Cancer letters最新文献_第6页

The Zeb1/system Xc− axis safeguards iron-loaded cancer-associated fibroblasts against ferroptosis and promotes immunosuppression in prostate cancer Zeb1/System Xc- Axis保护铁负载癌相关成纤维细胞免受铁凋亡并促进前列腺癌的免疫抑制。

IF 10.1 1区医学 Q1 ONCOLOGY

Cancer letters

Pub Date : 2026-01-02 DOI: 10.1016/j.canlet.2026.218243

Yingchao Zhang , Huifang Zhao , Penghui Xu , Kaiyuan Liu , Genyu Du , Xinyu Chen , Na Jing , Wei Bao , Chaping Cheng , Jinming Wang , Mingyue Wang , Nan Wang , Xialian Xi , Yiyun Liu , Yujiao Sun , Wei-Qiang Gao , Helen He Zhu , Kai Zhang

A subset of iron-loaded cancer-associated fibroblasts is unraveled in the tumor microenvironment of prostate cancer (PCa) and termed as the ferrum iron CAFs (FerroCAFs) in our previous study. Importantly, FerroCAFs have been identified as a source of C-C motif ligand 2 (CCL2), C-X-C motif ligand chemokines 1/2 (CXCL1/2), and colony-stimulating factor 1 (CSF1) to induce immunosuppression. However, the iron-loaded phenotype of FerroCAFs also elicits high amounts of lethal oxygen radicals, lipid peroxides and reactive oxygen species (ROS) due to iron excess. Consequently, the mechanism by which FerroCAFs resist ferroptosis, a form of cell death induced by iron-dependent lipid peroxidation, remains to be elucidated. Here, we find that the upregulation of cystine/glutamate antiporter System X_c⁻, specifically Slc7a11, functions as a protective mechanism that preserves FerroCAFs against ferroptosis. The zinc finger E-box binding homeobox 1 (Zeb1) occupies the Slc7a11 gene promoter region and activates Slc7a11 transcription. Knockdown of FerroCAF-specific Slc7a11 suppresses tumor growth and subverts immunosuppression. Collectively, this study demonstrates that Zeb1/System X_c⁻ axis protects FerroCAFs against ferroptosis. Targeting this vulnerability of FerroCAFs by blockade of Zeb1/System X_c⁻ axis provokes anti-tumor immunity in PCa, implying a promising CAF-centric immunotherapeutic strategy.

在我们之前的研究中，在前列腺癌（PCa）的肿瘤微环境中发现了一种负载铁的癌症相关成纤维细胞亚群，称为铁CAFs （FerroCAFs）。重要的是，FerroCAFs已被确定为C-C基序配体2 （CCL2）、C-X-C基序配体趋化因子1/2 （CXCL1/2）和集落刺激因子1 （CSF1）的来源，可诱导免疫抑制。然而，铁负载型的FerroCAFs也会由于铁过量而引起大量的致命氧自由基、脂质过氧化物和活性氧（ROS）。因此，FerroCAFs抵抗铁下垂（一种由铁依赖性脂质过氧化引起的细胞死亡形式）的机制仍有待阐明。在这里，我们发现胱氨酸/谷氨酸反转运系统Xc-的上调，特别是Slc7a11，作为保护FerroCAFs免受铁凋亡的保护机制。锌指E-box结合同源盒1 （Zeb1）占据Slc7a11基因启动子区域，激活Slc7a11转录。敲低ferrocaf特异性Slc7a11抑制肿瘤生长和破坏免疫抑制。总的来说，本研究表明Zeb1/System Xc- axis保护FerroCAFs免受铁下垂。通过阻断Zeb1/System Xc-轴靶向FerroCAFs的这一脆弱性，可以在PCa中激发抗肿瘤免疫，这意味着一种有前途的以cafc为中心的免疫治疗策略。

