Cellular Oncology最新文献

{"title":"Postoperative continuous saline bladder irrigation reduces active urinary cancer cells: a prospective study in NMIBC.","authors":"Qi Zhang, Yanhua Du, Dong Wang, Gan Du, Chuanzhen Cao, Xiaomin Yu, Xiaoli Zhang, Peipei Xie, Duo Wan, Li Wen, Hongzhe Shi, Youyan Guan, Li Lu, Xingang Bi, Shujun Cheng, Kaitai Zhang, Wen Zhang, Jianzhong Shou","doi":"10.1007/s13402-025-01059-4","DOIUrl":"10.1007/s13402-025-01059-4","url":null,"abstract":"<p><strong>Purpose: </strong>There is a lack of clinical evidence on whether further clinical strategies are needed after TURBT combined with immediate bladder instillation. This study intends to establish a reliable quantitative assay for active urinary cancer cells (AUCC) and to investigate the clinical efficacy of continuous saline bladder irrigation (CSBI) as a feasible option by analyzing the perioperative AUCC changes in TURBT.</p><p><strong>Methods: </strong>An AUCC assay was developed and its reliability was verified by single-cell whole genome sequencing. Bladder cancer patients (N = 324) diagnosed by cystoscopy and pathologic biopsy and control individuals (N = 92) were included from 2021 to 2023 in the study. Enrolled patients with non-muscle invasive bladder cancer (NMIBC) underwent TURBT followed by immediate bladder instillation of epirubicin, after subgroups received CSBI or not, and AUCCs were tested on the first and fifth postoperative day. The patients were followed up for two years for postoperative recurrence.</p><p><strong>Results: </strong>The AUCC assay achieved good detection accuracy, with a sensitivity of 0.821 and specificity of 0.902. AUCC increased on the first day after TURBT in combination with immediate bladder instillation, regardless of whether or not the patient received CSBI. However, AUCCs decreased more rapidly on the fifth day in patients treated with CSBI, and patients with concomitant risk factors benefited more from CSBI. The two-year follow-up results showed that high-risk patients with complex surgeries could benefit significantly from CSBI.</p><p><strong>Conclusions: </strong>We pioneered a quantitative assay for AUCC and provided laboratory evidence that TURBT causes tumor cell dissemination and CSBI can be a further clinical strategy to reduce the risk of potential recurrence.</p>","PeriodicalId":49223,"journal":{"name":"Cellular Oncology","volume":" ","pages":"991-1003"},"PeriodicalIF":4.9,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12238213/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143991887","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":"Sirtuin 3-mediated delactylation of malic enzyme 2 disrupts redox balance and inhibits colorectal cancer growth.","authors":"Chaoqun Li, Cun Ge, Qingwen Wang, Peng Teng, Heyuan Jia, Surui Yao, Zhaohui Huang","doi":"10.1007/s13402-025-01058-5","DOIUrl":"10.1007/s13402-025-01058-5","url":null,"abstract":"<p><strong>Purpose: </strong>Post-translational modifications, such as lactylation, are emerging as critical regulators of metabolic enzymes in cancer progression. Mitochondrial malic enzyme 2 (ME2), a key enzyme in the TCA cycle, plays a pivotal role in maintaining redox homeostasis and supporting tumor metabolism. However, the functional significance of ME2 lactylation and its regulatory mechanisms remain unclear. This study investigates the role of ME2 K352 lactylation in modulating enzymatic activity, redox balance, and tumor progression.</p><p><strong>Methods: </strong>Immunoprecipitation and western blotting were used to assess ME2 lactylation and its interaction with Sirtuin 3 (SIRT3). Mass spectrometry identified the lactylation site on ME2. Enzymatic activity was measured using NADH production assays. The functional effects of ME2 K352 lactylation were analyzed by measuring ROS levels, NADP⁺/NADPH ratios, metabolic intermediates, and mitochondrial respiration parameters. Cell proliferation was evaluated via CCK-8 and colony formation assays. Xenograft tumor models and Ki-67 immunohistochemical staining were used to assess tumor growth and proliferation in vivo.