Translational Oncology最新文献

Integrative bioinformatics identifies NSCLC biomarkers associated with LPS metabolism and circadian disruption 综合生物信息学鉴定与LPS代谢和昼夜节律中断相关的非小细胞肺癌生物标志物

IF 5 2区医学 Q2 Medicine

Translational Oncology

Pub Date : 2026-04-01 Epub Date: 2026-02-14 DOI: 10.1016/j.tranon.2026.102699

Yu Chen , Yifan Zhao , Qinghua Kong , Yabin Li , Ping Jiang , Lichao Fan

Purpose

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.

Methods

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.

Results

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.

Conclusion

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.

非小细胞肺癌（NSCLC）是世界范围内癌症相关死亡的主要原因，突出了早期发现和靶向治疗的迫切需要。虽然脂多糖（LPS）代谢和昼夜节律破坏正在成为癌症进展的重要因素，但它们在非小细胞肺癌中的具体作用仍然知之甚少。方法整合多个GEO数据集，鉴定nsclc相关差异表达基因（DEGs）。加权基因共表达网络分析（WGCNA）确定关键基因模块，然后进行功能富集分析。采用Lasso回归和随机森林相结合的混合机器学习方法识别轮毂基因。免疫浸润分析评估了与肿瘤微环境的关联，并在独立队列中验证了诊断性能。候选基因CACNA2D2的功能作用通过A549细胞的功能获得和功能丧失实验来评估，评估其活力、增殖、迁移和侵袭。结果在炎症和免疫相关途径中发现了889个显著的deg。WGCNA显示洋红色模块与非小细胞肺癌高度相关，参与血管生成和细胞外基质组织。机器学习识别出9个枢纽基因（CACNA2D2、ASPA、LRRN3、ABCA6、TNFSF12、AHNAK、TACC1、ID4、TSLP），诊断效果良好（AUC: 0.832-0.906）。这些基因与免疫细胞浸润模式显著相关。功能验证证实了CACNA2D2是一种肿瘤抑制因子，其缺失增强了恶性表型，而过表达则抑制了它们。本研究确定了一个与非小细胞肺癌LPS代谢和昼夜节律紊乱相关的新基因特征，具有有效的诊断效用和肿瘤免疫调节意义。CACNA2D2作为一种关键的肿瘤抑制因子出现，为早期发现和靶向治疗的发展提供了见解。

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引用次数: 0

OSBPL3 promotes LUAD metastasis and glycolysis through transcriptional upregulation of PLAU via NFE2L2 OSBPL3通过NFE2L2转录上调PLAU，促进LUAD转移和糖酵解

IF 5 2区医学 Q2 Medicine

Translational Oncology

Pub Date : 2026-04-01 Epub Date: 2026-02-12 DOI: 10.1016/j.tranon.2026.102693

Qingqiong Zhang , Jingshun Zhang , Junxian Li , Shuang Chen , Yijun Liu , Kaidi Li , Minzhang Guo

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.

肺腺癌（LUAD）的进展涉及多个分子决定因素，其中氧甾醇结合蛋白样3 （OSBPL3）已被认为有助于肿瘤发生，尽管其在LUAD中的功能意义尚不清楚。在本研究中，我们阐明了OSBPL3在LUAD发病机制中的致癌功能和潜在机制。临床标本分析显示，LUAD中OSBPL3表达上调，这与患者预后不良相关。OSBPL3基因缺失在体外抑制细胞增殖、迁移能力和细胞周期进程，同时诱导凋亡细胞死亡。机制上，OSBPL3被发现与转录因子NFE2L2相互作用，促进其核易位并增强下游靶基因PLAU的转录激活。PLAU的上调随后通过PI3K/AKT通路激活刺激关键糖酵解酶的表达，导致葡萄糖消耗和乳酸分泌增加。这种向有氧糖酵解的代谢重编程促进了恶性进展。基因抑制PLAU和药理阻断AKT信号通路均可消除OSBPL3诱导的促肿瘤表型。在体内，OSBPL3沉默可显著减弱肿瘤生长并促进细胞凋亡。总之，这些发现确定了一个驱动糖酵解代谢和LUAD进展的OSBPL3-NFE2L2-PLAU-AKT信号轴，显示其作为治疗靶点的潜力。

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引用次数: 0

Multi-omics analysis of NET+ TAN explains the immunosuppressive TME and prognosis value of malignant clinical characteristics in TNBC NET+ TAN的多组学分析解释了TNBC恶性临床特征的免疫抑制TME及预后价值。

IF 5 2区医学 Q2 Medicine

Translational Oncology

Pub Date : 2026-04-01 Epub Date: 2026-02-10 DOI: 10.1016/j.tranon.2026.102692

Qiannan Zhu , Xiangxin Zheng , Xiaochao Zhu , Peng Yang , Mengzhu Yang

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.