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引用次数: 0

CAR-T Cell Exhaustion in Cancer over the Past Decade: Mitochondrial Metabolism as a Target for Counteraction CAR-T细胞衰竭在过去十年中的癌症：线粒体代谢作为对抗的目标。

IF 10.1 1区医学 Q1 ONCOLOGY

Cancer letters

Pub Date : 2026-01-02 DOI: 10.1016/j.canlet.2026.218240

Lingling Si , Di Wei , Jinghao Pan , Renato B. Baleeiro , Louisa S. Chard Dunmall , Yaohe Wang

Chimeric antigen receptor T (CAR-T) cell therapy has emerged as a transformative advancement in cancer immunotherapy, but remains limited by multiple challenges. The exhaustion of T cells represents a critical obstacle limiting the success of immunotherapeutic interventions. Targeting mitochondrial metabolism offers a promising approach to mitigate exhaustion and enhance CAR-T persistence. Mechanistically, mitochondrial dysfunction within the tumor microenvironment disrupts energy metabolism, reactive oxygen species (ROS) homeostasis, and cell survival, impairing CAR-T function. Here, we review the current challenges facing the clinical application of CAR-T therapy in cancers and summarize mitochondrial-centered approaches to overcome some of these obstacles by optimizing mitochondrial metabolic pathways. We emphasize the essential role of mitochondrial metabolism in augmenting therapeutic efficacy and persistence of CAR-T cells. Future breakthroughs will depend on robust clinical evidence and precise metabolic modulation to enhance CAR-T therapies.

嵌合抗原受体T （CAR-T）细胞疗法已成为癌症免疫治疗的一项革命性进展，但仍受到多重挑战的限制。T细胞的衰竭是限制免疫治疗干预成功的关键障碍。靶向线粒体代谢为缓解衰竭和增强CAR-T持久性提供了有希望的方法。从机制上讲，肿瘤微环境中的线粒体功能障碍会破坏能量代谢、活性氧（ROS）稳态和细胞存活，从而损害CAR-T功能。在这里，我们回顾了目前CAR-T治疗在癌症临床应用中面临的挑战，并总结了以线粒体为中心的方法，通过优化线粒体代谢途径来克服这些障碍。我们强调线粒体代谢在增强CAR-T细胞的治疗效果和持久性方面的重要作用。未来的突破将取决于强有力的临床证据和精确的代谢调节来增强CAR-T疗法。

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引用次数: 0

KLF7 promotes progression of Head and Neck Squamous Cell Carcinoma by remodeling tumor immune microenvironment KLF7通过重塑肿瘤免疫微环境促进头颈部鳞状细胞癌的进展

IF 10.1 1区医学 Q1 ONCOLOGY

Cancer letters

Pub Date : 2025-12-31 DOI: 10.1016/j.canlet.2025.218237

Xin Fan , Wenying Chen , Yuzhou Wang , Fang Liu , Minhua Zheng , Ningbo Wang , Yuchen Wei , Yu Jiang , Xiuli Mu , Zhuan Ju , Xiaofang Zhang , Rui Zhang , Ka Bian

Aberrantly high activation of oncogenic transcription factors has been implicated in initiation and progression of malignant diseases. However, the landscape of dysregulated TFs in HNSCC remains poorly characterized, and especially their biological contributions to remodeling of cancer immune microenvironment are unknown. Here, by globally investigating oncogenic TF-target interactions in clinic, we identified that KLF7 is one of the most potential oncogenic TFs in HNSCC. In vitro and in vivo experiments showed that KLF7 governs not only the autonomous malignant behaviors but also recruitment of macrophage in the cancer microenvironment, consequently promoting progression of HNSCC in a tumor-associated macrophage (TAM) dependent manner. Mechanistically, we found that LOX is a bona fide target directly transcriptionally activated by KLF7 in HNSCC cells. In vivo assay showed that LOX-driven crosslinking of extracellular matrix conducted a stiff extracellular matrix environment for macrophage recruitment and consequent disruption of CD8⁺ T cell mediated killing effect in cancer microenvironment. More importantly, we elucidated the clinical significance of the correlation of KLF7, LOX and TAM in HNSCCs. Our study reveals an extrinsic mechanism of the oncogenic role of KLF7 and further demonstrates that a KLF7/LOX/TAM signaling could be a potential therapeutic vulnerability for HNSCC patients.

