Cancer Biology & Therapy最新文献

{"title":"UCHL5 suppresses thyroid carcinoma progression via ZRANB1 stabilization and ferroptosis regulation.","authors":"Wenxia Xiao, Yu Ding, Xuesuo Wu, Fenglian Que, Baozhi Wang, Shanshan Hong, Fenghua Zhang","doi":"10.1080/15384047.2026.2663610","DOIUrl":"10.1080/15384047.2026.2663610","url":null,"abstract":"<p><strong>Objective: </strong>This study investigated the role of UCHL5 in thyroid carcinoma (THCA) progression, focusing on its tumor-suppressive mechanisms and regulation of ferroptosis.</p><p><strong>Methods: </strong>We performed multi-omics analysis of TCGA and GEO datasets and validated the findings using clinical samples. The CRISPR/Cas9-mediated knockout and stable overexpression in THCA cell lines were constructed, followed by comprehensive functional assays including co-immunoprecipitation (Co-IP), ubiquitination analysis, xenograft tumor models, and ferroptosis sensitivity tests using erastin/ferrostatin-1 with BODIPY C11 lipid ROS measurement. Weighted gene co-expression network analysis (WGCNA) was performed to identify hub genes and to analyze associated pathways.</p><p><strong>Results: </strong>Clinical data revealed significant downregulation of UCHL5 in advanced thyroid cancers, particularly in lymph node metastases. UCHL5 knockout markedly accelerated cell proliferation and xenograft tumor growth, while its overexpression suppressed both. Mechanistically, we identified a direct interaction between UCHL5 and ZRANB1 through co-IP, with UCHL5 extending the protein half-life of ZRANB1 by over 2-fold. In ferroptosis regulation, erastin treatment (10 μM) revealed that UCHL5 overexpression enhanced sensitivity, while UCHL5 knockout conferred significant protection, accompanied by altered GSH levels, Fe²⁺ accumulation, and lipid ROS production. Western blot analysis revealed that UCHL5 upregulated ZRANB1 and downregulated SLC7A11/GPX4 expression.</p><p><strong>Conclusion: </strong>This study demonstrates that UCHL5 acts as a critical tumor suppressor in thyroid cancer by stabilizing ZRANB1 through deubiquitination and regulating ferroptosis via the SLC7A11-GPX4 axis.</p>","PeriodicalId":9536,"journal":{"name":"Cancer Biology & Therapy","volume":"27 1","pages":"2663610"},"PeriodicalIF":5.7,"publicationDate":"2026-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13123060/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147763285","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Identification of coilin in bone marrow as a potential neuroblastoma tumor progression marker transcriptionally regulated by MYCN.","authors":"Zhixia Yue, Lan Li, Shuguang Liu, Chao Gao, Sidou He, Tianlin Xue, Wen Zhao, Chunying Cui, Chao Duan, Yan Su","doi":"10.1080/15384047.2025.2600709","DOIUrl":"10.1080/15384047.2025.2600709","url":null,"abstract":"<p><strong>Background: </strong>Current risk stratification for neuroblastoma (NB) relies on limited markers like MYCN amplification. Coilin, a key Cajal body component, regulates cellular processes. This study investigates whether coilin expression in bone marrow (BM) serves as a predictive biomarker for NB progression and elucidate its function in this disease.</p><p><strong>Methods: </strong>The functions and molecular mechanisms of coilin were investigated by employing cell lines and animal models. Coilin mRNA levels in patient samples were measured by RT-PCR, and their relationships with clinicobiological characteristics and outcomes were analyzed.</p><p><strong>Results: </strong>Cisplatin induced dramatic changes of coilin distribution and expression. Databases showed that high expression of coilin exerted predictive values for poor outcome in NB. Coilin promoted proliferation <i>in vitro</i> and <i>in vivo</i>. Knockdown of coilin expression inhibited cell migration and invasion, promoted apoptosis and increased the Cisplatin drug sensitivity. Moreover, coilin activates p53/p21 signaling pathway and was a direct target of MYCN. Analysis of BM samples demonstrated that high expression of coilin was obviously associated with adverse clinical biological features. Importantly, the levels of coilin at diagnosis were markedly higher than those at the time before maintenance treatment in the exact paired patients. Survival analysis presented that high coilin expression in BM is associated with poor prognosis.