三阴性乳腺癌（TNBC）继续表现出对免疫治疗和内分泌治疗的不良反应，主要是由于其复杂的遗传异质性和肿瘤免疫微环境（TIME）。中性粒细胞胞外陷阱（NETs）参与治疗耐药肿瘤的中性粒细胞发育和脱颗粒，特别是TNBC和转移病例。利用单细胞RNA测序（scRNA-seq）数据集、来自癌症基因组图谱（TCGA）队列的大量mRNA测序数据、来自METABRIC和GEO数据库的微阵列数据以及表观遗传测序资源，我们全面研究了TNBC中NET阳性肿瘤相关中性粒细胞（NET+ TAN）的功能特征和预后潜力。NET+ TAN衍生的六基因组已被确定为TNBC患者生存的可靠诊断生物标志物，并已在多个独立队列中得到验证。值得注意的是，我们的研究结果表明，NET+ TAN促进TNBC中T细胞重编程，从而建立抑制时间并促进肿瘤进展。本研究对NETs在TNBC患者中的意义提供了一个全面的视角，旨在为NETs从冷肿瘤表型向热肿瘤表型转变的机制提供遗传学和表观遗传学的见解，并为治疗策略提供有价值的建议。

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引用次数: 0

Overcoming the leptomeningeal seeding of medulloblastoma by targeting HSP70 利用HSP70靶向治疗成神经管细胞瘤的小脑膜播散。

IF 5 2区医学 Q2 Medicine

Translational Oncology

Pub Date : 2026-04-01 Epub Date: 2026-02-09 DOI: 10.1016/j.tranon.2026.102695

Seung Ah Choi , Sokhoeun Heng , Saehim Ha , Seung-Ki Kim , Do Won Hwang , Hyewon Youn , Ji Hoon Phi

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.

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.

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.

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.

髓母细胞瘤（MB）经脑脊液播散小脑膜（LMS）是一种常见且常常致命的进展，其预后显著恶化。然而，人们对其分子驱动机制知之甚少，有效的治疗方法仍然有限。本研究旨在通过对种子细胞生物学的详细表征，建立生理相关的MB - LMS模型，并寻找新的治疗靶点。通过三轮连续原位异种移植物移植和体内选择，我们分离出不同的播种（S3）和非播种（N3） MB细胞群。功能和转录组学分析揭示了独特的表型和差异表达基因（DEGs）。基于DEGs，我们筛选了抑制剂，并评估了HSP70抑制剂VER155008单独或与化疗药物（异环磷酰胺或顺铂）在体外和通过小脑植入S3细胞建立的临床前LMS小鼠模型中的治疗效果。与N3细胞相比，S3细胞增殖较慢，迁移行为改变，对IV型胶原的粘附增加。转录组学分析发现，HSP70是S3细胞中表达上调最多的基因，在代谢途径中富集。在6个候选化合物中，VER155008对S3细胞活力的抑制效果最好。在体外，VER155008与4-氢过氧环磷酰胺（活性异环磷酰胺代谢物）联合可产生协同抗肿瘤作用。这种协同作用在体内得到了证实，VER155008与异环磷酰胺显著降低了脊柱LMS。这些发现强调了HSP70作为MB LMS的一个有希望的治疗靶点。观察到的VER155008和异环磷酰胺之间的协同作用支持选择性联合策略，为改善MB轻脑膜播散患者的预后提供了一种新的治疗途径。

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引用次数: 0

SPP1⁺ macrophage-FADS1⁺ tumor cell crosstalk via the PDGFB-PDGFRB axis drives liver metastasis in colorectal cancer SPP1 +巨噬细胞- fads1 +经PDGFB-PDGFRB轴串扰驱动结直肠癌肝转移。

IF 5 2区医学 Q2 Medicine

Translational Oncology

Pub Date : 2026-04-01 Epub Date: 2026-02-07 DOI: 10.1016/j.tranon.2026.102696

Pingfan Zhao , Fuyong Pei , Yanmin Liu , Yinan Jiang , Xiaochang Fang , Lin Shu , Xin Hu , Feiyang Chen , Maohui Feng , Xuanfei Li

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.