</p><p><strong>Results: </strong>Mass spectrometry identified K352 as the primary lactylation site on ME2. Sodium lactate treatment enhanced ME2 lactylation and enzymatic activity, while SIRT3-mediated delactylation at K352 reduced ME2 activity, disrupting redox homeostasis. Cells expressing the K352R mutant exhibited elevated ROS levels, higher NADP⁺/NADPH ratios, and altered levels of metabolic intermediates, including increased malate and lactate with reduced pyruvate. Additionally, re-expression of ME2 K352R in HCT116 cells significantly impaired proliferation and colony formation. In vivo, xenograft models demonstrated that ME2 K352R expression suppressed tumor growth, as evidenced by reduced tumor volume, weight, and Ki-67 staining.</p><p><strong>Conclusions: </strong>This study reveals that ME2 K352 lactylation is a critical regulatory mechanism that modulates enzymatic activity, mitochondrial function, and tumor progression. SIRT3-mediated delactylation of ME2 K352 disrupts redox homeostasis and inhibits tumor growth. These findings highlight the potential of targeting ME2 lactylation as a therapeutic strategy in cancer treatment.</p>","PeriodicalId":49223,"journal":{"name":"Cellular Oncology","volume":" ","pages":"979-990"},"PeriodicalIF":4.9,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12238175/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143796852","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":"SPTSSA facilitates gastric cancer progression with modulating PD-L1 in immunomicroenvironment through Wnt/β-catenin pathway.","authors":"Pingping Sun, Weiwei Qin, Haiyan Xu, Hang Yin, Lei Yang, Xiaojing Zhang, Xiaoxia Jin, Qiang Xu, Han Wu, Xiaoling Kuai, Lizhou Jia, Jianfei Huang, Yao Wang","doi":"10.1007/s13402-025-01072-7","DOIUrl":"10.1007/s13402-025-01072-7","url":null,"abstract":"<p><strong>Purpose: </strong>Gastric cancer (GC) remains a considerable global health concern, underscoring the necessity for dependable biomarkers for its diagnosis and treatment. This investigation seeks to investigate the clinical predictive value and functional roles of SPTSSA in GC.</p><p><strong>Methods: </strong>The mRNA expression of SPT family molecules was analyzed through bioinformatics approaches. In vitro and in vivo studies assessed the function of SPTSSA in the malignant progression of GC. Additionally, SPTSSA protein levels in GC tissues and peripheral venous blood were measured using immunofluorescence staining and enzyme-linked immunosorbent assay, respectively. The link between SPTSSA expression and immune cell infiltration in GC was also evaluated by multiplex immunohistochemistry.</p><p><strong>Results: </strong>Patients exhibiting elevated levels of SPTSSA mRNA experienced the poorest prognosis in comparison to other members of the SPT family. SPTSSA overexpression enhanced the malignant phenotype of GC in in vitro and in vivo experiments. Mechanistically, SPTSSA facilitated the accumulation of β-catenin and the transcription of programmed death ligand 1 (PD-L1) through the Wnt signaling pathway. SPTSSA protein levels were markedly elevated in both GC tissues and peripheral venous blood. Furthermore, increased expression of SPTSSA was linked to a reduction in CD8⁺ T cell infiltration, heightened M2 macrophage infiltration, and increased PD-L1 expression in GC patients.</p><p><strong>Conclusion: </strong>SPTSSA promotes GC progression by modulating PD-L1 expression in immunomicroenvironment via the Wnt signaling pathway. Consequently, SPTSSA emerges as a promising new prognostic indicator and a potential therapeutic target for GC management.