Translational Oncology最新文献

{"title":"Piperlongumine suppresses YAP-ET-1-CXCL2 signaling to modulates aggressiveness of triple-negative breast cancer cells","authors":"Ming-Yi Hsieh ,&nbsp;Ching-Chieh Yang ,&nbsp;Wen-Jing Hsu ,&nbsp;Zei-Wei Liu ,&nbsp;Hsin-Ying Lu ,&nbsp;Ming-Chen Chiang ,&nbsp;Cheng-Jui Huang ,&nbsp;Ching-Yun Liao ,&nbsp;Cheng-Wei Lin ,&nbsp;Pei-Wei Shueng","doi":"10.1016/j.tranon.2026.102700","DOIUrl":"10.1016/j.tranon.2026.102700","url":null,"abstract":"<div><div>Triple-negative breast cancer (TNBC) is characterized by highly aggressive and metastatic properties, and appropriate molecular targets and therapeutics for effective treatment remain limited. In the present study, by using RNA sequencing (RNA-Seq) analysis of upregulated genes expression in metastatic breast tumor cells, we identified that the Yes-associated protein (YAP)- endothelin (ET)-1 signaling axis were concomitantly elevated in metastatic breast tumor tissues and their overexpression conferred poor survival outcomes, particular in patients with TNBC. Moreover, we identified that piperlongumine (PL), a naturally occurring small molecule derived from long pepper, exhibits potent antitumor activities in TNBC cells. PL effectively suppressed cell proliferation, promoted apoptosis, and inhibited tumor migration and invasion. Furthermore, PL activates Hippo signaling which was accompanied by downregulation of YAP level. Consequently, PL suppressed YAP signaling to further downregulate ET-1 expression. Additionally, ET-1 elevation was identified to be associated with cancer-associated fibroblast (CAF) and C-X-C motif chemokine ligand 2 (CXCL2) signature, while treatment with PL significantly downregulated CXCL2 expression and consequently decreased CAF activation. Finally, PL treatment significantly inhibited <em>in vivo</em> tumor growth and suppressed CAF infiltration in the tumor microenvironment. Together, these findings demonstrated that PL might be a promising chemotherapeutic agent to efficiently target YAP-ET-1-CXCL2 signaling and thus has therapeutic potential for TNBC patients.</div></div>","PeriodicalId":48975,"journal":{"name":"Translational Oncology","volume":"66 ","pages":"Article 102700"},"PeriodicalIF":5.0,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146175127","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":"An unfavorable biologic profile associated with decreased overall survival and cancer-specific survival in non-metastatic breast cancer: A latent class analysis","authors":"Claire Falandry ,&nbsp;Sigrid Hatse ,&nbsp;Barbara Brouwers ,&nbsp;Cindy Kenis ,&nbsp;Ann Smeets ,&nbsp;Patrick Neven ,&nbsp;Charlotte Cuerq ,&nbsp;Frederic Pamoukdjian ,&nbsp;Karim Chikh ,&nbsp;Hans Wildiers","doi":"10.1016/j.tranon.2026.102694","DOIUrl":"10.1016/j.tranon.2026.102694","url":null,"abstract":"<div><h3>Background</h3><div>Chronological age is an imperfect proxy for risk assessment in geriatric oncology. There is an urgent need for an objective, easily measurable biological aging signature to refine patient stratification and personalize therapeutic decisions.</div></div><div><h3>Methods</h3><div>We analyzed a panel of seven aging-related biomarkers (including markers of inflammation, anabolic reserve, and telomere status) in 244 nonmetastatic breast cancer patients from two age groups (“Old”, ≥70 years, <em>N</em> = 162; “Young”, ≤60 years, <em>N</em> = 82). We used Latent Class Analysis (LCA) to integrate these markers and identify distinct biological risk profiles. These profiles were then evaluated for their association with Overall Survival (OS) and Cancer-Specific Death (CSD) via Competing Risk Analysis.</div></div><div><h3>Results</h3><div>LCA identified two patient profiles. The Unfavorable Biologic Profile (56.1% of the cohort) was defined by a triad of high MCP-1, high Chitinase activity, and low IGF-1. This profile was strongly associated with poorer OS (Age-adjusted HR=1.82, <em>p</em> = 0.018). Crucially, 15% of chronologically “Young” patients were assigned to this high-risk profile, while 23% of “Old” patients were assigned to the Favorable Profile. Furthermore, the Unfavorable Profile was more strongly and specifically associated with CSD (Subdistribution HR: 2.05, <em>p</em> = 0.012) than with Non-Cancer Death.