致癌转录因子的异常高激活与恶性疾病的发生和发展有关。然而，在HNSCC中，TFs失调的情况仍然不清楚，特别是它们对癌症免疫微环境重塑的生物学贡献尚不清楚。在这里，通过在全球范围内研究临床中的致癌tf靶点相互作用，我们发现KLF7是HNSCC中最潜在的致癌tf之一。体外和体内实验表明，KLF7不仅调控自主恶性行为，还调控肿瘤微环境中巨噬细胞的募集，从而以肿瘤相关巨噬细胞（TAM）依赖的方式促进HNSCC的进展。在机制上，我们发现LOX在HNSCC细胞中是KLF7直接转录激活的真正靶点。体内实验表明，lox驱动的细胞外基质交联为巨噬细胞募集提供了一个坚硬的细胞外基质环境，从而破坏了CD8+ T细胞介导的癌症微环境中的杀伤作用。更重要的是，我们阐明了KLF7、LOX和TAM在HNSCCs中的相关性的临床意义。我们的研究揭示了KLF7致癌作用的外在机制，并进一步证明KLF7/LOX/TAM信号可能是HNSCC患者的潜在治疗脆弱性。

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引用次数: 0

Co-phagocytosis by bispecific antibodies, a novel strategy for targeted degradation of soluble factors in the tumor microenvironment 双特异性抗体的共吞噬作用，肿瘤微环境中可溶性因子靶向降解的新策略。

IF 10.1 1区医学 Q1 ONCOLOGY

Cancer letters

Pub Date : 2025-12-29 DOI: 10.1016/j.canlet.2025.218236

Zhen Fan

引用次数: 0

Anti-BCMA-CAR-IL15 natural killer cells prevent multiple myeloma growth in the bone marrow but allow subsequent emergence of extramedullary disease 抗bcma - car - il - 15自然杀伤细胞可防止多发性骨髓瘤在骨髓中的生长，但随后会出现髓外疾病。

IF 10.1 1区医学 Q1 ONCOLOGY

Cancer letters

Pub Date : 2025-12-24 DOI: 10.1016/j.canlet.2025.218235

Shelby Kaczmarek , Donghyeon Jo , Safa Ghaziasgar , Bryan Marr , Stefania Berton , Lisheng Wang , Mehdi Arbabi Ghahroudi , Mihue Jang , Alissa Visram , Scott McComb , Seung-Hwan Lee

Multiple myeloma (MM) is an aggressive blood cancer arising from plasma cells. B cell maturation antigen (BCMA)-directed chimeric antigen receptor T cell (α-BCMA-CAR-T) immunotherapies currently provide life-saving treatment for MM patients. Unfortunately, the high cost and manufacturing complexity of autologous CAR-T therapy remain important limitations. Novel research is underway to use CAR-expressing natural killer (NK) cells as an allogeneic CAR-T alternative, but studies have yet to evaluate long-term CAR-NK efficacy against MM. In this study, NK cells were isolated, expanded via feeder-cell stimulation, and engineered to express α-BCMA-CAR with or without human IL-15 co-expression using lentiviral vectors. In a xenograft model, both α-BCMA-CAR and IL-15 expression were required for persistent restriction of MM growth in the blood and bone marrow. Despite near complete and sustained elimination of MM in the bone marrow, long-term assessment of mice treated with α-BCMA-CAR-IL15 NK cells revealed the emergence of extramedullary disease (EMD) in the form of BCMA-positive MM plasmacytomas. This study showcases α-BCMA-CAR-IL15 NK cell therapy as a potent anti-MM therapeutic, achieving sustained MM elimination from the bone marrow and greatly extending survival. However, α-BCMA-CAR-IL15 NK cells appeared ineffective at eliminating extramedullary disease. By demonstrating the strengths and weaknesses of α-BCMA-CAR-IL15 cells, we hope this study could help direct the use of such therapies in clinical trials and provide a valuable pre-clinical MM model for studying and developing interventions for aggressive MM-EMD.

