Translational Oncology最新文献

{"title":"Integrative bioinformatics identifies NSCLC biomarkers associated with LPS metabolism and circadian disruption","authors":"Yu Chen ,&nbsp;Yifan Zhao ,&nbsp;Qinghua Kong ,&nbsp;Yabin Li ,&nbsp;Ping Jiang ,&nbsp;Lichao Fan","doi":"10.1016/j.tranon.2026.102699","DOIUrl":"10.1016/j.tranon.2026.102699","url":null,"abstract":"<div><h3>Purpose</h3><div>Non-small cell lung carcinoma (NSCLC) is a leading cause of cancer-related mortality worldwide, highlighting the urgent need for early detection and targeted therapies. While lipopolysaccharide (LPS) metabolism and circadian rhythm disruption are emerging as important factors in cancer progression, their specific roles in NSCLC remain poorly understood.</div></div><div><h3>Methods</h3><div>We integrated multiple GEO datasets to identify NSCLC-associated differentially expressed genes (DEGs). Weighted gene co-expression network analysis (WGCNA) identified key gene modules, followed by functional enrichment analysis. A hybrid machine learning approach combining Lasso regression and random forest was used to identify hub genes. Immune infiltration analysis evaluated associations with the tumor microenvironment, and diagnostic performance was validated in an independent cohort. Functional roles of the candidate gene CACNA2D2 were assessed through gain- and loss-of-function experiments in A549 cells, evaluating viability, proliferation, migration, and invasion.</div></div><div><h3>Results</h3><div>We identified 889 significant DEGs enriched in inflammatory and immune-related pathways. WGCNA revealed the magenta module as highly associated with NSCLC, involved in angiogenesis and extracellular matrix organization. Machine learning identified nine hub genes (CACNA2D2, ASPA, LRRN3, ABCA6, TNFSF12, AHNAK, TACC1, ID4, TSLP) showing excellent diagnostic performance (AUC: 0.832–0.906). These genes correlated significantly with immune cell infiltration patterns. Functional validation established CACNA2D2 as a tumor suppressor, where its depletion enhanced malignant phenotypes while overexpression suppressed them.</div></div><div><h3>Conclusion</h3><div>This study identifies a novel gene signature linked to LPS metabolism and circadian disruption in NSCLC, with validated diagnostic utility and implications for tumor immune regulation. CACNA2D2 emerges as a key tumor suppressor, offering insights for early detection and targeted therapy development.</div></div>","PeriodicalId":48975,"journal":{"name":"Translational Oncology","volume":"66 ","pages":"Article 102699"},"PeriodicalIF":5.0,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146175124","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":"OSBPL3 promotes LUAD metastasis and glycolysis through transcriptional upregulation of PLAU via NFE2L2","authors":"Qingqiong Zhang ,&nbsp;Jingshun Zhang ,&nbsp;Junxian Li ,&nbsp;Shuang Chen ,&nbsp;Yijun Liu ,&nbsp;Kaidi Li ,&nbsp;Minzhang Guo","doi":"10.1016/j.tranon.2026.102693","DOIUrl":"10.1016/j.tranon.2026.102693","url":null,"abstract":"<div><div>The progression of lung adenocarcinoma (LUAD) involves multiple molecular determinants, among which Oxysterol-binding protein-like 3 (OSBPL3) has been suggested to contribute to tumorigenesis, though its functional significance in LUAD remains poorly characterized. In this study, we elucidate the oncogenic functions and underlying mechanisms of OSBPL3 in LUAD pathogenesis. Analysis of clinical specimens revealed upregulated OSBPL3 expression in LUAD, which correlated with unfavorable patient outcomes. Genetic depletion of OSBPL3 in vitro impeded cellular proliferation, migratory capacity, and cell cycle progression, while inducing apoptotic cell death. Mechanistically, OSBPL3 was found to interact with the transcription factor NFE2L2, promoting its nuclear translocation and enhancing the transcriptional activation of PLAU, a downstream target gene. Upregulation of PLAU subsequently stimulated expression of key glycolytic enzymes through PI3K/AKT pathway activation, resulting in increased glucose consumption and lactate secretion. This metabolic reprogramming toward aerobic glycolysis facilitated malignant progression. Both genetic inhibition of PLAU and pharmacological blockade of AKT signaling abrogated the tumor-promoting phenotypes induced by OSBPL3. In vivo, OSBPL3 silencing significantly attenuated tumor growth and promoted apoptosis. Collectively, these findings identify an OSBPL3–NFE2L2–PLAU–AKT signaling axis that drives glycolytic metabolism and LUAD progression, showing its potential as a therapeutic target.