Cellular Oncology最新文献

{"title":"Structural architecture of collagen and collagen-fibronectin networks is associated with the invasive behavior of liver cancer cells.","authors":"Alexander Hayn, Madlen Matz-Soja, Thomas Berg, Florian van Bömmel","doi":"10.1007/s13402-026-01235-0","DOIUrl":"10.1007/s13402-026-01235-0","url":null,"abstract":"<p><strong>Purpose: </strong>The remodeling of the extracellular matrix (ECM) is a key feature of tumor development in the liver, particularly in hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (iCCA). Fibrosis and cirrhosis are risk factors for tumorigenesis and define serious structural changes in the ECM. Fibrotic-induced collagen and fibronectin alter the stiffness and heterogeneity of the ECM. A stiffened and heterogeneous ECM promotes the proliferation, migration, and invasion of tumor cells. Direct effects of structural changes in the ECM on HCC/iCCA cancer cells are insufficiently studied.</p><p><strong>Methods: </strong>HCC and iCCA cells were examined in contact with differently structured collagen and collagen-fibronectin networks. The structural architecture of the networks was defined by combining the normalized stiffness, pore size, and network distribution values as the ECM Architectural Index (EAI). The effects of cell-matrix interactions on cell stiffness, invasiveness, and the ability to interact with network structures through fiber displacement in relation to network architecture were determined.</p><p><strong>Results: </strong>Increased EAI caused a decrease in cell stiffness, an increase in cell invasiveness, and altered fiber displacements. Different effects on HCC and iCCA cells depending on the EAI were identified. High EAI resulted in low cell stiffness and high cell invasion across cancer cell types.</p><p><strong>Conclusions: </strong>We present a model system that is applicable to identify structurally induced influences of the extracellular matrix on cancer cells and to investigate the risk factor of structural changes in the tumor environment.</p>","PeriodicalId":9690,"journal":{"name":"Cellular Oncology","volume":"49 3","pages":""},"PeriodicalIF":4.8,"publicationDate":"2026-06-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13263367/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148223544","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Onco-neurology: a clinical perspective on cancer-associated neurological complications.","authors":"Yaying Song, Wenbin Wan, Ying Zhang, Gang Wang","doi":"10.1007/s13402-026-01234-1","DOIUrl":"10.1007/s13402-026-01234-1","url":null,"abstract":"<p><p>Advances in cancer screening and treatment have improved survival, while neurological complications in patients with cancer are gaining clinical relevance. Many of these complications are not attributable to direct tumor invasion, compression, or metastasis, but rather reflect immune-mediated mechanisms, treatment exposure, systemic disturbances, or tumor-associated biological processes. They are commonly discussed under categories such as paraneoplastic neurological syndromes, treatment-related neurotoxicity, immune-related adverse events, or related disorders. However, these categories often overlap and require integrated assessment across oncology and neurology. In this Correspondence, we propose \"onco-neurology\" as a term to describe cancer-associated neurological complications that extend beyond direct nervous system involvement. This concept complements neuro-oncology and paraneoplastic neurological syndromes by emphasizing treatment-related, immune-mediated, systemic, and mixed neurological disorders. Recognition of this field may reduce diagnostic fragmentation, support multidisciplinary evaluation, and promote tumor-immune-neural research.</p>","PeriodicalId":9690,"journal":{"name":"Cellular Oncology","volume":"49 3","pages":""},"PeriodicalIF":4.8,"publicationDate":"2026-06-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13253905/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148216571","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"P2RY6⁺ tumor-associated macrophages as a therapeutic target: suppressing tumor growth and enhancing chemosensitivity in triple-negative breast cancer.","authors":"Xin Wang, Mingyue Ma, Mingyu Zhang, Han Lu, Ying Liu, Yang Zhou, Bing Han","doi":"10.1007/s13402-026-01239-w","DOIUrl":"10.1007/s13402-026-01239-w","url":null,"abstract":"<p><strong>Background: </strong>Triple-negative breast cancer (TNBC) harbors an immunosuppressive tumor microenvironment dominated by tumor-associated macrophages (TAMs). P2RY6, a UDP-sensitive purinergic receptor, is implicated in immune modulation, but its functional role in TNBC TAMs remains elusive.