多发性骨髓瘤（MM）是一种起源于浆细胞的侵袭性血癌。B细胞成熟抗原（BCMA）靶向嵌合抗原受体T细胞（α-BCMA-CAR-T）免疫疗法目前为MM患者提供了挽救生命的治疗方法。不幸的是，自体CAR-T疗法的高成本和制造复杂性仍然是重要的限制。新的研究正在进行中，使用表达car的自然杀伤（NK）细胞作为异体CAR-T的替代品，但研究尚未评估CAR-NK对MM的长期疗效。在这项研究中，NK细胞被分离，通过饲养细胞刺激扩增，并利用慢病毒载体表达α-BCMA-CAR，或不表达人IL-15共表达。在异种移植模型中，α-BCMA-CAR和IL-15的表达是持续限制MM在血液和骨髓中的生长所必需的。尽管骨髓中的MM几乎完全和持续消除，但α-BCMA-CAR-IL15 NK细胞治疗小鼠的长期评估显示，髓外疾病（EMD）以bcma阳性MM浆细胞瘤的形式出现。本研究表明α-BCMA-CAR-IL15 NK细胞治疗是一种有效的抗MM治疗方法，可实现骨髓中MM的持续消除，并大大延长生存期。然而，α-BCMA-CAR-IL15 NK细胞在消除髓外疾病方面似乎无效。通过展示α-BCMA-CAR-IL15细胞的优势和劣势，我们希望本研究能够帮助指导此类疗法在临床试验中的应用，并为研究和开发侵袭性MM- emd的干预措施提供有价值的临床前MM模型。

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引用次数: 0

A novel phenomena: extrachromosomal DNA harboring highly amplified and overexpressed genes undergo intercellular transmission in ovarian cancer cells 一种新的现象：染色体外DNA携带高度扩增和过表达的基因在卵巢癌细胞中进行细胞间传播。

IF 10.1 1区医学 Q1 ONCOLOGY

Cancer letters

Pub Date : 2025-12-24 DOI: 10.1016/j.canlet.2025.218231

Kexian Dong , Mengdi Cai , Xueyuan Jia , Han Qu , Rong Guan , Shuomeng Du , Wankui Ren , Qiao Li , Shihao Zhu , Linlin Li , Wenjing Sun , Songbin Fu

引用次数: 0

A phase Ib/II trial of XL888 (HSP90 inhibitor) and pembrolizumab in metastatic pancreatic cancer with translational immune profiling XL888 （HSP90抑制剂）和派姆单抗治疗转移性胰腺癌的Ib/II期临床试验

IF 10.1 1区医学 Q1 ONCOLOGY

Cancer letters

Pub Date : 2025-12-23 DOI: 10.1016/j.canlet.2025.218233

Natalie K. Horvat , Maria Diab , Maggie J. Phillips , Ashley McCook-Veal , Erin E. Grundy , Olatunji B. Alese , Emily Greene , Olumide Gbolahan , Kathleen Coleman , Deon Doxie , Cameron J. Herting , Jacklyn Hammons , Zaid Mahdi , Jeffrey M. Switchenko , Chrystal M. Paulos , Bassel F. El-Rayes , Gregory B. Lesinski

Pancreatic adenocarcinoma is marked by high mortality and limited treatment options. In mice, HSP90 inhibition limits cancer-associated fibroblasts activation and enhances T cell infiltration, sensitizing tumors to PD-1 blockade. We hypothesized that co-administration of pembrolizumab (anti-PD-1) with XL888 (an HSP90 inhibitor) would be safe and induce measurable immunological changes in the PDAC tumor microenvironment that could influence clinical outcome.