</p><p><strong>Conclusions: </strong>A novel and accessible coilin-targeted liquid biopsy method was developed, capable of detecting minimal residual disease (MRD) in early-stage NB and predicting disease progression and recurrence. Coilin was transcriptionally regulated by MYCN, offering potential avenues for the development of novel drugs or intervention strategies.</p>","PeriodicalId":9536,"journal":{"name":"Cancer Biology & Therapy","volume":"27 1","pages":"2600709"},"PeriodicalIF":4.6,"publicationDate":"2026-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12754697/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145803260","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Stress-specific 14-3-3-client modules in digestive cancers: an evidence-graded review of adaptive survival and therapy resistance.","authors":"Rudong Li, Zhipeng Zhao, Xudong Wang","doi":"10.1080/15384047.2026.2710413","DOIUrl":"10.1080/15384047.2026.2710413","url":null,"abstract":"<p><p>14-3-3 proteins are phosphoserine- and phosphothreonine-binding adaptors that regulate client localization, stability and activity under cellular stress. This narrative review synthesizes stress-specific 14-3-3-client modules in gastric, colorectal, pancreatic, hepatocellular and biliary cancers. Modules were classified as high, moderate, early/context-dependent or background according to mechanistic evidence, functional perturbation, client mapping, treatment-state validation and clinical association. In gastric cancer, G3BP stress granule assembly factor 1 (G3BP1) cooperates with YWHAZ-encoded 14-3-3ζ to retain pro-apoptotic Bax in the cytoplasm. In colorectal cancer, SFN-encoded 14-3-3σ restricts Yin Yang 1 (YY1), sustaining the unfolded protein response and chemotherapy tolerance. In pancreatic cancer, SFN-encoded 14-3-3σ interacts with Yes-associated protein 1 (YAP1) to promote ribonucleotide reductase expression and gemcitabine resistance. In hepatobiliary cancers, SFN-related modules support anoikis resistance but remain context dependent. Clinically relevant units are stress-specific 14-3-3-client complexes rather than total 14-3-3 expression.</p>","PeriodicalId":9536,"journal":{"name":"Cancer Biology & Therapy","volume":"27 1","pages":"2710413"},"PeriodicalIF":5.7,"publicationDate":"2026-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13418467/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148599372","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"MBD2 suppresses SFRP1 expression and promotes colorectal cancer development by blocking MED19 binding to its methylated promoter.","authors":"Xiuji Huang, Tingting Luo, Lingling Ke, Shaoting Guan, Huixian Wu, Bo Li, Yuting Liu, Jian Qi","doi":"10.1080/15384047.2026.2667568","DOIUrl":"10.1080/15384047.2026.2667568","url":null,"abstract":"<p><strong>Background: </strong>The Wnt signaling pathway antagonist SFRP1 is frequently silenced by promoter DNA hypermethylation in colorectal cancer (CRC). MBD2, a DNA methylation reader, is known to contribute to SFRP1 epigenetic silencing. Previous work showed that MBD2 critically suppresses SFRP1 expression without altering promoter methylation, though the underlying mechanism remained unclear. Elucidating how DNA methylation silences tumor suppressor genes, such as <i>SFRP1</i>, could reveal novel therapeutic targets with significant clinical potential.</p><p><strong>Methods: </strong>MBD2 was inhibited in CRC models using either siRNA or a small molecule inhibitor (KCC07). The effects on SFRP1 and β-catenin expression, Wnt pathway activity, cell proliferation, and apoptosis were assessed. Tumor growth was also evaluated in vivo. Mechanistic studies investigated the role of MBD2 in mediating MED19 binding to the SFRP1 promoter and its impact on RNA polymerase II CTD-S7 phosphorylation.</p><p><strong>Results: </strong>The IC50 of KCC07 was 23.25 μM in SW480 cells, 26.83 μM in HCT116 cells, and 39.66 μM in NCM460 cells. Inhibition of MBD2, either genetically or pharmacologically with KCC07, upregulated SFRP1 expression, downregulated β-catenin, and suppressed the Wnt pathway. KCC07 treatment also inhibited CRC cell proliferation, promoted apoptosis, and suppressed tumor growth in vivo. Mechanistically, MBD2 was found to silence SFRP1 by blocking MED19 binding to its promoter, which subsequently reduced RNA polymerase II CTD-S7 phosphorylation and impaired transcription.</p><p><strong>Conclusions: </strong>This study reveals a novel mechanism whereby DNA methylation suppresses gene expression via MBD2, independent of changes in methylation status, by disrupting MED19 binding and subsequent transcription. Targeting MBD2 represents a promising therapeutic strategy for colorectal cancer.