</p>","PeriodicalId":49223,"journal":{"name":"Cellular Oncology","volume":" ","pages":"1127-1144"},"PeriodicalIF":4.9,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12238128/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144267791","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":"GMPS inhibits the proliferation and migration of non-small cell lung cancer via the regulation of the DNMT 1/SERPINB2 axis.","authors":"Tingting Guo, Lei Liu, Lingyan Zeng, Ying Yang, Tingting Song, Huachang Zhao, Zhixin Qiu","doi":"10.1007/s13402-025-01078-1","DOIUrl":"10.1007/s13402-025-01078-1","url":null,"abstract":"<p><strong>Background: </strong>Non-small cell lung cancer (NSCLC) mainly includes lung squamous cell carcinoma and lung adenocarcinoma, and its extremely high morbidity and mortality are the main causes of poor prognosis in NSCLC patients. Therefore, it is particularly important to study the mechanisms associated with tumor proliferation and metastasis and explore new molecular targets of NSCLC. Studies have shown that Guanosine monophosphate synthase (GMPS) may serve as a potential drug target, but its biological function and molecular mechanism in NSCLC are still unknown. Therefore, it is urgently needed to investigate the molecular mechanisms of GMPS.</p><p><strong>Methods: </strong>We first analyzed 30 cases of lung adenocarcinoma, lung squamous carcinoma and adjacent tissues; Then, lentiviral technology was used to construct overexpressed or knocked out cell lines to verify the function of GMPS. Then, RNA sequencing and Western blot experiments were carried out in animal experiments to explore the mechanism of GMPS. Our experimental results suggest that GMPS plays an important role in the progression of NSCLC.</p><p><strong>Results: </strong>We found that GMPS was highly expressed in lung adenocarcinoma and lung squamous cell carcinoma tissues, and was associated with poor prognosis of patients. Down-regulation of GMPS inhibits tumor progression. And GMPS promotes lung cancer cell migration through the SERPINB2-uPA axis, and DNMT1 is an intermediate factor in GMPS regulating SERPINB2 expression. Our experimental results show that GMPS expression is associated with lung cancer invasion and migration.</p><p><strong>Conclusions: </strong>Our findings revealed the correlation between GMPS and the prognosis of NSCLC at the tissue level. Secondly, GMPS can promote the progression of NSCLC. The molecular mechanism of GMPS affecting the metastasis of lung cancer cells was elucidated. These findings highlight the important role of GMPS in NSCLC, so as to provide new insights for the identification of new targets and lay a theoretical foundation for the clinical application of GMPS.</p>","PeriodicalId":49223,"journal":{"name":"Cellular Oncology","volume":" ","pages":"1145-1158"},"PeriodicalIF":4.8,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12238071/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144267790","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":"Fbxo2 inhibits cell proliferation, migration and invasion by the ubiquitin-mediated degradation of WEE1 in renal cell carcinoma.","authors":"Lixia Wang, Yachen Zang, Chuanlai Yang, Ming Xu, Guangcheng Dai, Han Xiang, Jia Ma, Zhiwei Wang, Xiaolong Liu, Boxin Xue","doi":"10.1007/s13402-025-01091-4","DOIUrl":"https://doi.org/10.1007/s13402-025-01091-4","url":null,"abstract":"<p><strong>Background: </strong>Fbxo2 is part of the SKP1-Cullin-F-box (SCF) E3 ubiquitin ligase complex. While increasing evidence indicates that Fbxo2 influences tumorigenesis and progression in various human malignancies, its biological importance and molecular mechanisms in renal cell carcinoma (RCC) are poorly understood.</p><p><strong>Methods: </strong>Bioinformatic analysis of publicly available datasets was utilized to determine the association between Fbxo2 expression and survival in RCC patients. CCK8, colony-formation, and EdU assays were carried out to measure cell proliferation after Fbxo2 modulation in RCC cells. Coimmunoprecipitation, mass spectrometry, Western blotting, and ubiquitin assays were performed to explore the molecular mechanism of Fbxo2-involved tumorigenesis in RCC.</p><p><strong>Results: </strong>Fbxo2 suppresses RCC cell growth. Moreover, higher Fbxo2 expression was positively associated with improved overall survival in RCC patients. In RCC, Fbxo2 inhibition increased cell motility and proliferation and inhibited cell apoptosis. WEE1 was identified as a novel substrate of Fbxo2 in RCC. Fbxo2 binds to the kinase domain of WEE1 through its FBA domain. Consistently, in xenograft mouse models, Fbxo2 knockdown increased tumor growth, whereas WEE1 depletion partially abolishes the tumorigenic effects caused by Fbxo2 silencing in vivo.