</div></div>","PeriodicalId":48975,"journal":{"name":"Translational Oncology","volume":"66 ","pages":"Article 102693"},"PeriodicalIF":5.0,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146175125","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":"Multi-omics analysis of NET+ TAN explains the immunosuppressive TME and prognosis value of malignant clinical characteristics in TNBC","authors":"Qiannan Zhu ,&nbsp;Xiangxin Zheng ,&nbsp;Xiaochao Zhu ,&nbsp;Peng Yang ,&nbsp;Mengzhu Yang","doi":"10.1016/j.tranon.2026.102692","DOIUrl":"10.1016/j.tranon.2026.102692","url":null,"abstract":"<div><div>Triple-negative breast cancer (TNBC) continues to exhibit a poor response to both immunotherapy and endocrine therapy, primarily due to its complex genetic heterogeneity and tumor immune microenvironment (TIME). Neutrophil extracellular traps (NETs) are involved in neutrophil development and degranulation in treatment-resistant tumors, particularly TNBC and metastatic cases. Using a combination of single-cell RNA sequencing (scRNA-seq) datasets, bulk mRNA sequencing data from The Cancer Genome Atlas (TCGA) cohort, microarray data from the METABRIC and GEO databases, and epigenetic sequencing resources, we comprehensively investigated the functional characteristics and prognostic potential of NET-positive tumor-associated neutrophils (NET+ TAN) in TNBC. A six-gene panel derived from NET+ TAN has been identified as a reliable diagnostic biomarker for the survival of patients with TNBC and has been validated across several independent cohorts. Notably, our findings indicate that NET+ TAN facilitate T cell reprogramming in TNBC, thereby establishing a suppressive TIME and promoting tumor progression. This study provides a comprehensive perspective on the significance of NETs in patients with TNBC, with the aim of offering genetic and epigenetic insights into the mechanisms by which NETs may transition from cold to hot tumor phenotype, as well as valuable recommendations for therapeutic strategies.</div></div>","PeriodicalId":48975,"journal":{"name":"Translational Oncology","volume":"66 ","pages":"Article 102692"},"PeriodicalIF":5.0,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146166798","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":"Overcoming the leptomeningeal seeding of medulloblastoma by targeting HSP70","authors":"Seung Ah Choi ,&nbsp;Sokhoeun Heng ,&nbsp;Saehim Ha ,&nbsp;Seung-Ki Kim ,&nbsp;Do Won Hwang ,&nbsp;Hyewon Youn ,&nbsp;Ji Hoon Phi","doi":"10.1016/j.tranon.2026.102695","DOIUrl":"10.1016/j.tranon.2026.102695","url":null,"abstract":"<div><div>Leptomeningeal seeding (LMS) via cerebrospinal fluid is a common and often fatal progression in medulloblastoma (MB), significantly worsening prognosis. However, its molecular drivers are poorly understood, and effective treatments remain limited. This study aimed to establish a physiologically relevant MB LMS model and identify novel therapeutic targets through detailed characterization of seeding cell biology.</div><div>Using three rounds of serial orthotopic xenograft transplantation and in vivo selection, we isolated distinct seeding (S3) and non-seeding (N3) MB cell populations. Functional and transcriptomic analyses revealed unique phenotypes and differentially expressed genes (DEGs). Based on DEGs, we screened inhibitors and assessed the therapeutic efficacy of the HSP70 inhibitor VER155008, alone and with chemotherapeutics (ifosfamide or cisplatin), both in vitro and in a preclinical LMS mouse model established by cerebellar implantation of S3 cells.