</p>","PeriodicalId":9536,"journal":{"name":"Cancer Biology & Therapy","volume":"27 1","pages":"2667568"},"PeriodicalIF":5.7,"publicationDate":"2026-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13155016/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147834098","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Efficacy and safety profiles of CDK4/6 inhibitor in patients with hormone receptor-positive and human epidermal growth factor receptor 2-negative (HR+/HER2-) advanced breast cancer (ABC) from the high-altitude <i>versus</i> low-altitude regions: a multi-center retrospective study.","authors":"Yujing Tan, Yinyin Ye, Weihong Zhao, Hangfang Jiang, Jiani Wang, Jiuda Zhao, Fei Ma","doi":"10.1080/15384047.2026.2683159","DOIUrl":"10.1080/15384047.2026.2683159","url":null,"abstract":"<p><strong>Background: </strong>CDK4/6 inhibitors (CDK4/6i) represent the standard treatment for HR+/HER2- ABC. The study assessed the efficacy and safety profiles of CDK4/6i from first-line (1 L) to third-line (3 L) in patients with HR+/HER2- ABC from high-altitude <i>versus</i> low-altitude regions.</p><p><strong>Materials: </strong>HR+/HER2- ABC patients who received CDK4/6i were enrolled from four cancer centers in China.</p><p><strong>Results: </strong>A total of 350 patients were eligible for the study, involving 268 from the low-altitude group and 82 from the high-altitude group. In the 1 L, objective response rate (ORR, 23.7% <i>versus</i> 5.3%, <i>p</i> = 0.01), clinical benefit rate (CBR, 88.1% <i>versus</i> 57.9%, <i>p</i> < 0.0001), and median progression-free survival (PFS, 42.1 months <i>versus</i> 15.2 months, <i>p</i> = 0.001) in the low-altitude group were superior to those in the high-altitude group. In the second-line treatment, CBR in the low-altitude group was higher (87.5% <i>versus</i> 48.0%, <i>p</i> = 5.3E-4). The ORR (20.8% <i>versus</i> 4.0%, <i>p</i> = 0.08) and PFS (15.8 months <i>versus</i> 8.2 months, <i>p</i> = 0.11) were not significantly different. In the 3 L settings, no significance was observed in PFS (5.2 months <i>versus</i> 5.8 months, <i>p</i> = 0.45), ORR (16.5% <i>versus</i> 21.1%, <i>p</i> = 0.74), and CBR (47.1% <i>versus</i> 47.4%, <i>p</i> = 1). The incidence of anemia (43.9% <i>versus</i> 28.3%, <i>p</i> = 0.01), ≥grade 3 anemia (9.8% <i>versus</i> 1.9%, <i>p</i> = 3.10E-03), ≥grade 3 thrombocytopenia (9.8% <i>versus</i> 1.9%, <i>p</i> = 3.10E-03), ≥grade 3 ALT (6.1% <i>versus</i> 0.4%, <i>p</i> = 3.10E-03) and AST (7.3% <i>versus</i> 1.9%, <i>p</i> = 0.02) dysfunction occurred more frequently in the high-altitude group.</p><p><strong>Conclusion: </strong>Patients with HR+/HER2- ABC in the high-altitude region experienced inferior survival outcomes and individualized tolerability to CDK4/6i, which may inform scientific research and the management of CDK4/6i in Chinese patients with HR+/HER2- ABC.</p>","PeriodicalId":9536,"journal":{"name":"Cancer Biology & Therapy","volume":"27 1","pages":"2683159"},"PeriodicalIF":5.7,"publicationDate":"2026-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13313246/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148306933","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Molecular interplay of insulin resistance and cancer: advances in monoclonal antibody therapeutics.","authors":"Sivakumar S Moni, Fatma Ayish, Shaqraa Musawi, Ahmad Salawi, Mohamed Eltaib Elmobark, Aamena Jabeen, Mawada Abubaker Abdelgadir Mohammed, Maha Jubran Aqdi, Maram Yahya Aziabi, Raneem Hafiz Harbi, Al Anoud Mohammed Ghazwani, Sara Hassan Almalki, Raghad Abdullah Sharif, Hanin Mohammed Ezzi, Hind Mohammed Suwaydi, Taif E Alajam, Safa Abdullah Awaji, Amwaj Yahya Marwai Nammazi, Amirah Mosa Maashi, Nesreen Ibrahim Faqiri, Atyaf Saleh Ahmed Dohal, Nahlah Salah Burayk","doi":"10.1080/15384047.2026.2708386","DOIUrl":"10.1080/15384047.2026.2708386","url":null,"abstract":"<p><p>Insulin resistance (IR) is involved in the development, progression, and treatment resistance of cancer. Apart from contributing to obesity and type 2 diabetes, IR leads to hyperinsulinemia, disruption of insulin-like growth factor signaling, chronic inflammation, and metabolic remodeling, which fosters a pro-tumorigenic milieu. These changes stimulate the PI3K-Akt-mTOR, MAPK, JAK-STAT, and NF-κB pathways, which increase proliferation, survival, angiogenesis, immune escape, and metastasis. IR also modifies the tumor microenvironment (TME) and dampens anti-tumor immunity. IGF-1R, IL-6, IL-1β, TNF-<i>α</i>, PD-1, PD-L1, and CTLA-4 monoclonal antibodies could be beneficial by inhibiting inflammatory and oncogenic pathways and reinitiating immune surveillance. Tumor resistance and heterogeneity are significant obstacles. This is a structured narrative review of the molecular connections, antibody treatments, translational obstacles, and future refined approaches in oncology.