We report results from an expansion cohort of patients with advanced PDAC (n = 16), who were enrolled in a single-center, open-label, nonrandomized, dose-escalation study. Patients received one cycle of either pembrolizumab (200 mg) alone or in combination with XL888 (90 mg, orally twice per week) over a 21-day cycle, followed by crossover to combination therapy. Peripheral blood and image guided liver biopsies were collected on Day 1 before treatment (C1D1) and Day 15 on-treatment (C1D15) for correlative studies.

The combination regimen was well-tolerated with no unexpected adverse events. No objective responses were observed; two patients (13.3 %) achieved stable disease, while the remaining 13 (86.7 %) experienced disease progression. Median progression-free survival was 2.0 months, and median overall survival was 4.4 months. Treatment was associated with increased circulating Th1-associated cytokines and chemokines. Peripheral blood mononuclear cell (PBMC) analysis revealed elevated terminal effector CD8⁺ T cells and CD4⁺ regulatory T cells in the combination arm compared to pembrolizumab alone. Paired liver biopsies revealed no significant changes across treatment groups.

While the combination of XL888 and pembrolizumab was safe and induced systemic immune modulation, limited clinical efficacy was observed and did not impact the PDAC TME.

胰腺腺癌的特点是高死亡率和有限的治疗选择。在小鼠中，抑制HSP90限制了癌症相关成纤维细胞的激活，增强了T细胞的浸润，使肿瘤对PD-1阻断敏感。我们假设pembrolizumab（抗pd -1）与XL888（一种HSP90抑制剂）联合给药是安全的，并且会在PDAC肿瘤微环境中诱导可测量的免疫变化，从而影响临床结果。我们报告了一项扩展队列的结果，这些患者（n=16）被纳入了一项单中心、开放标签、非随机、剂量递增的研究。患者接受一个周期的pembrolizumab （200 mg）单独或与XL888 （90 mg，每周口服两次）在21天的周期，然后交叉到联合治疗。在治疗前第1天（C1D1）和治疗后第15天（C1D15）采集外周血和图像引导下的肝活检进行相关研究。联合治疗方案耐受性良好，无意外不良事件。未观察到客观反应；2例（13.3%）病情稳定，其余13例（86.7%）病情进展。中位无进展生存期为2.0个月，中位总生存期为4.4个月。治疗与循环th1相关的细胞因子和趋化因子增加有关。外周血单核细胞（PBMC）分析显示，与单独使用派姆单抗相比，联合用药组的末端效应CD8+ T细胞和CD4+调节性T细胞升高。配对肝活检显示各组间无显著变化。虽然XL888联合派姆单抗是安全的，并能诱导全身免疫调节，但临床疗效有限，不影响PDAC TME。