</div><div>S3 cells showed slower proliferation, altered migration behavior, and increased adhesion to collagen IV versus N3 cells. Transcriptomic profiling identified HSP70 as the most upregulated gene in S3 cells, with strong enrichment in metabolic pathways. Among six candidate compounds, VER155008 most effectively suppressed S3 cell viability. In vitro, VER155008 combined with 4-hydroperoxycyclophosphamide (active ifosfamide metabolite) produced a synergistic antitumor effect. This synergy was confirmed in vivo, where VER155008 with ifosfamide significantly reduced spinal LMS.</div><div>These findings highlight HSP70 as a promising therapeutic target for MB LMS. The observed synergy between VER155008 and ifosfamide supports a selective combination strategy, offering a novel therapeutic avenue to improve outcomes in patients with leptomeningeal dissemination of MB.</div></div>","PeriodicalId":48975,"journal":{"name":"Translational Oncology","volume":"66 ","pages":"Article 102695"},"PeriodicalIF":5.0,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146158283","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":"CMS subtypes correlate with complete response in trial of neoadjuvant Galunisertib plus chemoradiation in rectal cancer","authors":"Venkatesh Rajamanickam ,&nbsp;Noah D. Simons ,&nbsp;Wesley Rosales ,&nbsp;Anton Kravchenko ,&nbsp;Tomoko Yamazaki ,&nbsp;Brady Bernard ,&nbsp;Brian Piening ,&nbsp;Enric Domingo ,&nbsp;Timothy Maughan ,&nbsp;Charlems Alvarez-Jimenez ,&nbsp;Thomas Desilvio ,&nbsp;Satish Viswanath ,&nbsp;Mark Whiteford ,&nbsp;Amanda Hayman ,&nbsp;David O’Brien ,&nbsp;Maria X. Kiely ,&nbsp;Rehan Ahmad ,&nbsp;Michael J. Gough ,&nbsp;Marka R. Crittenden ,&nbsp;Kristina H. Young","doi":"10.1016/j.tranon.2026.102690","DOIUrl":"10.1016/j.tranon.2026.102690","url":null,"abstract":"<div><div>Improving responses to neoadjuvant therapy for patients with locally advanced rectal cancer has the potential to improve organ preservation and disease-free survival. Knowing which patients may need therapeutic escalation or de-escalation from standard-of-care treatment remains an area of investigation. We previously reported the primary and secondary endpoints of our single-arm study combining transforming growth factor beta receptor inhibitor, Galunisertib, with neoadjuvant chemoradiation in patients with locally advanced rectal cancer. Here we analyze RNA sequencing data obtained from tissue biopsies at baseline and after 2 weeks of galunisertib. Differences in expression of genes associated with MYC, inflammation, and epithelial-to-mesenchymal transition were observed between complete responders (CR) and &lt;CR, with galunisertib upregulating <em>MYC</em> pathway expression in CR. Radiosensitivity and TGFβ response scores demonstrated limited ability to predict for response to galunisertib + chemoradiation. Typically treatment-resistant consensus molecular subtype 4 (CMS4), characterized by TGFβ expression, and metabolic subtype (CMS3) were associated with response to galunisertib + chemoradiation. Differences in correlations between RNA based measures of cell composition and immunohistologic quantification of infiltrates and extracted MRI parameters were observed for CIBERSORT, MCPcounter, and xCell methodologies. Based on these data, we hypothesize that the stromal radioresistant phenotype driven by TGFβ can be overcome by the addition of galunisertib to chemoradiation in rectal cancer.