</p><p><strong>Methods: </strong>The clinical relevance of P2RY6⁺ TAMs was assessed via bioinformatics, tissue microarrays, and survival analysis. In vitro, P2RY6 function in macrophage polarization, signaling, and paracrine regulation of TNBC cells was evaluated using genetic/pharmacological approaches, RNA sequencing, calcium imaging, and secretome analysis. The downstream effector S100A9 and its receptor (TLR4/RAGE)-NF-κB axis in TNBC cells were validated. Orthotopic TNBC mouse models were used to evaluate therapeutic targeting of P2RY6 and S100A9 in vivo.</p><p><strong>Results: </strong>P2RY6⁺ TAM infiltration correlates with poor prognosis in TNBC patients. UDP activation of P2RY6 drives M2-like macrophage polarization via the PLC-IP3-Ca²⁺/CREB1 pathway, leading to transcriptional upregulation and secretion of S100A9. Macrophage-derived S100A9 binds TLR4/RAGE on TNBC cells, activates NF-κB signaling, and promotes tumor proliferation. Genetic or pharmacological inhibition of P2RY6, or neutralization of S100A9, suppresses TNBC growth in vitro and in vivo, and synergizes with chemotherapy to enhance antitumor efficacy.</p><p><strong>Conclusions: </strong>Our study unveils a UDP-P2RY6-S100A9 paracrine axis wherein P2RY6⁺ TAMs foster an immunosuppressive and pro-tumorigenic niche in TNBC. This axis represents a novel therapeutic target to disrupt TAM-tumor crosstalk and overcome chemoresistance in TNBC.</p>","PeriodicalId":9690,"journal":{"name":"Cellular Oncology","volume":" ","pages":""},"PeriodicalIF":4.8,"publicationDate":"2026-06-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13473056/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148175626","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"DIO3 associates with sorting nexins and endosomal trafficking networks in ovarian cancer.","authors":"Daniel Maman-Shinar, Shachar Vanmak, David Bern, Nir Ben-Tal, Amit Rosemarin, Dotan Moskovich, Noi Haim, Ulrich Schweizer, Marietta Fabiano, Avivit Weisz, Aviva Katzav, Debora Kidron, Mario Beiner, Aula Asali, Yael Hants, Maya Gottfried, Osnat Ashur-Fabian","doi":"10.1007/s13402-026-01236-z","DOIUrl":"10.1007/s13402-026-01236-z","url":null,"abstract":"<p><strong>Puropose: </strong>Type 3 iodothyronine deiodinase (DIO3) is a membrane-associated enzyme that inactivates thyroid hormones and promotes high-grade serous ovarian cancer (HGSOC) progression. Although DIO3 undergoes continuous recycling between the plasma membrane and endosomal compartments, the mechanisms governing its intracellular routing and functional stability remain unknown.</p><p><strong>Methods: </strong>We used Human ovarian cancer cells (ES-2, OVCAR3, OVSAHO, KURAMOCHI, NCI/ADR (NAR)), ovarian cancer tumors and normal tissues from patients, immortalized fallopian tube cells (FT109, FT237 and FT282) and HEK293T cells. DIO3 was knocked-down (shRNA) or overexpressed (CRISPR activation system). Flow cytometry (cell counts and apoptosis assay), proteomics, co-immunoprecipitation, proximity ligation assay, confocal imaging in the presence of endosomal transport inhibitors, and AlphaFold-based structural modeling were performed.</p><p><strong>Results: </strong>We identify sorting nexins SNX2 and SNX6 as components of the DIO3 trafficking machinery in ovarian cancer. Computer-based structural analysis provide a potential interface for SNXs association, requiring intact linker and catalytic domains of DIO3. Studies in ovarian cancer cells suggest that SNX6 is linked with DIO3 progression through endosomal and Golgi compartments, whereas SNX2 is associated with its recycling to the plasma membrane via RAB11-positive vesicles. Disruption of these pathways destabilizes DIO3-SNXs colocalization and selectively impairs proliferation and survival of DIO3-overexpressing cells.</p><p><strong>Conclusion: </strong>These findings establish intracellular trafficking as a fundamental determinant of DIO3 stability and function and uncover sorting nexin-associated routing as a previously unrecognized dependency and therapeutic vulnerability in ovarian cancer cells.