{"title":"A phase Ib/II trial of XL888 (HSP90 inhibitor) and pembrolizumab in metastatic pancreatic cancer with translational immune profiling","authors":"Natalie K. Horvat , Maria Diab , Maggie J. Phillips , Ashley McCook-Veal , Erin E. Grundy , Olatunji B. Alese , Emily Greene , Olumide Gbolahan , Kathleen Coleman , Deon Doxie , Cameron J. Herting , Jacklyn Hammons , Zaid Mahdi , Jeffrey M. Switchenko , Chrystal M. Paulos , Bassel F. El-Rayes , Gregory B. Lesinski","doi":"10.1016/j.canlet.2025.218233","DOIUrl":"10.1016/j.canlet.2025.218233","url":null,"abstract":"<div><div>Pancreatic adenocarcinoma is marked by high mortality and limited treatment options. In mice, HSP90 inhibition limits cancer-associated fibroblasts activation and enhances T cell infiltration, sensitizing tumors to PD-1 blockade. We hypothesized that co-administration of pembrolizumab (anti-PD-1) with XL888 (an HSP90 inhibitor) would be safe and induce measurable immunological changes in the PDAC tumor microenvironment that could influence clinical outcome.</div><div>We report results from an expansion cohort of patients with advanced PDAC (n = 16), who were enrolled in a single-center, open-label, nonrandomized, dose-escalation study. Patients received one cycle of either pembrolizumab (200 mg) alone or in combination with XL888 (90 mg, orally twice per week) over a 21-day cycle, followed by crossover to combination therapy. Peripheral blood and image guided liver biopsies were collected on Day 1 before treatment (C1D1) and Day 15 on-treatment (C1D15) for correlative studies.</div><div>The combination regimen was well-tolerated with no unexpected adverse events. No objective responses were observed; two patients (13.3 %) achieved stable disease, while the remaining 13 (86.7 %) experienced disease progression. Median progression-free survival was 2.0 months, and median overall survival was 4.4 months. Treatment was associated with increased circulating Th1-associated cytokines and chemokines. Peripheral blood mononuclear cell (PBMC) analysis revealed elevated terminal effector CD8<sup>+</sup> T cells and CD4<sup>+</sup> regulatory T cells in the combination arm compared to pembrolizumab alone. Paired liver biopsies revealed no significant changes across treatment groups.</div><div>While the combination of XL888 and pembrolizumab was safe and induced systemic immune modulation, limited clinical efficacy was observed and did not impact the PDAC TME.</div></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"639 ","pages":"Article 218233"},"PeriodicalIF":10.1,"publicationDate":"2025-12-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145833202","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

HNRNPC lactylation promotes pancreatic cancer progression through mediating the alternative splicing of PAK6 HNRNPC乳酸化通过介导PAK6的选择性剪接促进胰腺癌的进展。

IF 10.1 1区医学 Q1 ONCOLOGY

Cancer letters

Pub Date : 2025-12-22 DOI: 10.1016/j.canlet.2025.218230

BoHao Li , HanXiang Zhan , Fei Gao , MingXin Wen , Yunhan Ma , YuChen Xiu , ZhenYa Liu , KaiWei Huang , YunShan Wang , GuangWei Wei , YangMiao Duan

Pancreatic cancer (PC) is a highly malignant and lethal tumor in gastrointestinal tract. Lactate accumulation is a classical feature of metabolic reprogramming in cancers. Lactate-derived lysine lactylation (Kla) is identified as a new type of post-translational modifications (PTMs), which is confirmed to be involved in multiple biological processes. However, the cancer-specific regulation of protein Kla in PC requires further elucidation. Here, we report a range of dysregulated Kla sites specifically related to RNA splicing in human pancreatic cancer, leading to the observation that the Kla at lysine 176 of heterogeneous nuclear ribonucleoprotein C (HNRNPC K176la) is significantly elevated in PC. Blocking HNRNPC K176la dramatically inhibits pancreatic cancer growth and metastasis. Mechanistically, K176la strengthened the binding of HNRNPC with poly-U motifs in p21-activated kinase 6 (PAK6) pre-mRNA, facilitating the expression of the oncogenic isoform PAK6S. Therefore, our study identifies a number of cancer-specific Kla sites spanned on alternative splicing (AS)-related proteins and unravels the significance of HNRNPC K176la in RNA splicing and PC development.