</div></div>","PeriodicalId":48975,"journal":{"name":"Translational Oncology","volume":"66 ","pages":"Article 102690"},"PeriodicalIF":5.0,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146122687","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":"SPP1⁺ macrophage-FADS1⁺ tumor cell crosstalk via the PDGFB-PDGFRB axis drives liver metastasis in colorectal cancer","authors":"Pingfan Zhao ,&nbsp;Fuyong Pei ,&nbsp;Yanmin Liu ,&nbsp;Yinan Jiang ,&nbsp;Xiaochang Fang ,&nbsp;Lin Shu ,&nbsp;Xin Hu ,&nbsp;Feiyang Chen ,&nbsp;Maohui Feng ,&nbsp;Xuanfei Li","doi":"10.1016/j.tranon.2026.102696","DOIUrl":"10.1016/j.tranon.2026.102696","url":null,"abstract":"<div><div>Liver metastasis is the predominant cause of mortality among individuals diagnosed with colorectal cancer (CRC). However, the mechanisms underlying the tumor-microenvironment interactions that promote this process remain poorly defined. Here, we developed an integrative multiomics framework to dissect the cellular and molecular determinants of colorectal cancer liver metastasis (CRLM). By analyzing 1,156 metastasis-associated genes, we identified three molecular subtypes with distinct prognostic and immunometabolic features: C1 with mixed phenotypes and favorable survival, C2 with metabolic activation and immune suppression, and C3 with immune activation and signaling dysregulation, which had the poorest outcomes.</div><div>Mechanistically, we discovered that SPP1⁺ macrophages secrete PDGFB, which activates PDGFRB signaling in FADS1⁺ tumor cells to trigger epithelial-mesenchymal transition (EMT) and promote liver metastasis. This macrophage-tumor crosstalk was validated by single-cell transcriptomics, genetic perturbation, and coculture experiments. Collectively, our findings define a macrophage-derived PDGFB-PDGFRB axis that drives CRC liver metastasis and highlight a potential therapeutic target for overcoming metastatic progression and immune resistance.</div></div>","PeriodicalId":48975,"journal":{"name":"Translational Oncology","volume":"66 ","pages":"Article 102696"},"PeriodicalIF":5.0,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146143573","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":"FOSL1 promotes homologous recombination repair and camptothecin resistance via TCOF1-mediated ribosome biogenesis in non-small cell lung cancer","authors":"Chunmei Hao ,&nbsp;Luojun Chen ,&nbsp;Fuben Liao ,&nbsp;Lulu Chen ,&nbsp;Yi Yao ,&nbsp;Qibin Song","doi":"10.1016/j.tranon.2026.102701","DOIUrl":"10.1016/j.tranon.2026.102701","url":null,"abstract":"<div><h3>Background</h3><div>Camptothecin (CPT) and its derivatives are important chemotherapeutic agents; however, intrinsic and acquired tolerance frequently limits their long-term efficacy. This study aimed to identify key transcriptional regulators of CPT responsiveness in non-small cell lung cancer (NSCLC) and to elucidate the underlying molecular mechanisms.</div></div><div><h3>Methods</h3><div>Single-cell RNA sequencing-based transcriptomic profiling, integrated with bulk RNA-seq, was used to prioritize CPT-responsive transcriptional programs and nominate candidate regulators. Functional roles were validated using gain- and loss-of-function approaches in NSCLC cell lines. DNA damage repair, ribosome biogenesis, and translational activity were assessed using molecular and reporter assays. Pharmacological inhibition of ribosome biogenesis was evaluated using the RNA polymerase I inhibitor BMH-21, and therapeutic relevance was further examined in xenograft models.</div></div><div><h3>Results</h3><div>We identified <em>FOSL1</em> as a CPT-responsive transcription factor that was associated with poor prognosis in lung adenocarcinoma. CPT treatment induced FOSL1 expression and nuclear accumulation, whereas <em>FOSL1</em> depletion markedly enhanced CPT-induced cytotoxicity. Mechanistically, loss of <em>FOSL1</em> resulted in persistent DNA damage accumulation and selective impairment of homologous recombination (HR) repair. <em>FOSL1</em> sustained HR repair indirectly by promoting ribosome biogenesis through transcriptional activation of <em>TCOF1</em>. Pharmacological inhibition of ribosome biogenesis phenocopied <em>FOSL1</em> depletion and significantly potentiated CPT efficacy both in vitro and in vivo.</div></div><div><h3>Conclusion</h3><div>Our study defines a FOSL1-TCOF1-ribosome axis that promotes CPT tolerance in NSCLC by maintaining HR repair. These findings provide a rationale for targeting ribosome biogenesis to enhance CPT-based treatment and highlight coordinated regulation of transcription, protein synthesis, and DNA repair under chemotherapeutic stress.