</p>","PeriodicalId":9690,"journal":{"name":"Cellular Oncology","volume":" ","pages":""},"PeriodicalIF":4.8,"publicationDate":"2026-06-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13447639/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148148598","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeting tumor-associated G-protein coupled receptors: beyond single-axis inhibition toward multidimensional regulation.","authors":"Xia Zhou, Bilin Tan, Tingting Zhang, Wenli Liu, Yi Zuo, Bo Ren, Tianbao Wang, Liuying Li, Shilin Chen, Jun Lu","doi":"10.1007/s13402-026-01223-4","DOIUrl":"10.1007/s13402-026-01223-4","url":null,"abstract":"<p><p>G protein-coupled receptors (GPCRs) serve as central hubs in tumor signal transduction and microenvironment regulation. However, their therapeutic exploitation is confounded by a fundamental complexity: GPCR functions are exquisitely context-dependent, varying across cell types and spatial locations within the heterogeneous tumor microenvironment. A single receptor may drive malignant proliferation while simultaneously recruiting immunosuppressive cells, and pathways inhibited by small molecules can be reactivated through parallel axes. This multidimensional regulatory conundrum renders conventional single-axis inhibition strategies inherently limited. This review systematically examines the distribution and pathological functions of tumor-associated GPCRs, critically analyze why current mainstream modalities often fail in the TME context, and spotlight next-generation strategies such as allosteric modulation, targeted protein degradation, nucleic acid therapeutics, and engineered cell therapies that are uniquely poised to actively modulate the TME in a context-aware manner. By integrating enabling technologies including artificial intelligence, cryo-electron microscopy, and organoid models, we chart a transformative path from single-axis inhibition toward multi-dimensional regulation, ultimately advancing more durable cancer therapies.</p>","PeriodicalId":9690,"journal":{"name":"Cellular Oncology","volume":" ","pages":""},"PeriodicalIF":4.8,"publicationDate":"2026-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13365099/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147970709","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Platelet-neutrophil cooperation in cancer: mechanisms of metastatic niche formation and implications for prognostic stratification and therapy.","authors":"Na Yang, Jiahui Gong, Chang Ge, Gujie Wu, Guopeng Chen, Jingjing Li, Weiwei Tang, Bin Wang, Xisha Li, Lee Sheung, Ziyue Wang, Jiangchao Li","doi":"10.1007/s13402-026-01178-6","DOIUrl":"10.1007/s13402-026-01178-6","url":null,"abstract":"<p><p>Metastasis remains the leading cause of cancer-related mortality and arises from ongoing interactions between malignant cells and their surrounding microenvironment. Among host factors, platelets and neutrophils have emerged as key regulators of metastatic potential. Growing evidence indicates that their coordinated activity-particularly through platelet-neutrophil aggregates（PNAs） and related mixed-cell complexes-forms an important but underrecognized pathway that promotes immune escape, vascular adaptation, and preparation of distant metastatic sites. This combination alters many critical steps in the spreading process. It includes survival within the circulation, evading the immune response, adhesion to the vessel wall and egress, and shifting target tissues. These are the result of collaborative mechanisms such as the use of soluble signaling factors, cell-cell adhesion, the NET-inflammatory response linked to coagulation, and the more persistent changes conferred by EVs and metabolism. Despite substantial progress in defining these mechanisms, important challenges limit clinical translation. Blood count-based platelet and neutrophil markers are not consistently used to assess metastatic risk across cancer types; the factors that control when and how neutrophils change functional states within tumors remain unclear; and therapeutic strategies that target platelet-neutrophil cooperation must carefully balance antimetastatic efficacy with risks such as bleeding and weakened host defense. In this review, we integrate current evidence on platelet-neutrophil-tumor interactions into a unified framework that connects biological mechanisms with clinically measurable indicators and therapeutic entry points. We examine emerging approaches to reduce metastasis supported by platelet-neutrophil interactions and NET-associated processes, consider how these strategies may complement existing cancer treatments, and emphasize the potential of combined biomarker models-such as integrating platelet measures with the neutrophil-to-lymphocyte ratio（NLR）-to improve prognostic assessment and guide future clinical validation.