胰腺癌是一种高度恶性、致死性的胃肠道肿瘤。乳酸积累是癌症代谢重编程的典型特征。乳酸源性赖氨酸乳酸化（Lactate-derived lysine lactyation, Kla）是一种新型的翻译后修饰（post-translational modification, PTMs），被证实参与多种生物过程。然而，蛋白质Kla在PC中的癌症特异性调控需要进一步阐明。在这里，我们报道了一系列与人类胰腺癌中RNA剪接特异性相关的Kla位点失调，导致观察到异质核核糖核蛋白C （HNRNPC K176la）赖氨酸176处的Kla在PC中显著升高。阻断HNRNPC K176la可显著抑制胰腺癌生长和转移。在机制上，K176la增强了HNRNPC与p21活化激酶6 （PAK6）前体mrna中多u基序的结合，促进了致癌亚型PAK6S的表达。因此，我们的研究确定了一些癌症特异性的Kla位点跨越在选择性剪接（AS）相关蛋白上，并揭示了HNRNPC K176la在RNA剪接和PC发育中的意义。

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引用次数: 0

YTHDF2-mediated stabilization of SREBF1 promotes lipid metabolic reprogramming and ferroptosis-associated radioresistance in anaplastic thyroid carcinoma ythdf2介导的SREBF1的稳定促进了间变性甲状腺癌的脂质代谢重编程和铁中毒相关的放射耐药。

IF 10.1 1区医学 Q1 ONCOLOGY

Cancer letters

Pub Date : 2025-12-21 DOI: 10.1016/j.canlet.2025.218232

Bao Dai , Jinghua Li , Lei Xu , Weijian Chen , Jianghong Chen , Muye Song , Yongchen Liu , Linhe Wang , Lingyun Zhang , Jian Chen , Zeyu Wu

Anaplastic thyroid carcinoma (ATC) is the most aggressive endocrine malignancy and frequently resistant to radiotherapy. Lipid metabolic reprogramming has been implicated in ferroptosis evasion and therapeutic resistance in cancers; however, the specific mechanisms of lipid metabolic rewiring in regulating radioresistance in ATC remain unclear. This study employed an integrated multi-omics profiling, including RNA sequencing (RNA-seq), methylated RNA immunoprecipitation sequencing (MeRIP-seq), and RNA immunoprecipitation sequencing (RIP-seq), lipidomics profiling, and mRNA stability assays, to characterize YTHDF2- mediated regulation of metabolic pathways in ATC. Functional validation assessments were performed using Seahorse XF metabolic flux analysis, fluorescence recovery after photobleaching (FRAP) imaging, ferroptosis induction/rescue models, and radiation-exposed xenograft models. Our results demonstrated that YTHDF2 directly bound to N⁶-methyladenosine (m⁶A)-modified motifs within the 3′ untranslated region (3′UTR) of SREBF1 mRNA, thereby enhancing its stability and promoting the expression of downstream lipogenic enzymes, including stearoyl-CoA desaturase-1(SCD1). This lipid remodeling increased membrane fluidity, suppressed ferroptosis, and protected cells from lipid peroxidation while sustaining mitochondrial respiration, accompanied by maintenance of cellular homeostasis, including endoplasmic reticulum integrity. Notably, reintroduction of SREBF1 in YTHDF2-deficient ATC cells restored radiotolerance and reversed ferroptotic susceptibility. Additionally, both pharmacologic and genetic inhibition of YTHDF2 significantly sensitized tumors to ionizing radiation and increased ferroptosis-associated cytotoxicity in vivo. Our findings reveal a novel regulatory YTHDF2–SREBF1 axis that links m⁶A-dependent post-transcriptional regulation to ferroptosis modulation through lipid metabolic remodeling. Therapeutically targeting the YTHDF2-SREBF1 pathway may represent a promising strategy to overcome radiotherapy resistance in ATC through metabolic intervention.

