini, Raffaele Armentano, Gianluigi Giannelli, Marialessandra Contino, Rosalba D'Alessandro","doi":"10.1186/s13046-025-03476-7","DOIUrl":"10.1186/s13046-025-03476-7","url":null,"abstract":"<p><p>Gastric cancer (GC) has poor survival in advanced stages, with limited treatment options. Paclitaxel (PTX) is commonly used, but resistance often arises, highlighting the need for targeted therapies. Cannabinoid receptor type 2 (CB2R) is overexpressed in several cancers and its activation has been associated with reduced tumor growth and metastasis. This study evaluated the antitumor activity of selected CB2R agonists with dual activity (CC48 and Fi9) compared to single-target compounds (ASF151), a reference agonist (compound 1), and an antagonist (AM630). The compounds' cytotoxicity was determined in GC lines, including PTX-resistant cells, with different levels of CB2R expression. Firstly, were ported that the addition of CB2R ligands to PTX significantly reduces the actively proliferating cells (Ki67+) even in chemotherapy-resistant GC cells. Concentrations below the IC50 of all compounds were used to minimise toxicity. Activation of Akt/mTORC1 and MAPK cascades were found to be related to antiproliferative activity, which was found to be independent of CB2R expression in the different cell lines. Surprisingly, both agonist and antagonist compounds inhibited cell growth. The interaction of CC48 and the reference compounds 1 and AM630, with P-glycoprotein (P-gp) could explain their greater effectiveness in overcoming PTX resistance. Furthermore, CC48 was particularly effective among the agonists in inducing the expression of key autophagy proteins and activating the apoptotic pathway via caspase 3/7 (p < 0.05). The combination of CC48 with PTX further amplified this effect in both sensitive and resistant cells (p < 0.01). CC48 significantly reduced GC cells migration and epithelial-mesenchymal transition (EMT) by modulating the vimentin protein (p < 0.05). In an orthotopic mouse model, CC48 inhibits tumor volume (p < 0.01)and also reduces the number of Ki67 + cells (p < 0.05), without cytotoxic effects. Histological analysis revealed widespread necrosis with inflammatory and apoptotic features, including pyknotic nuclei and fibrotic replacement in CC48-treatedtumors. Moreover, CC48 treatment reduced circulating levels of G-CSF, IL-12 (p40), and eotaxin (p < 0.05), suggesting an immunomodulatory role. In conclusion CC48, a novel multi-target ligand (MTDL), activating CB2R and inhibiting Fatty Acid Amide Hydrolase (FAAH), effectively blocks GC progression modulating the immune response and overcoming PTX resistance.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"44 1","pages":"209"},"PeriodicalIF":11.4,"publicationDate":"2025-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12265377/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144644032","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":"Tumor-intrinsic ENO1 inhibition promotes antitumor immune response and facilitates the efficacy of anti-PD-L1 immunotherapy in bladder cancer.","authors":"Chengquan Shen, Jing Liu, Ding Hu, Changxue Liu, Fei Xie, Yonghua Wang","doi":"10.1186/s13046-025-03464-x","DOIUrl":"10.1186/s13046-025-03464-x","url":null,"abstract":"<p><p>Immunotherapy has revolutionized cancer treatment, yet understanding immunotherapy resistance mechanisms remains challenging. Here, a CRISPR cas9 screening in vivo and an RNA-sequencing for clinical immunotherapy resistance BC samples identified enolase 1 (ENO1) as a potent regulator of anti-PD-L1 treatment efficacy. Investigation of clinical BC samples demonstrated a correlation between ENO1 overexpression and immune evasion in BC, evidenced by reduced CD8⁺ T cell infiltration and resistance to anti-PD-L1 therapy. Increased CD8⁺ T cell infiltration and function were indicative of antitumor immunity, which was elicited by ENO1 knockdown, which also suppressed carcinogenesis. Single-cell RNA sequencing demonstrated that wild-type (WT) and ENO1 knockout (KO) tumors have different immune cell compositions with the latter preferring an immunostimulatory microenvironment. Mechanistically, ENO1 regulated CD8⁺ T cell function and tumor-associated macrophage (TAM) polarization via the SPP1-ITGA4/ITGB1 pathway in the TME. Importantly, genetic and pharmacological inhibition of ENO1 sensitizes tumors to anti-tumor immunity and synergizes with anti-PD-L1 therapy. The results highlight tumor-intrinsic ENO1 as a critical regulator of tumor immune evasion in BC. Targeting ENO1 enhance the efficacy of immune checkpoint blockade therapy by promoting antitumor immunity.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"44 1","pages":"207"},"PeriodicalIF":11.4,"publicationDate":"2025-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12261641/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144644036","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":"CCNY-mediated phosphorylation and TET2-BACH1-driven DNA demethylation activate PRC1 to augment NSCLC progression.","authors":"Dayu Huang, Xianglin Chu, Chunxiao Wu, Xuan Wang, Mengkun Shi, Xiaofeng Chen, Yubao Lyu, Dapeng Li, Xuyu Gu","doi":"10.1186/s13046-025-03472-x","DOIUrl":"10.1186/s13046-025-03472-x","url":null,"abstract":"<p><strong>Background: </strong>The protein regulator of cytokinesis 1 (PRC1) is a prognostic marker characterized by low DNA methylation in lung cancer. This study aims to examine the function of PRC1 in non-small cell lung cancer (NSCLC) cells and investigates its regulatory mechanisms.</p><p><strong>Methods: </strong>PRC1 expression in NSCLC cells was assessed using qPCR and western blot analyses. Loss- and gain-of-function assays of PRC1 were performed in NSCLC cells to analyze its effect on cell cycle progression and growth. Genetic knockdown or pharmaceutical inhibition of cyclin Y (CCNY), tet methylcytosine dioxygenase 2 (TET2), and BTB domain and CNC homolog 1 (BACH1) was conducted to analyze their influence on PRC1 phosphorylation or transcription. Subcutaneous xenograft and orthotopic isograft tumor models were generated for in vivo verification. Tissue microarray (TMA) and bioinformatics analyses were employed to evaluate the clinical prognostic value of CCNY, TET2, and PRC1 in NSCLC.</p><p><strong>Results: </strong>PRC1 was highly expressed in NSCLC cells. Silencing either PRC1 or CCNY, which promotes PRC1 phosphorylation, substantially reduced cell growth in vitro, impaired spindle formation, promoted G2/M phase cell cycle arrest, increased multi-nucleated cells, and weakened tumorigenic activity of cells. Moreover, TET2 was found to induce DNA demethylation of PRC1 and activate its transcription by interacting with BACH1. Inhibition of TET2, BACH1, or the PLK1-PRC1 interaction weakened the tumorigenic potential of NSCLC cells in vivo. The TMA analysis revealed increased levels of CCNY, TET2, and phosphorylated PRC1 in tumor tissues. Bioinformatics analyses suggested that these molecules were correlated with unfavorable prognosis in NSCLC patients.</p><p><strong>Conclusion: </strong>This study demonstrates a critical oncogenic role of PRC1 in NSCLC. CCNY, which modulates PRC1 phosphorylation, and the TET2-BACH1 cascade, which modulates demethylation and transcription of PRC1, may serve as promising targets for NSCLC management.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"44 1","pages":"206"},"PeriodicalIF":11.4,"publicationDate":"2025-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12261648/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144644033","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}