</p>","PeriodicalId":9690,"journal":{"name":"Cellular Oncology","volume":" ","pages":""},"PeriodicalIF":4.8,"publicationDate":"2026-05-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13350642/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147970720","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"NAA50-mediated SLU7 stabilization promotes cisplatin resistance in bladder cancer via regulating MAP3K3 mRNA nuclear export and p38 MAPK activation.","authors":"Benlin Wang, Xianchong Zheng, Qingsheng Hua, Feng Zou, Tao Huang, Jiawei Chen","doi":"10.1007/s13402-026-01219-0","DOIUrl":"10.1007/s13402-026-01219-0","url":null,"abstract":"<p><strong>Background: </strong>Cisplatin-based chemotherapy is first-line for muscle-invasive bladder cancer (BLCA), but chemoresistance remains the primary barrier to clinical efficacy. RNA-binding proteins (RBPs) orchestrate post-transcriptional gene regulation and are increasingly implicated in cancer chemoresistance; however, the role and regulatory mechanism of the splicing factor RBP SLU7 in BLCA cisplatin resistance remain completely unknown.</p><p><strong>Methods: </strong>We analyzed SLU7 expression and clinical prognosis in two independent cisplatin-treated BLCA cohorts (GSE87304, GSE169455). Cisplatin-resistant BLCA cell lines (T24-CIS, UMUC3-CIS) were established for functional assays (CCK-8, qRT-PCR, western blotting). Molecular interactions were validated by RIP-qPCR, immunofluorescence(IF), RNA-FISH, nucleocytoplasmic fractionation, co-immunoprecipitation (co-IP), and mass spectrometry (MS). In vivo therapeutic efficacy was assessed in BLCA xenograft models.</p><p><strong>Results: </strong>SLU7 was significantly upregulated in cisplatin-resistant BLCA cells, and high SLU7 expression independently predicted poor cancer-specific survival (CSS) and recurrence-free survival (RFS) in cisplatin-treated patients. SLU7 knockdown suppressed MAP3K3 expression, inhibited p38 MAPK pathway, and restored cisplatin sensitivity. Mechanistically, SLU7 directly bound MAP3K3 mRNA and promoted its nuclear export-a non-canonical function independent of its canonical splicing activity. MS and Co-IP identified NAA50 as the upstream regulator that catalyzes N-terminal acetylation of SLU7 to prevent its ubiquitin-proteasomal degradation, thereby sustaining SLU7 stability. Pharmacological inhibition of NAA50 with Naa50-IN-1 destabilized SLU7, blocked the MAP3K3-p38 axis, and reversed cisplatin resistance in vitro and in vivo.</p><p><strong>Conclusions: </strong>We uncover a novel NAA50-SLU7-MAP3K3-p38 MAPK regulatory axis that drives cisplatin resistance in BLCA. NAA50-mediated N-terminal acetylation stabilizes SLU7, which in turn facilitates MAP3K3 mRNA nuclear export to activate p38 MAPK signaling. Targeting NAA50 represents a promising therapeutic strategy to overcome cisplatin resistance in BLCA, and SLU7 serves as a predictive biomarker for cisplatin response.</p>","PeriodicalId":9690,"journal":{"name":"Cellular Oncology","volume":" ","pages":""},"PeriodicalIF":4.8,"publicationDate":"2026-05-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13350617/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147970779","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"CTMP-REV7 axis modulates MHC-I antigen presentation via CDK1-AKT crosstalk in MSI-L/MSS colorectal cancer.","authors":"Cheng Gu, Rong He, Xiaolan Yin, Jie Wang, Jing Yang, Jie Gao, Rongjia Xie, Yangyang Geng, Jingyi Lu, Zhui Ke, Zhuqing Liu, Qing Xu","doi":"10.1007/s13402-026-01222-5","DOIUrl":"10.1007/s13402-026-01222-5","url":null,"abstract":"<p><strong>Purpose: </strong>Microsatellite instability-low/microsatellite stable (MSI-L/MSS) colorectal cancer (CRC) exhibits limited responsiveness to immune checkpoint inhibitors due to low tumor mutational burden and insufficient neoantigen generation. Carboxyl-terminal modulator protein (CTMP) is a potential regulatory molecule that may reshape tumor immunogenicity and metabolic patterns, yet its mechanisms in MSI-L/MSS CRC remain poorly understood.