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.

肝转移是结直肠癌（CRC）患者死亡的主要原因。然而，促进这一过程的肿瘤-微环境相互作用的机制仍然不明确。在这里，我们开发了一个综合多组学框架来剖析结直肠癌肝转移（CRLM）的细胞和分子决定因素。通过分析1156个转移相关基因，我们确定了三种具有不同预后和免疫代谢特征的分子亚型：C1具有混合表型和有利生存，C2具有代谢激活和免疫抑制，C3具有免疫激活和信号失调，其预后最差。在机制上，我们发现SPP1 +巨噬细胞分泌PDGFB，激活FADS1 +肿瘤细胞中的PDGFRB信号，触发上皮-间质转化（EMT），促进肝转移。通过单细胞转录组学、遗传扰动和共培养实验验证了这种巨噬细胞-肿瘤串扰。总的来说，我们的研究结果确定了巨噬细胞来源的PDGFB-PDGFRB轴驱动结直肠癌肝转移，并强调了克服转移进展和免疫抵抗的潜在治疗靶点。

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引用次数: 0

FOSL1 promotes homologous recombination repair and camptothecin resistance via TCOF1-mediated ribosome biogenesis in non-small cell lung cancer 在非小细胞肺癌中，FOSL1通过tcof1介导的核糖体生物发生促进同源重组修复和喜树碱耐药性

IF 5 2区医学 Q2 Medicine

Translational Oncology

Pub Date : 2026-04-01 Epub Date: 2026-02-12 DOI: 10.1016/j.tranon.2026.102701

Chunmei Hao , Luojun Chen , Fuben Liao , Lulu Chen , Yi Yao , Qibin Song

Background

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.

Methods

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.

Results

We identified FOSL1 as a CPT-responsive transcription factor that was associated with poor prognosis in lung adenocarcinoma. CPT treatment induced FOSL1 expression and nuclear accumulation, whereas FOSL1 depletion markedly enhanced CPT-induced cytotoxicity. Mechanistically, loss of FOSL1 resulted in persistent DNA damage accumulation and selective impairment of homologous recombination (HR) repair. FOSL1 sustained HR repair indirectly by promoting ribosome biogenesis through transcriptional activation of TCOF1. Pharmacological inhibition of ribosome biogenesis phenocopied FOSL1 depletion and significantly potentiated CPT efficacy both in vitro and in vivo.

Conclusion

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.

喜树碱（CPT）及其衍生物是重要的化疗药物；然而，内在的和后天的耐受性往往限制了它们的长期疗效。本研究旨在确定非小细胞肺癌（NSCLC）中CPT反应性的关键转录调节因子，并阐明其潜在的分子机制。方法基于单细胞RNA测序的转录组学分析，结合大量RNA-seq，用于确定cpt应答转录程序的优先级并提名候选调节因子。在非小细胞肺癌细胞系中使用功能获得和功能丧失方法验证了功能作用。DNA损伤修复、核糖体生物发生和翻译活性通过分子和报告基因检测进行评估。使用RNA聚合酶I抑制剂BMH-21评估核糖体生物发生的药理学抑制作用，并在异种移植模型中进一步检查治疗相关性。结果我们发现FOSL1是一种cpt反应性转录因子，与肺腺癌的不良预后相关。CPT处理诱导了FOSL1的表达和核积累，而FOSL1缺失显著增强了CPT诱导的细胞毒性。从机制上讲，FOSL1的缺失导致持续的DNA损伤积累和同源重组（HR）修复的选择性损伤。FOSL1通过TCOF1转录激活促进核糖体生物发生，间接维持HR修复。核糖体生物发生的药理学抑制导致FOSL1耗竭，并显著增强CPT在体内和体外的疗效。我们的研究确定了一个fosl1 - tcof1核糖体轴，通过维持HR修复来促进非小细胞肺癌的CPT耐受性。这些发现为靶向核糖体生物发生以增强基于cpt的治疗提供了理论依据，并强调了化疗应激下转录、蛋白质合成和DNA修复的协调调节。