</p><p><strong>Conclusions: </strong>Our research revealed that Fbxo2 impedes the progression of RCC by interacting with WEE1, promoting its ubiquitination and degradation. Therefore, targeting the Fbxo2/WEE1 axis may represent a promising therapeutic strategy for treating RCC.</p>","PeriodicalId":49223,"journal":{"name":"Cellular Oncology","volume":" ","pages":""},"PeriodicalIF":4.9,"publicationDate":"2025-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144660879","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}

{"title":"Novel insights into lncRNAs as key regulators of post-translational modifications in cancer: mechanisms and therapeutic potential.","authors":"Yaqian Han, Shizhen Li, Linda Oyang, Shiwen Cui, Wenlong Zhang, Wenjuan Yang, Mingjing Peng, Shiming Tan, Longzheng Xia, Jinguan Lin, Xuemeng Xu, Nayiyuan Wu, Xianjie Jiang, Qiu Peng, Yanyan Tang, Xia Luo, Qianjin Liao, Yujuan Zhou","doi":"10.1007/s13402-025-01086-1","DOIUrl":"https://doi.org/10.1007/s13402-025-01086-1","url":null,"abstract":"<p><p>Abnormal post-translational modifications (PTMs) play a crucial role in tumor initiation and progression. However, the mechanisms by which lncRNAs, as emerging epigenetic regulators, mediate PTMs remain largely unexplored. This review provides a comprehensive summary of the latest research on the interplay between lncRNA-mediated PTMs and tumorigenesis. We delve into the molecular mechanisms underlying these interactions, focusing on how lncRNAs regulate PTMs to influence tumor progression. We place particular emphasis on the lncRNA-mediated PTMs as a driver of therapeutic resistance, shedding light on its potential as a novel target for cancer intervention. Furthermore, we highlight the therapeutic potential of targeting lncRNA-PTM networks, emphasizing novel RNA-based strategies and their clinical relevance in cancer treatment. We believe that an in-depth understanding of lncRNA-mediated PTMs could uncover novel therapeutic targets, paving the way for innovative approaches in cancer diagnosis and treatment.</p>","PeriodicalId":49223,"journal":{"name":"Cellular Oncology","volume":" ","pages":""},"PeriodicalIF":4.9,"publicationDate":"2025-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144545786","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}

{"title":"Cancer-associated fibroblast-derived extracellular vesicles facilitate metastasis in hepatocellular carcinoma by delivering CTGF.","authors":"Mengli Zheng, Luyao Liu, Haochen Cui, Yuchong Zhao, Wei Chen, Shuya Bai, Wang Peng, Yun Wang, Yanling Li, Ronghua Wang, Xiju Wang, Bin Cheng","doi":"10.1007/s13402-025-01085-2","DOIUrl":"https://doi.org/10.1007/s13402-025-01085-2","url":null,"abstract":"<p><strong>Purpose: </strong>The tumor microenvironment (TME) plays a crucial role in cancer progression. Cancer-associated fibroblasts (CAFs) are key components of the TME and play critical roles in tumor development and metastasis. However, the mechanisms by which CAFs influence hepatocellular carcinoma (HCC) metastasis are not fully understood.</p><p><strong>Methods: </strong>Extracellular vesicles (EVs) from CAFs and normal fibroblasts (NFs) were characterized via western blotting, transmission electron microscopy, and nanoparticle tracking analysis. An iTRAQ-based proteomic sequencing analysis was conducted to quantify proteins in the EVs from these cells. Colony formation assays and Transwell assays were used to assess tumor cell proliferation and migration. Xenograft tumor models were established in nude mice to evaluate tumor progression in vivo. Coimmunoprecipitation and molecular docking were performed to explore the interactions between CTGF and Notch1.