</div></div>","PeriodicalId":48975,"journal":{"name":"Translational Oncology","volume":"66 ","pages":"Article 102701"},"PeriodicalIF":5.0,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146175126","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":"Development and validation of prognostic nomograms based on peripheral blood T-cell counts and their dynamic changes for patients with nasopharyngeal carcinoma receiving radiotherapy","authors":"Kegui Weng ,&nbsp;Qianqian Lei ,&nbsp;Ye Hong ,&nbsp;Kaihua Chen ,&nbsp;Yongchu Sun ,&nbsp;Ying Wang ,&nbsp;Xiaodong Zhu","doi":"10.1016/j.tranon.2025.102661","DOIUrl":"10.1016/j.tranon.2025.102661","url":null,"abstract":"<div><h3>Aim</h3><div>To develop and validate prognostic nomograms incorporating peripheral blood lymphocyte counts and their dynamic changes in patients with nasopharyngeal carcinoma (NPC) undergoing radiotherapy.</div></div><div><h3>Methods</h3><div>In this retrospective cohort study, consecutive patients with NPC who received radiotherapy at Chongqing University Cancer Hospital were included as the internal cohort (randomly divided 70 %/30 % for training and validation), while patients treated at Guangxi Medical University Cancer Hospital served as the external validation cohort. Prognostic nomograms for progression-free survival (PFS) and overall survival (OS) were constructed using multivariable Cox regression analyses.</div></div><div><h3>Results</h3><div>The internal and external cohorts comprised 746 and 138 patients, respectively. Age, gross tumor volume dose, neoadjuvant chemotherapy, clinical stage, plasma EBV-DNA level, baseline total T-cell count, and its post-treatment change (ΔT cells) were identified as independent prognostic factors. The nomograms demonstrated strong predictive performance, with concordance indices of 0.701, 0.716, and 0.714 for PFS, and 0.759, 0.735, and 0.734 for OS in the training, internal validation, and external datasets, respectively. The areas under the receiver operating characteristic curves for 3-year and 5-year PFS and OS exceeded 0.7 across all cohorts. Calibration plots indicated good agreement between predicted and observed outcomes, and decision curve analysis confirmed greater net clinical benefit compared with TNM staging and EBV-DNA-based models.</div></div><div><h3>Conclusion</h3><div>The proposed T-cell-based nomograms reliably predict PFS and OS in patients with NPC undergoing radiotherapy and were validated in an external cohort. These models provide improved prognostic discrimination beyond conventional staging systems and may assist in individualized risk stratification and management planning.</div></div>","PeriodicalId":48975,"journal":{"name":"Translational Oncology","volume":"66 ","pages":"Article 102661"},"PeriodicalIF":5.0,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146143558","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":"Imaging–guided optimization of biodistribution and antitumor efficacy of L19-based immunocytokines","authors":"Tommaso Virgilio ,&nbsp;Kamil Chahine ,&nbsp;Jordi Guixeras Carreras ,&nbsp;Alain Pulfer ,&nbsp;Chiara Pizzichetti ,&nbsp;Irene Latino ,&nbsp;Daniel Molina-Romero ,&nbsp;Arianna Capucetti ,&nbsp;Louis Luca Renner ,&nbsp;Dario Neri ,&nbsp;Emanuele Puca ,&nbsp;Roberto De Luca ,&nbsp;Santiago F. Gonzalez","doi":"10.1016/j.tranon.2026.102698","DOIUrl":"10.1016/j.tranon.2026.102698","url":null,"abstract":"<div><div>Antibody-based targeted delivery of pharmaceuticals is an attractive approach to preferentially localize anti-cancer payloads to neoplastic lesions. The L19 antibody, specific for the extra domain B of fibronectin, is used in several antibody-cytokine fusion proteins investigated in clinical trials involving different tumor types. However, improving the efficacy of L19-based immunotherapies requires a detailed understanding of how delivery strategies influence intratumoral distribution and therapeutic outcomes.