</p><p><strong>Methods: </strong>We systematically investigated CTMP function by integrating clinical sample analysis (GEO database, n = 71 paired tissue microarray, and pretreatment specimens from 11 refractory patients receiving anti-PD-1 plus fruquintinib), in vitro experiments (MSS CRC cells with CTMP knockdown/overexpression, assessed for proliferation, mitochondrial function, lipid metabolism, AKT/PD-L1 signaling, and MHC-I/HLA-B expression), proteomic screening (immunoprecipitation-mass spectrometry to identify CTMP-interacting proteins), structural validation (co-immunoprecipitation, AlphaFold Multimer, GST pulldown with truncation/point mutations), and in vivo studies (immunocompetent BALB/c mice with CT26 syngeneic tumors).</p><p><strong>Results: </strong>High CTMP expression and low HLA-B expression were significantly associated with shortened overall survival in patients with MSI-L/MSS colon adenocarcinoma, as well as with progressive disease in an anti-PD-1/fruquintinib resistance cohort. Mechanistically, CTMP orchestrated an immunosuppressive tumor microenvironment by sustaining AKT/PD L1 signaling, suppressing HLA B expression, and promoting fatty acid metabolism. Proteomic screening identified a previously unreported high-affinity interaction between CTMP and REV7, which facilitated CDK1 mediated G2/M progression and further repressed HLA B expression. CTMP knockdown or REV7 overexpression diminished CDK1 activity, induced G2/M phase arrest, and restored HLA B expression in a cGAS signaling-relevant manner. Furthermore, disruption of the CTMP-REV7 signaling axis modulated CDK1 and AKT activity under IFN-γ-driven immune stress, affecting MHC-I expression. In immunocompetent murine models, CTMP knockdown or REV7 overexpression suppressed tumor growth, upregulated HLA B expression, and enhanced intratumoral CD8⁺ T cell infiltration. Moreover, REV7 overexpression synergized with IFN-γ to promote the release of chemokines (CXCL9, CXCL10, TNF α), leading to marked tumor regression in CTMP-KD tumors.</p><p><strong>Conclusions: </strong>We delineate that CTMP drives immune evasion in MSI-L/MSS CRC through a novel CTMP-REV7-CDK1 axis that couples metabolic reprogramming, cell cycle control, and MHC-I antigen presentation, with AKT signaling serving as a critical crosstalk node. These findings implicate this integrated axis as a therapeutic target to restore tumor immunogenicity and overcome immunotherapy resistance in immunologically \"cold\" MSI-L/MSS colorectal cancer.</p>","PeriodicalId":9690,"journal":{"name":"Cellular Oncology","volume":" ","pages":""},"PeriodicalIF":4.8,"publicationDate":"2026-05-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13194846/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147959769","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Machine learning-based integrative analysis identifies CXCL13-driven tertiary lymphoid structures as favorable immune and prognostic features in osteosarcoma.","authors":"Jie Jiang, Jiuhui Xu, Lu Xie, Yiyang Yu, Xin Sun, Xiaojiao Sun, Shen Yang, Huanmin Wang, Tingting Ren, Xiaodong Tang","doi":"10.1007/s13402-026-01226-1","DOIUrl":"10.1007/s13402-026-01226-1","url":null,"abstract":"<p><strong>Background: </strong>Osteosarcoma, an aggressive bone malignancy with limited response to immunotherapy, remains a major clinical challenge. Tertiary lymphoid structures (TLS), as organized ectopic lymphoid aggregates, play a pivotal role in modulating antitumor immune responses. However, their landscape, clinical significance, and molecular determinants in osteosarcoma remain largely unexplored.</p><p><strong>Methods: </strong>TLS were identified in osteosarcoma tissues by immunohistochemistry and multiplex immunofluorescence. Using transcriptomic data from the TARGET, GEO (GSE21257, GSE16091, GSE39055), and PKUPH cohorts, we developed a TLS-based prognostic index (TLSPI) through integrative machine-learning modeling. Functional enrichment, immune infiltration, and immunotherapy response prediction analyses were performed to characterize TLSPI-related biological features. The role of the key TLS-associated gene CXCL13 was validated through immunohistochemistry, single-cell transcriptomic profiling, and in vitro functional experiments.