</p><p><strong>Results: </strong>A high CAF abundance is associated with poor prognosis in HCC patients. EVs from CAFs significantly enhanced the proliferative and invasive abilities of HCC cells in vitro and in vivo. Connective tissue growth factor (CTGF) was found to be highly upregulated in CAF-derived EVs, and CTGF knockdown in CAF-derived EVs attenuated their tumor-promoting capacities. Mechanistically, CTGF derived from CAF-EVs activated the Notch1/Snail1 signaling pathway in recipient cells via interaction with the Notch1 receptor, enhancing HCC cell proliferation and invasion. Furthermore, high CTGF expression was significantly correlated with poor clinicopathological features in HCC patients.</p><p><strong>Conclusion: </strong>Our findings revealed that CTGF derived from CAF-EVs promoted the proliferation and invasion of HCC cells via activation of the Notch1/Snail1 pathway, highlighting CTGF derived from CAF-EVs as a prognostic biomarker and therapeutic target in HCC.</p>","PeriodicalId":49223,"journal":{"name":"Cellular Oncology","volume":" ","pages":""},"PeriodicalIF":4.9,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144545785","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}

{"title":"Lipid metabolism in cancer stem cells: reprogramming, mechanisms, crosstalk, and therapeutic approaches.","authors":"Haksoo Lee, Sujin Park, Jongwon Lee, Chaeyoung Lee, Hyunkoo Kang, JiHoon Kang, Jung Sub Lee, Eunguk Shin, HyeSook Youn, BuHyun Youn","doi":"10.1007/s13402-025-01081-6","DOIUrl":"https://doi.org/10.1007/s13402-025-01081-6","url":null,"abstract":"<p><p>Cancer stem cells (CSCs) are a highly plastic subpopulation of tumor cells with capabilities for self-renewal, therapy resistance, and metastasis. Recent evidence highlights lipid metabolic reprogramming as a central mechanism supporting these malignant traits. This review synthesizes current findings on key lipid metabolic processes in CSCs-including lipid uptake via CD36, intracellular storage in lipid droplets, de novo fatty acid synthesis by fatty acid synthase (FASN), fatty acid oxidation (FAO) regulated by carnitine palmitoyltransferase 1A (CPT1A), and cholesterol biosynthesis through the mevalonate pathway. Although many of these pathways are active in bulk cancer cells, CSCs demonstrate greater functional reliance on them, leading to enhanced survival, redox balance, and adaptation to therapy. These metabolic preferences vary by cancer type, underscoring the need for context-specific approaches. Moreover, stromal components of the tumor microenvironment (TME), such as cancer-associated fibroblasts, adipocytes, and mesenchymal stem cells, modulate CSC lipid metabolism through paracrine signals and substrate transfer, reinforcing CSC maintenance and drug resistance. Therapeutic strategies targeting lipid metabolism-such as inhibition of SCD1, CPT1A, and HMG-CoA reductase-have shown promising preclinical results in selectively depleting CSC populations and sensitizing tumors to treatment. However, challenges remain in preserving normal stem cell function, which also depends on lipid pathways. This review underscores the emerging significance of lipid metabolism as both a hallmark and vulnerability of CSCs, offering opportunities for novel targeted cancer therapies.</p>","PeriodicalId":49223,"journal":{"name":"Cellular Oncology","volume":" ","pages":""},"PeriodicalIF":4.9,"publicationDate":"2025-06-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144530709","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}

{"title":"Trends in immunotherapy for oral squamous cell carcinoma.","authors":"Ningning Xue, Ying Wang, Ziyuan Wang, Xin Zeng, Jiongke Wang, Xuefeng Zhang","doi":"10.1007/s13402-025-01068-3","DOIUrl":"https://doi.org/10.1007/s13402-025-01068-3","url":null,"abstract":"<p><p>Oral squamous cell carcinoma (OSCC) is a prevalent malignant tumor of the head and neck, characterized by an immunosuppressive tumor microenvironment. The traditional treatment approach for OSCC typically involves a combination of surgical resection, radiotherapy, and chemotherapy. Over the last few decades, the 5-year overall survival rate for OSCC has remained relatively stagnant at approximately 50-60%. Recently, the rapid progress in immunotherapy has revolutionized