</div></div><div><h3>Conclusion</h3><div>Our results delineate an unfavorable, trans-chronological biological profile that identifies patients with low host reserve, largely driven by inflammaging and catabolism. This integrated signature provides a robust, objective screening tool to identify biologically frail patients, validating the need for Comprehensive Geriatric Assessment (CGA) and biomarker-guided therapeutic de-escalation (e.g., avoiding adjuvant chemotherapy) to improve individualized outcomes in oncology.Trial registration: BS32220096117.</div></div>","PeriodicalId":48975,"journal":{"name":"Translational Oncology","volume":"66 ","pages":"Article 102694"},"PeriodicalIF":5.0,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146175128","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":"A review of treatment strategies for elderly patients with Philadelphia chromosome-negative B-cell acute lymphoblastic leukemia","authors":"Kaihang Shi,&nbsp;Gaoxiang Wang,&nbsp;Xueyan Sun","doi":"10.1016/j.tranon.2026.102706","DOIUrl":"10.1016/j.tranon.2026.102706","url":null,"abstract":"<div><div>The treatment of elderly patients with Philadelphia chromosome-negative B-cell acute lymphoblastic leukemia (pH⁻ B-ALL) remains challenging because of the high frequency of adverse genetic features, common comorbidities, and significant treatment-related toxicities, which collectively limit the efficacy of conventional chemotherapy and result in poor long-term survival. Recent years have witnessed the emergence of novel targeted agents and immunotherapies, substantially improving the therapeutic outlook for this population. This review summarizes recent advances in the application of low-intensity chemotherapy, CD19/CD22-targeting antibodies such as blinatumomab and inotuzumab ozogamicin, the BCL-2 inhibitor venetoclax, and chimeric antigen receptor (CAR) T-cell therapy for elderly pH⁻ B-ALL patients. Clinical studies indicate that these strategies can increase remission rates and survival while reducing treatment-related toxicity, offering particular benefit to older patients who are unsuitable for intensive chemotherapy. Future efforts should focus on optimizing combination and sequential regimens, as well as personalizing treatment approaches to further improve efficacy and safety.</div></div>","PeriodicalId":48975,"journal":{"name":"Translational Oncology","volume":"66 ","pages":"Article 102706"},"PeriodicalIF":5.0,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146175210","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":"Application of radiomics in head and neck squamous cell carcinoma","authors":"Siyi Wu ,&nbsp;Zaiyu Wang ,&nbsp;Yu Zhang ,&nbsp;Qi Chen ,&nbsp;Honghao Liu ,&nbsp;Yedong Shen ,&nbsp;Juxiong Xiao ,&nbsp;Luqing Zhao ,&nbsp;Yitao Mao","doi":"10.1016/j.tranon.2026.102689","DOIUrl":"10.1016/j.tranon.2026.102689","url":null,"abstract":"<div><div>Head and neck squamous cell carcinoma (HNSCC) is the most prevalent histopathological subtype of head and neck malignancies. Owing to the lack of early specific symptoms, the majority of patients are diagnosed at intermediate or advanced stages, which is associated with an unfavorable prognosis and a substantial decline in quality of life. Radiomics, which leverages large-scale medical imaging data, enables the extraction of high-dimensional quantitative features through advanced image analysis, thereby providing deeper insights into tumor biology. In this review, we summarize recent advances in radiomics for the diagnosis, prognostic prediction, and evaluation of treatment-related toxicity in HNSCC. Furthermore, we highlight emerging applications of radiomics in genomics and proteomics, illustrating the associations between tumor molecular phenotypes and imaging-derived features. Finally, we discuss the challenges related to feature standardization and reproducibility, and outline the key limitations of current radiomics studies.