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引用次数: 0

CMS subtypes correlate with complete response in trial of neoadjuvant Galunisertib plus chemoradiation in rectal cancer 在直肠癌新辅助加放化疗试验中，CMS亚型与完全缓解相关

IF 5 2区医学 Q2 Medicine

Translational Oncology

Pub Date : 2026-04-01 Epub Date: 2026-02-06 DOI: 10.1016/j.tranon.2026.102690

Venkatesh Rajamanickam , Noah D. Simons , Wesley Rosales , Anton Kravchenko , Tomoko Yamazaki , Brady Bernard , Brian Piening , Enric Domingo , Timothy Maughan , Charlems Alvarez-Jimenez , Thomas Desilvio , Satish Viswanath , Mark Whiteford , Amanda Hayman , David O’Brien , Maria X. Kiely , Rehan Ahmad , Michael J. Gough , Marka R. Crittenden , Kristina H. Young

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 <CR, with galunisertib upregulating MYC 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.

改善局部晚期直肠癌患者对新辅助治疗的反应有可能改善器官保存和无病生存。了解哪些患者可能需要从标准治疗升级或降级治疗，仍是一个研究领域。我们之前报道了将转化生长因子β受体抑制剂Galunisertib与局部晚期直肠癌患者的新辅助放化疗联合进行的单臂研究的主要和次要终点。在这里，我们分析了基线和2周galunisertib后组织活检获得的RNA测序数据。在完全缓解者（CR）和完全缓解者（lt；CR）之间，观察到MYC、炎症和上皮-间质转化相关基因的表达差异，galunisertib上调CR中MYC通路的表达。放射敏感性和TGFβ反应评分表明，预测galunisertib +放化疗反应的能力有限。典型的治疗耐药共识分子亚型4 (CMS4)，以TGFβ表达为特征，和代谢亚型（CMS3）与galunisertib +放化疗反应相关。在CIBERSORT、MCPcounter和xCell方法中，观察到基于RNA的细胞组成测量和浸润的免疫组织学定量与提取的MRI参数之间的相关性差异。基于这些数据，我们假设可以通过在直肠癌放化疗中添加galunisertib来克服TGFβ驱动的基质放射抗性表型。

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引用次数: 0

Development and validation of prognostic nomograms based on peripheral blood T-cell counts and their dynamic changes for patients with nasopharyngeal carcinoma receiving radiotherapy 基于外周血t细胞计数及其动态变化的鼻咽癌放疗患者预后图的开发和验证。

IF 5 2区医学 Q2 Medicine

Translational Oncology

Pub Date : 2026-04-01 Epub Date: 2026-02-07 DOI: 10.1016/j.tranon.2025.102661

Kegui Weng , Qianqian Lei , Ye Hong , Kaihua Chen , Yongchu Sun , Ying Wang , Xiaodong Zhu

Aim

To develop and validate prognostic nomograms incorporating peripheral blood lymphocyte counts and their dynamic changes in patients with nasopharyngeal carcinoma (NPC) undergoing radiotherapy.

Methods

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.

Results

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.

Conclusion

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.

目的：建立并验证鼻咽癌放疗患者外周血淋巴细胞计数及其动态变化的预后形态图。方法：采用回顾性队列研究，将在重庆大学肿瘤医院连续接受放疗的鼻咽癌患者作为内部队列（随机分为70% / 30%进行培训和验证），将在广西医科大学肿瘤医院治疗的患者作为外部验证队列。使用多变量Cox回归分析构建无进展生存期（PFS）和总生存期（OS）的预后图。结果：内部和外部队列分别包括746例和138例患者。年龄、肿瘤总体积剂量、新辅助化疗、临床分期、血浆EBV-DNA水平、基线总t细胞计数及其治疗后变化（ΔT细胞）被确定为独立的预后因素。在训练集、内部验证集和外部数据集中，PFS的一致性指数分别为0.701、0.716和0.714，OS的一致性指数分别为0.759、0.735和0.734，显示出较强的预测性能。在所有队列中，3年和5年PFS和OS的受试者工作特征曲线下的面积均超过0.7。校正图显示预测结果与观察结果吻合良好，决策曲线分析证实，与TNM分期和基于ebv - dna的模型相比，净临床获益更大。结论：提出的基于t细胞的x线图可靠地预测鼻咽癌放疗患者的PFS和OS，并在外部队列中得到验证。这些模型提供了优于传统分期系统的预后判别，并可能有助于个体化风险分层和管理规划。