</div><div>In this study, we investigate the biodistribution of the L19 antibody in murine models of primary Eμ-myc lymphoma and metastatic MC38 colon carcinoma. Using high-resolution in vivo and <em>ex vivo</em> microscopy, we compared subcutaneous (s.c.) and intravenous (i.v.) administration of L19, revealing rapid accumulation in tumor invaded lymph nodes within 10–30 min post injection. While both routes enabled initial tumor targeting, i.v. injection led to longer retention (up to 72 h) and greater selectivity for tumor associated blood vasculature. In contrast, s.c. delivery favored transient accumulation near lymphatic vessels and exhibited reduced tumor residence. These distribution patterns directly influenced the therapeutic efficacy of the L19-IL2 immunocytokine, which showed superior tumor control following i.v. administration in the MC38 model, consistent with enhanced blood vascularization in this model.</div><div>Our findings demonstrate that L19 binds both blood and lymphatic vasculature in primary and metastatic disease, underscoring the critical impact of the administration route on antibody biodistribution, microanatomical localization, and therapeutic outcome. Moreover, this work highlights the utility of microscopy guided analysis in optimizing delivery strategies and supports the rationale for tailoring administration routes based on tumor type and vascular context in antibody-based theranostics.</div></div>","PeriodicalId":48975,"journal":{"name":"Translational Oncology","volume":"66 ","pages":"Article 102698"},"PeriodicalIF":5.0,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146175055","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":"The novel tertiary amine LSD1 inhibitor 596 inhibits endometrial cancer through the mTOR signal transduction pathway","authors":"Chunli Wang ,&nbsp;Dandan Shen ,&nbsp;Nanshan Lin ,&nbsp;Panjie Wang ,&nbsp;Yaping Bi ,&nbsp;Huina Hu ,&nbsp;Yujia Shang ,&nbsp;Chenchen Ren ,&nbsp;Li Yang ,&nbsp;Qisheng Ma","doi":"10.1016/j.tranon.2026.102688","DOIUrl":"10.1016/j.tranon.2026.102688","url":null,"abstract":"<div><div>Lysine-specific demethylase 1 (LSD1) is a promising target in cancer therapy and plays an important role in the occurrence and development of tumors. However, research on LSD1 in endometrial cancer (EC) is indeed limited, and the related research on LSD1 inhibitors targeting EC is even rarer. In this study, our group developed a novel Tertiary Amine LSD1 inhibitor-596. 596 could specifically target LSD1 and inhibit the demethylation levels of H3K4me1/2 in a dose-dependent manner, thereby inhibited the proliferation of EC cells in vitro and in vivo. Moreover, in-depth studies have shown that 596 induces cell death in EC cells through the autophagy pathway, increasing the formation of autophagosomes and the expression of autophagy-related proteins. Transcriptomic sequencing revealed that 596-induced gene enrichment was related to the PI3K/AKT/mTOR pathway. The treatment group of 596 was able to attenuate the activation of the mTOR signaling cascade, and the combination treatment of 596 and the mTOR inhibitor rapamycin (RAPA) effectively reduced the survival rate, migration ability, and invasion ability of EC cells. Further studies in vitro and in vivo indicated that 596 could reduce the feedback activation of AKT mediated by the mTOR inhibitor rapamycin. In summary, our findings demonstrate that the LSD1 inhibitor 596 enhances the activity of the mTOR inhibitor by attenuating the feedback activation of AKT. LSD1 may be as a potential therapeutic target in EC, and LSD1 inhibitors represent an important therapeutic strategy in EC treatment.</div></div>","PeriodicalId":48975,"journal":{"name":"Translational Oncology","volume":"66 ","pages":"Article 102688"},"PeriodicalIF":5.0,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146166936","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}