</div></div>","PeriodicalId":48975,"journal":{"name":"Translational Oncology","volume":"66 ","pages":"Article 102689"},"PeriodicalIF":5.0,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146143513","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":"Advances in FLASH radiation therapy: A review on biological foundations and clinical prospects","authors":"Yupeng Di ,&nbsp;Lingling Meng ,&nbsp;Yingjie Wang ,&nbsp;Jing Li","doi":"10.1016/j.tranon.2026.102676","DOIUrl":"10.1016/j.tranon.2026.102676","url":null,"abstract":"<div><div>This paper provides a comprehensive review of the fundamental theories, clinical practices, technological advancements, current status, and future prospects of FLASH radiation therapy (FLASH-RT). As an emerging technique, FLASH-RT offers the potential to enhance therapeutic efficacy while minimizing damage to healthy tissues. We elaborate on the physical principles of the “FLASH effect” in radiation biology and its dose-distribution characteristics, describe clinical applications in tumor treatment, and evaluate protective effects on normal tissues. Furthermore, the review discusses technical advancements in equipment, dosimetry, and imaging, while analyzing current research hotspots and technical bottlenecks. We also examine pathological mechanisms, future applications, and prevailing controversies regarding safety, efficacy uncertainty, and ethics. This comprehensive discussion provides a valuable reference for deepening the understanding of FLASH-RT’s translational journey.</div></div>","PeriodicalId":48975,"journal":{"name":"Translational Oncology","volume":"65 ","pages":"Article 102676"},"PeriodicalIF":5.0,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145981178","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":"Integrated multi-omics analysis of prognostic model and immune microenvironment in intrahepatic cholangiocarcinoma","authors":"Xi Li ,&nbsp;Yixian Wang ,&nbsp;Xiangbao Yin ,&nbsp;Junwen Hu ,&nbsp;Hongcheng Lu ,&nbsp;Die Li ,&nbsp;Mingming Wu","doi":"10.1016/j.tranon.2026.102675","DOIUrl":"10.1016/j.tranon.2026.102675","url":null,"abstract":"<div><h3>Background</h3><div>Intrahepatic cholangiocarcinoma (iCCA) is an aggressive malignancy originating from the epithelial lining of second-order bile ducts. Despite advances in immunotherapy, which underscore the pivotal roles of T-cell dynamics and tumor microenvironment (TME) remodeling in anti-tumor immunity, iCCA remains a clinical challenge due to its rapid progression. Consequently, there is a pressing need for integrated multi-omics approaches to elucidate the immune landscape of iCCA and guide effective precision immunotherapy.</div></div><div><h3>Methods</h3><div>To comprehensively characterize iCCA, we integrated single-cell RNA-seq data for microenvironment analysis and bulk RNA-seq cohorts for prognostic model construction using machine learning, followed by external validation and functional experimental verification of key genes.</div></div><div><h3>Results</h3><div>Integrated single-cell and spatial transcriptomic analysis of iCCA uncovered interacting epithelial-fibroblast subpopulations and guided the machine learning-based derivation of a five-gene prognostic signature. Furthermore, spatial transcriptomics confirmed the physical co-localization between SPP1+ Macrophage and NDRG1+ CAF. Finally, functional experiments established that MT1X, a gene highly expressed in iCCA, drives tumor proliferation, migration, and invasion.</div></div><div><h3>Conclusion</h3><div>This study establishes a prognostic model based on five key genes and elucidates their role in the immunosuppressive TME. MT1X was validated as a pro-tumorigenic factor, highlighting its potential as a therapeutic target.</div></div>","PeriodicalId":48975,"journal":{"name":"Translational Oncology","volume":"65 ","pages":"Article 102675"},"PeriodicalIF":5.0,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146012545","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":"NEIL1 suppresses ROS accumulation to promote temozolomide resistance and malignant progression in glioma cells","authors":"Shuo Li ,&nbsp;Chenhao Fang ,&nbsp;Qingyue Yuan ,&nbsp;Xianzhen Chen","doi":"10.1016/j.tranon.2026.102667","DOIUrl":"10.1016/j.tranon.2026.102667","url":null,"abstract":"<div><h3>Background</h3><div>Glioma is the most common malignant primary brain tumor. Temozolomide (TMZ) is the standard first-line chemotherapy, but its efficacy is severely limited by acquired resistance. Understanding resistance mechanisms, especially beyond traditional DNA repair, is crucial for improving outcomes.</div></div><div><h3>Methods</h3><div>We integrated multi-database glioma transcriptomics (TCGA, GTEx, CGGA). Bioinformatics (differential expression, WGCNA, glycolipid metabolism gene screening) and machine learning (LASSO, random forest) identified key genes, focusing on the DNA glycosylase NEIL1. Its expression was assessed in U251 MG cells versus TMZ-resistant (U251 MG/TMZ) cells. Gain/loss-of-function studies (lentiviral knockdown/overexpression) and pharmacological inhibition (a 2-thioxanthine derivative, TX16) were used to evaluate NEIL1′s role in proliferation (CCK-8, EdU), migration, invasion, apoptosis (TUNEL), ROS, and TMZ sensitivity (IC50). A subcutaneous nude mouse model provided in vivo validation.