</p><p><strong>Results: </strong>TLS were detected in osteosarcoma and were significantly associated with improved overall survival (p = 0.024). Differential expression and enrichment analyses revealed that TLSPI-related genes were primarily involved in immune activation and antigen presentation pathways. Immune profiling revealed that the low-TLSPI group was characterized by greater immune infiltration and higher expression of immune checkpoint molecules, as well as lower TIDE scores, which indicated greater predicted sensitivity to immunotherapy. CXCL13 was identified as a key TLS-associated gene whose high expression correlated with improved survival. Immunohistochemical analysis confirmed the prognostic significance of CXCL13, while single-cell and functional assays demonstrated its association with B-cell activation within the osteosarcoma microenvironment.</p><p><strong>Conclusion: </strong>This study provides a comprehensive characterization of TLS in osteosarcoma and establishes a TLS-based prognostic index with potential clinical applicability. CXCL13 may serve as a critical mediator linking TLS formation and antitumor immunity, providing potential therapeutic implications for osteosarcoma immunotherapy.</p>","PeriodicalId":9690,"journal":{"name":"Cellular Oncology","volume":" ","pages":""},"PeriodicalIF":4.8,"publicationDate":"2026-05-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13350786/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147959787","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"EZH2 inhibition triggers a context-specific ACSS2-H3K9ac-HK2 metabolic circuit in EZH2 non-mutant solid tumors.","authors":"Xiaoyun Lin, Yue Song, Qingqin Peng, Sanfang Tu, Peidong Yang, Liyan Zhou, Yuhua Li","doi":"10.1007/s13402-026-01221-6","DOIUrl":"https://doi.org/10.1007/s13402-026-01221-6","url":null,"abstract":"<p><strong>Background & objectives: </strong>EZH2 inhibitors show limited efficacy in solid versus hematologic cancers, but the underlying mechanisms are unknown. We investigated whether tumor-type-specific adaptive responses underlie this differential sensitivity.</p><p><strong>Methods: </strong>Glycolytic and acetylation gene signatures were analyzed across multiple transcriptomic datasets. Findings were validated in a panel of solid tumor cell lines using transcriptomic, biochemical (WB, qPCR), cellular (flow cytometry, immunofluorescence), and mechanistic (Cut&Tag, ChIP-qPCR) approaches.</p><p><strong>Results: </strong>Cross-tumor analysis revealed that EZH2/PRC2 inhibition selectively upregulates glycolytic genes and HK2 in EZH2-wildtype solid tumors, distinguishing them from both EZH2-mutant and EZH2-wildtype hematologic malignancies. Time-course analysis confirmed that EZH2 inhibition (GSK126/Tazemetostat) induced progressive HK2 upregulation in the EZH2-wildtype solid tumor cell lines tested, but not in EZH2-mutant hematologic (SU-DHL-4) cells. GSK126 time-dependently increased lactate production in hypoxic B16-F10 cells, and lactate exacerbated Treg polarization under low-glucose conditions. In vivo, this aligned with increased intratumoral Treg infiltration and KI67/HK2 upregulation in GSK126-treated tumors. Dual EZH2/HK2 inhibition synergistically suppressed tumor growth, while reducing Treg accumulation. Mechanistic studies showed that EZH2 inhibition time-dependently upregulated H3K9ac in EZH2-non-mutant solid tumor cells, but not in SU-DHL-4 cells, with Cut&Tag and ChIP-qPCR confirming H3K9ac enrichment at the HK2 promoter in B16-F10 cells. Stratified analysis identified a metabolism-associated acetylation gene set (including ACSS2 and ACLY) as most significantly upregulated in EZH2-non-mutant solid tumors. Functional validation confirmed that EZH2 inhibition-induced HK2 upregulation correlated with ACSS2, but not ACLY, expression in EZH2-non-mutant solid tumor cells. The ACSS2-H3K9ac axis in HK2 regulation was further supported by the finding that ACSS2 knockdown or overexpression correspondingly altered HK2 and H3K9ac levels in a human EZH2-non-mutant solid tumor cell line. We further demonstrated that EZH2 inhibition reduces H3K27me3 enrichment at the ACSS2 promoter, leading to its transcriptional upregulation. Consequently, pharmacological inhibition of ACSS2 reversed GSK126-induced H3K9ac enrichment at the HK2 promoter, downregulated HK2 expression, and synergistically suppressed B16-F10 model growth.</p><p><strong>Conclusion: </strong>We identified a novel ACSS2-H3K9ac-HK2 signaling axis that is characteristically activated in EZH2-non-mutant solid tumors and drives metabolic reprogramming and resistance to EZH2 inhibition.</p>","PeriodicalId":9690,"journal":{"name":"Cellular Oncology","volume":" ","pages":""},"PeriodicalIF":4.8,"publicationDate":"2026-05-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147959821","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}