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引用次数: 0

Imaging–guided optimization of biodistribution and antitumor efficacy of L19-based immunocytokines 基于l19的免疫细胞因子的生物分布和抗肿瘤效果的成像引导优化

IF 5 2区医学 Q2 Medicine

Translational Oncology

Pub Date : 2026-04-01 Epub Date: 2026-02-13 DOI: 10.1016/j.tranon.2026.102698

Tommaso Virgilio , Kamil Chahine , Jordi Guixeras Carreras , Alain Pulfer , Chiara Pizzichetti , Irene Latino , Daniel Molina-Romero , Arianna Capucetti , Louis Luca Renner , Dario Neri , Emanuele Puca , Roberto De Luca , Santiago F. Gonzalez

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.

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 ex vivo 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.

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.

基于抗体的药物靶向递送是一种有吸引力的方法，可以优先将抗癌有效载荷定位到肿瘤病变。L19抗体对纤维连接蛋白的额外结构域B具有特异性，在涉及不同肿瘤类型的临床试验中研究了几种抗体-细胞因子融合蛋白。然而，提高基于l19的免疫疗法的疗效需要详细了解递送策略如何影响肿瘤内分布和治疗结果。在这项研究中，我们研究了L19抗体在小鼠原发性Eμ-myc淋巴瘤和转移性MC38结肠癌模型中的生物分布。通过高分辨率体内和离体显微镜，我们比较了皮下注射和静脉注射L19，发现注射后10-30分钟内，L19在肿瘤浸润淋巴结内迅速积聚。虽然这两种途径都能初始靶向肿瘤，但静脉注射可延长滞留时间（长达72小时），并对肿瘤相关血管有更大的选择性。相比之下，s.c.的递送有利于淋巴血管附近的短暂积聚，并显示出肿瘤停留时间缩短。这些分布模式直接影响了L19-IL2免疫细胞因子的治疗效果，在MC38模型中静脉给药后显示出更好的肿瘤控制，与该模型中增强的血管化一致。我们的研究结果表明，在原发性和转移性疾病中，L19结合血液和淋巴血管，强调了给药途径对抗体生物分布、微观解剖定位和治疗结果的关键影响。此外，这项工作强调了显微镜指导分析在优化给药策略中的效用，并支持基于抗体治疗中基于肿瘤类型和血管环境定制给药路线的基本原理。

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引用次数: 0

The novel tertiary amine LSD1 inhibitor 596 inhibits endometrial cancer through the mTOR signal transduction pathway 新型叔胺类LSD1抑制剂596通过mTOR信号转导途径抑制子宫内膜癌。

IF 5 2区医学 Q2 Medicine

Translational Oncology

Pub Date : 2026-04-01 Epub Date: 2026-02-10 DOI: 10.1016/j.tranon.2026.102688

Chunli Wang , Dandan Shen , Nanshan Lin , Panjie Wang , Yaping Bi , Huina Hu , Yujia Shang , Chenchen Ren , Li Yang , Qisheng Ma

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.

赖氨酸特异性去甲基酶1 （Lysine-specific demethylase 1, LSD1）在肿瘤的发生发展中起着重要作用，是肿瘤治疗中一个很有前景的靶点。然而，关于LSD1在子宫内膜癌（EC）中的研究确实有限，针对EC的LSD1抑制剂的相关研究更是罕见。本研究开发了新型叔胺类LSD1抑制剂-596。596能特异性靶向LSD1，并以剂量依赖的方式抑制H3K4me1/2的去甲基化水平，从而在体外和体内抑制EC细胞的增殖。此外，深入研究表明，596通过自噬途径诱导EC细胞死亡，增加自噬体的形成和自噬相关蛋白的表达。转录组测序显示596诱导的基因富集与PI3K/AKT/mTOR通路有关。596处理组能够减弱mTOR信号级联的激活，596与mTOR抑制剂雷帕霉素（rapamycin， RAPA）联合处理能有效降低EC细胞的存活率、迁移能力和侵袭能力。进一步的体外和体内研究表明，596可以降低mTOR抑制剂雷帕霉素介导的AKT的反馈激活。综上所述，我们的研究结果表明LSD1抑制剂596通过减弱AKT的反馈激活来增强mTOR抑制剂的活性。LSD1可能是EC的潜在治疗靶点，LSD1抑制剂是EC治疗的重要治疗策略。

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引用次数: 0