</div></div><div><h3>Results</h3><div>NEIL1 was aberrantly expressed in glioma and enriched in PI3K-Akt/cAMP signaling, suggesting that it may promote the malignant behavior of U251 MG cells through these pathways. Its expression was significantly higher in TMZ-resistant cells (<em>P</em> &lt; 0.001). NEIL1 overexpression promoted malignant phenotypes (proliferation, migration, invasion, <em>P</em> &lt; 0.05), while its knockdown suppressed them. Critically, NEIL1 overexpression attenuated TMZ-induced ROS and DNA damage, increased cell viability and IC₅₀ (1.2-fold), and bolstered TMZ resistance. The NEIL1 inhibitor TX16 reversed these malignant behaviors and restored TMZ sensitivity (<em>P</em> &lt; 0.05), reinstating ROS-driven apoptosis. In vivo, NEIL1 promoted tumor growth, which was suppressed by TX16.</div></div><div><h3>Conclusion</h3><div>NEIL1 drives glioma malignancy and TMZ resistance by mitigating oxidative stress and DNA damage, highlighting its role as a promising target to overcome chemoresistance.</div></div>","PeriodicalId":48975,"journal":{"name":"Translational Oncology","volume":"65 ","pages":"Article 102667"},"PeriodicalIF":5.0,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145981346","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":"AlphaMissense pathogenicity scores predict response to immunotherapy and enhances the predictive capability of tumor mutation burden","authors":"David Adeleke ,&nbsp;Adewale Oluwaseun Fadaka ,&nbsp;Nicole Remaliah Samantha Sibuyi ,&nbsp;Ashwil Klein ,&nbsp;Mervin Meyer ,&nbsp;Gomes Rahul ,&nbsp;Rick Jansen","doi":"10.1016/j.tranon.2026.102697","DOIUrl":"10.1016/j.tranon.2026.102697","url":null,"abstract":"<div><div>Tumor Mutational Burden (TMB) is a widely used biomarker for selecting cancer patients for immune checkpoint inhibitor (ICI) therapy. However, TMB alone has limited predictive power, as it fails to account for the functional impact of mutations. We introduce AlphaTMB, a composite biomarker that integrates the quantity of mutations (TMB) with the qualitative assessment of their pathogenicity using AlphaMissense, a deep learning model that predicts the deleteriousness of missense variants. Using a pan-cancer cohort of 1,662 patients from the MSK-IMPACT study who received ICI therapy, we computed three scores per patient: TMB, Alpha (sum of AlphaMissense scores), and AlphaTMB (product of TMB and Alpha). Patients were stratified using both cancer-specific and pan-cancer quantiles. Survival outcomes were evaluated using Kaplan-Meier and multivariate Cox proportional hazards models, controlling for cancer type, age, and ICI regimen. AlphaTMB showed strong correlation with TMB (Spearman ρ = 0.866, <em>p</em> &lt; 0.001), but offered improved prognostic accuracy. Patients in the bottom 80% AlphaTMB group had significantly poorer survival than those in the top 10% (HR &lt; 2.51, <em>p</em> &lt; 0.001), outperforming TMB and Alpha alone. AlphaTMB reclassified borderline cases, identifying subsets with low TMB but high deleterious mutation load, and vice versa. Gene mutation heatmaps and co-occurrence analysis confirmed that to 10% AlphaTMB-high tumors were enriched in mismatch repair and POLE mutations, reflecting a neoantigen-rich, immunotherapy-responsive phenotype. AlphaTMB improves survival prediction beyond TMB alone, better captures immunogenic tumor profiles, and reflects more accurate patient stratification. This AI derived somatic mutations pathogenicity scoring represents a step toward personalized immuno-oncology and merits further validation in prospective studies.</div></div>","PeriodicalId":48975,"journal":{"name":"Translational Oncology","volume":"65 ","pages":"Article 102697"},"PeriodicalIF":5.0,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146120273","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":"Computed tomography- and magnetic resonance imaging-based multi-modality radiomics models for predicting survival in esophageal cancer patients","authors":"Funing Chu ,&nbsp;Dexuan Li ,&nbsp;Zhaoqi Wang ,&nbsp;Bingmei Bai ,&nbsp;Keke Zhao ,&nbsp;Shuting Wang ,&nbsp;Chenglong Wang ,&nbsp;Guang Yang ,&nbsp;Jinrong Qu","doi":"10.1016/j.tranon.2026.102686","DOIUrl":"10.1016/j.tranon.2026.102686","url":null,"abstract":"<div><h3>Objectives</h3><div>This study explores the integration of radiomics features from contrast-enhanced CT and MRI with clinical and radiological risk factors for optimal prognosis models of disease-free survival (DFS) and overall survival (OS) in esophageal squamous cell carcinoma (ESCC).