</p>","PeriodicalId":9536,"journal":{"name":"Cancer Biology & Therapy","volume":"27 1","pages":"2708386"},"PeriodicalIF":5.7,"publicationDate":"2026-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13432918/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148599355","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Statement of Retraction: Didox (A Novel Ribonucleotide Reductase Inhibitor) Overcomes bc.l-2 Mediated Radiation Resistance in Prostate Cancer Cell Line PC-3.","authors":"","doi":"10.1080/15384047.2025.2607914","DOIUrl":"10.1080/15384047.2025.2607914","url":null,"abstract":"","PeriodicalId":9536,"journal":{"name":"Cancer Biology & Therapy","volume":"27 1","pages":"2607914"},"PeriodicalIF":4.6,"publicationDate":"2026-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12754698/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145803291","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Interaction between ZMIZ2 and AR promotes prostate cancer proliferation in vitro and in vivo.","authors":"Jing-Ze Yu, Xiao-Pan Zou, Xiao-Bei Wu, Yang-Yang Cui, Tan Wei, Jun Di, Xue-Chao Feng, Xiao-Meng Li","doi":"10.1080/15384047.2025.2604936","DOIUrl":"10.1080/15384047.2025.2604936","url":null,"abstract":"<p><strong>Background: </strong>ZMIZ2, an androgen receptor (AR) transcriptional co-regulator, promotes prostate cancer (PCa) cell proliferation by interacting with AR to upregulate genes associated with cell proliferation; however, its specific cooperative mechanisms remain unclear. This study aims to elucidate these mechanisms.</p><p><strong>Materials and methods: </strong>We analyzed the expression level and prognostic significance of ZMIZ2 in PCa using bioinformatics methods. ZMIZ2 expression and its correlation with the Gleason score were analyzed using clinical samples. LNCaP cells with ZMIZ2 overexpression or AR knockdown were employed to evaluate cell proliferation. RNA-seq, qPCR, Western blot, and co-immunoprecipitation were used to explore the molecular mechanisms. In vivo xenograft models were utilized to validate the effects.</p><p><strong>Results: </strong>ZMIZ2 expression was significantly higher in PCa tissues and positively correlated with the Gleason score. Overexpressing ZMIZ2 robustly promoted LNCaP cell growth, but this promoting effect was dramatically lessened in the absence of AR expression. Mechanistically, ZMIZ2 recruited multiple acetyltransferases and formed a transcriptional complex with the <i>N</i>-terminal domain of AR, which bound to the promoters of cell cycle-related genes CDK1, CCNA2, and CCNE2, leading to upregulated transcription. Both in vitro cell culture experiments and in vivo models supported ZMIZ2's role in promoting proliferation.</p><p><strong>Conclusion: </strong>ZMIZ2 promotes PCa cell proliferation through the AR signaling pathway by regulating key cell-cycle genes, highlighting it as a potential therapeutic target.</p>","PeriodicalId":9536,"journal":{"name":"Cancer Biology & Therapy","volume":"27 1","pages":"2604936"},"PeriodicalIF":4.6,"publicationDate":"2026-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12758332/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145809586","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Evaluating carboplatin and PARP inhibitor combination efficacy using high-grade serous carcinoma spheroids and organoids.","authors":"Emily J Tomas, Jennifer Davis, Yudith Ramos Valdes, Trevor G Shepherd","doi":"10.1080/15384047.2025.2611602","DOIUrl":"10.1080/15384047.2025.2611602","url":null,"abstract":"<p><strong>Background: </strong>PARP inhibitors (PARPis) are new targeted agents that exploit homologous recombination DNA repair deficiencies (HRDs), which are present in 50% of high-grade serous carcinoma (HGSC) cases. Currently, olaparib is approved as maintenance therapy for <i>BRCA1/2</i>-mutated HGSC, and niraparib is approved for platinum-sensitive recurrent disease. However, research is currently expanding their potential as front-line agents or in combination with carboplatin, a standard HGSC chemotherapeutic.