OSCC treatment, particularly through the use of immune checkpoint blockade therapies. Nivolumab and pembrolizumab have been approved by the US Food and Drug Administration (FDA) for the immunotherapy of head and neck squamous cell carcinoma (HNSCC). Additionally, other modalities such as costimulatory agonists, adoptive cellular therapy, cytokine immunotherapy, cancer vaccines, and photoimmunotherapy have shown promising feasibility and efficacy in relevant preclinical and clinical studies. Future directions for OSCC immunotherapy include precision medicine and research into the pathogenesis of immune-related adverse events (irAEs) and standardization of management methods. Furthermore, nano-immunotherapy is expected to be a significant trend in OSCC treatment. Clinical trial number Not applicable.</p>","PeriodicalId":49223,"journal":{"name":"Cellular Oncology","volume":" ","pages":""},"PeriodicalIF":4.9,"publicationDate":"2025-06-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144477495","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}

{"title":"Synthetic NKG2D receptor (SNR) armored CAR-T cells overcome antigen heterogeneity of solid tumor.","authors":"Minmin Sun, Linke Bian, Hongye Wang, Xin Liu, Yantao Li, Zhaorong Wu, Shuangshuang Zhang, Ruidong Hao, Hong Xin, Bo Zhai, Xuemei Zhang, Yuanguo Cheng","doi":"10.1007/s13402-025-01066-5","DOIUrl":"https://doi.org/10.1007/s13402-025-01066-5","url":null,"abstract":"<p><strong>Background: </strong>CAR-T cell therapy has demonstrated remarkable success in hematologic malignancies; however, its effectiveness against solid tumors remains limited due to tumor antigen heterogeneity. NKG2DLs, including MICA/B and the ULBP family, are stress-induced molecules frequently upregulated on the surface of tumor cells and components of the tumor microenvironment, providing attractive targets for immunotherapy. To broaden the targeting capability beyond conventional Claudin18.2-directed CAR-T cells, we engineered a Synthetic NKG2D Receptor (SNR). The SNR comprises the extracellular domain of NKG2D fused with the intracellular signaling domains of DAP10 and DAP12, enabling effective targeting of NKG2D ligands (NKG2DLs).</p><p><strong>Methods: </strong>Expression of NKG2DLs and CLDN18.2 were detected by immunohistochemistry on a gastric cancer tissue microarray. We designed SNR CAR-T cells by linking CLDN18.2 CAR with SNR by a 2A self-cleaving peptide. We assessed their cytotoxicity, tumor infiltration, persistence, and antitumor efficacy using in vitro assays, patient-derived xenograft (PDX) models, and murine syngeneic models. Additionally, transcriptomic analysis and flow cytometry were performed to evaluate exhaustion and memory markers.</p><p><strong>Results: </strong>SNR CAR-T cells demonstrated enhanced cytotoxicity against tumor cells with heterogeneous CLDN18.2 expression, effectively lysing both CLDN18.2-positive and NKG2DL-positive tumor cells in vitro. In PDX and murine models, SNR CAR-T cells exhibited superior antitumor efficacy, leading to significant tumor regression and CAR-T expansion compared to conventional CAR-T cells. Furthermore, SNR CAR-T cells displayed reduced expression of exhaustion markers and increased expression of memory-associated markers. Enhanced tumor infiltration, proliferation and cytotoxicity within the tumor microenvironment, and a reduced presence of myeloid-derived suppressor cells (MDSCs) and tumor neovasculature were observed. Importantly, SNR CAR-T cell therapy was well-tolerated, with no significant toxicity noted in all the treated animals.</p><p><strong>Conclusion: </strong>The SNR CAR-T cell approach addresses tumor antigen heterogeneity and suppressive tumor microenvironment, offering a promising therapeutic strategy for solid tumors and paving the way for its future clinical applications.</p>","PeriodicalId":49223,"journal":{"name":"Cellular Oncology","volume":" ","pages":""},"PeriodicalIF":4.9,"publicationDate":"2025-06-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144327502","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}