</div></div><div><h3>Materials and Methods</h3><div>A retrospective study is undertaken of 371 ESCC patients who underwent contrast-enhanced CT and MRI with StarVIBE sequence, from September 2014 to December 2019. Prognosis models for DFS and OS were developed using cross-validation and Elastic-Net-Cox regression. Patients were grouped by treatment type (surgery, chemoradiotherapy, neoadjuvant therapy) to create single-modality and multi-modality models (Model-S, Model-CRT, and Model-nT). Model performance was evaluated using nomograms, calibration curves, and decision curves.</div></div><div><h3>Results</h3><div>Twelve optimal prognosis models were identified. For DFS, MRI c-indices were 0.595, 0.608, and 0.721, while CT c-indices were 0.686, 0.616, and 0.667. For OS, MRI c-indices were 0.692, 0.597, and 0.650, and CT c-indices were 0.656, 0.623, and 0.695. Multi-modality models demonstrated c-indices of 0.750, 0.695, 0.839 for DFS and 0.898, 0.777, 0.819 for OS.</div></div><div><h3>Conclusion</h3><div>Single-modality radiomics models exhibit limited predictive ability for DFS and OS in ESCC patients, whereas multi-modality radiomics models enhance predictive accuracy significantly.</div></div>","PeriodicalId":48975,"journal":{"name":"Translational Oncology","volume":"65 ","pages":"Article 102686"},"PeriodicalIF":5.0,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146133020","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":"RHOJ-induced chemotherapy resistance through epithelial–mesenchymal transition in drug-tolerant persister cells of head and neck cancer","authors":"Hang Huong Ling ,&nbsp;Chih-Ming Huang ,&nbsp;Ming-Shou Hsieh ,&nbsp;Vijesh Kumar Yadav ,&nbsp;Iat-Hang Fong ,&nbsp;Kuang-Tai Kuo ,&nbsp;Chi-Tai Yeh ,&nbsp;Jo-Ting Tsai","doi":"10.1016/j.tranon.2026.102673","DOIUrl":"10.1016/j.tranon.2026.102673","url":null,"abstract":"<div><div>Background: Building on our previous identification of TXNRD1 and RHOJ as mediators of immunotherapy resistance in head and neck squamous cell carcinoma (HNSCC), this study investigates the role of RHOJ in regulating endothelial markers and signaling pathways in drug-tolerant persister (DTP) cells, as well as its contribution to immune suppression within the resistant tumor microenvironment. Methods: We examined the role of RHOJ in regulating tumor-associated macrophage polarization and enhancing M1 antitumor activity and evaluated the therapeutic potential of targeting the RHOJ/Rho kinase axis in an HNSCC DTP mouse model. Results: RHOJ expression was significantly upregulated in HNSCC DTP cells. RHOJ contributes to chemoresistance by increasing oxidative stress and initiating the DNA damage response. RNA sequencing revealed that the IPO9/EpCAM signaling pathway positively regulates RHOJ expression. Knockdown of RHOJ with shRNA suppressed HNSCC DTP cell migration and downregulated IPO9/EpCAM signaling. Gene enrichment analysis revealed high RHOJ expression in tumor-associated endothelial cells. Treatment with the RHOJ-dependent F-actin inhibitor Latrunculin B (HY-101,848) impaired actin polymerization and increased the chemosensitivity of HNSCC DTP cells. Silencing RHOJ inhibited M2 tumor-associated macrophage activation. RHOJ overexpression promoted M2 macrophage proliferation. Conclusion: RHOJ plays a critical role in modulating immunosuppressive signaling in both tumor and endothelial cells. RHOJ promotes the function of tumor-associated endothelial cells and drives EMT through its interaction with the IPO9/EpCAM signaling pathway, thereby increasing cell survival and drug resistance. Additionally, RHOJ may limit immune cell infiltration into the tumor core and promote immune evasion by contributing to vascular abnormalities and impaired barrier function.</div></div>","PeriodicalId":48975,"journal":{"name":"Translational Oncology","volume":"65 ","pages":"Article 102673"},"PeriodicalIF":5.0,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145981345","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}