</p><p><strong>Methods: </strong>Immortalized ovarian cancer (iOvCa) cell lines, developed from HGSC patient ascites, were treated with carboplatin, olaparib and niraparib to determine their sensitivity. Immunofluorescence analysis of RAD51 was conducted for HRD testing of all the cell lines. The cell lines were cultured as three-dimensional organoids and spheroids to mimic tumor growth and metastasis, respectively, and then treated to assess the effects of different drug combinations.</p><p><strong>Results: </strong>The half-maximal inhibitory concentrations of olaparib and niraparib varied across our iOvCa cell lines, with iOvCa195 <i>BRCA1</i>-mutant line exhibiting the expected high sensitivity to both PARPis. Direct combination of carboplatin with olaparib or niraparib enhanced cell killing, yet achieved cell viability levels to those of carboplatin alone. In sequential experiments, carboplatin followed by either PARPi or <i>vice versa</i> showed no significant difference in cell viability to carboplatin alone, except in iOvCa195 organoids when treated with a PARPi first.</p><p><strong>Conclusions: </strong>Overall, first-line carboplatin treatment remains ideal, yet there may be select utility for PARPi prior to chemotherapy. Using patient-derived tumor models such as spheroids and organoids may provide insights for on-going and future clinical trials to enhance therapeutic outcomes for HGSC patients.</p>","PeriodicalId":9536,"journal":{"name":"Cancer Biology & Therapy","volume":"27 1","pages":"2611602"},"PeriodicalIF":5.7,"publicationDate":"2026-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12795296/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145951137","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Prolonged intratumoral treatment with TLR7/8 agonist R848 regulates the tumor immune microenvironment resulting in enhanced antitumor activity.","authors":"Yue Zhang, Xueyi Sun, Shixuan Cheng, Siyu Qian, Na Wan, Fengyun Xing, Hongwen Li, Hang Gu, Zeyuan Wang, Meng Dong, Zhenzhen Yang, Shaoxuan Wu, Mingzhi Zhang, Zhiqiang Han, Xudong Zhang, Huitao Liu, Qingjiang Chen","doi":"10.1080/15384047.2026.2670801","DOIUrl":"10.1080/15384047.2026.2670801","url":null,"abstract":"<p><strong>Background: </strong>Toll-like receptor 7/8 agonists (TLR7/8a), such as resiquimod (R848), are highly potent in activating dendritic cells and thus hold promise for T cell-mediated tumor immunotherapies. However, the short half-life of these small molecules in the lesion and the associated systemic immunotoxicity post-leakage of the drug into the circulation make their clinical application challenging.</p><p><strong>Materials: </strong>To overcome these shortcomings, we tested prolonged TLR7/8a therapy by intratumoral infusion of R848 for 25 h using a micropump to achieve durable therapeutic effects while minimizing the proinflammatory cytokine levels in the plasma post leakage of the drug into the circulation.</p><p><strong>Results: </strong>The results showed that prolonged immunotherapy with R848 (as low as 1 μg) significantly suppressed tumor growth (inhibition rates up to 98%, <i>p</i> < 0.01) in treated mice compared to control mice receiving regular intratumoral injection of R848. Higher levels of CD86⁺or CD11c⁺ D.C.s, CD4⁺/CD8⁺/OX40⁺ T cells, and cytokines (TNF-α/IFN-γ) were observed in the tumors and spleens of the mice in the treated group compared to the sham group (<i>p</i> < 0.05), indicating efficient activation of local and abscopal immunity by prolonged therapy with R848. Furthermore, the R848 functional concentration assay demonstrated that the micropump prolonged the treatment time of R848 drugs in tumors and reduced the requirement for higher doses, enhancing safety.</p><p><strong>Conclusion: </strong>Taken together, this study provides new insights into TLR7/8a immunotherapy for improved clinical performance, with potential benefits for patients with superficial tumors amenable to prolonged intratumoral infusion via micropump.</p>","PeriodicalId":9536,"journal":{"name":"Cancer Biology & Therapy","volume":"27 1","pages":"2670801"},"PeriodicalIF":5.7,"publicationDate":"2026-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13173998/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147926637","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}