甲状腺间变性癌（ATC）是最具侵袭性的内分泌恶性肿瘤，常对放疗产生抵抗。脂质代谢重编程与癌症中铁中毒逃避和治疗耐药有关；然而，脂质代谢重布线调节ATC辐射抵抗的具体机制尚不清楚。本研究采用综合多组学分析，包括RNA测序（RNA-seq）、甲基化RNA免疫沉淀测序（MeRIP-seq）和RNA免疫沉淀测序（RIP-seq）、脂质组学分析和mRNA稳定性分析，来表征YTHDF2介导的ATC代谢途径的调节。通过海马XF代谢通量分析、光漂白后荧光恢复（FRAP）成像、铁下垂诱导/救援模型和辐射暴露的异种移植物模型进行功能验证评估。我们的研究结果表明，YTHDF2直接结合SREBF1 mRNA 3‘非翻译区（3’ utr）内n6 -甲基腺苷（m6A）修饰的基元，从而增强其稳定性并促进下游脂质酶的表达，包括硬脂酰辅酶a去饱和酶-1（SCD1）。这种脂质重塑增加了膜流动性，抑制了铁下沉，保护细胞免受脂质过氧化，同时维持线粒体呼吸，同时维持细胞稳态，包括内质网的完整性。值得注意的是，在ythdf2缺陷的ATC细胞中重新引入SREBF1可以恢复放射耐受性并逆转铁致衰敏感性。此外，在体内，YTHDF2的药理学和遗传抑制均显著使肿瘤对电离辐射敏感，并增加与铁中毒相关的细胞毒性。我们的研究结果揭示了一种新的调控YTHDF2-SREBF1轴，该轴通过脂质代谢重塑将m6a依赖性转录后调控与铁死亡调节联系起来。治疗上靶向YTHDF2-SREBF1途径可能是通过代谢干预克服ATC放疗耐药的一种有希望的策略。

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引用次数: 0

Targeting ephrin receptor A10 with antibody-drug conjugates for breast cancer 靶向Ephrin受体A10的抗体-药物偶联物治疗乳腺癌。

IF 10.1 1区医学 Q1 ONCOLOGY

Cancer letters

Pub Date : 2025-12-19 DOI: 10.1016/j.canlet.2025.218225

Mahdieh Safaei , Yi-Chuan Li , Chung-Yu Chen , Ping-Hua Hsieh , Srimathi Venkataraman , Wei-Chien Huang , Wei-Chung Cheng , Hirohito Yamaguchi , Yu-Fu Chen , Yuan-Soon Ho , Wei-Chao Chang , Chih-Wei Lin , Mien-Chie Hung

Despite advances in breast cancer therapy, effective treatment options remain a challenge. The Ephrin receptor A10 (EphA10), a receptor tyrosine kinase, has been reported to be overexpressed in several cancers, including breast and ovarian cancers yet absent in the majority of normal cells except for the male testis. This unique expression profile makes EphA10 an ideal therapeutic target for cancers in women. However, effective EphA10-directed therapies have yet to be developed. To investigate the therapeutic potential of targeting EphA10, we evaluated an antibody drug conjugate strategy. For this purpose, chimeric and humanized EphA10 antibodies were generated and conjugated with monomethyl auristatin E (MMAE). The results showed that EphA10-MMAE exhibited strong cytotoxic effects against EphA10-positive breast cancer cells, including those resistant to FDA-approved drugs such as trastuzumab, lapatinib, PARP inhibitors, and cyclin-dependent kinases 4 and 6 inhibitors. Taken together, these findings highlight EphA10-MMAE as a promising therapeutic strategy for breast cancer, with the potential to overcome drug resistance to existing treatments.

尽管乳腺癌治疗取得了进展，但有效的治疗选择仍然是一个挑战。Ephrin受体A10 （EphA10）是一种酪氨酸激酶受体，据报道在包括乳腺癌和卵巢癌在内的几种癌症中过度表达，但在除男性睾丸外的大多数正常细胞中不存在。这种独特的表达谱使EphA10成为女性癌症的理想治疗靶点。然而，有效的epha10定向疗法尚未开发出来。为了研究靶向EphA10的治疗潜力，我们评估了一种抗体药物偶联策略。为此，我们制备了嵌合和人源化的EphA10抗体，并与单甲基aurisatin E （MMAE）偶联。结果显示，EphA10-MMAE对epha10阳性乳腺癌细胞表现出很强的细胞毒性作用，包括那些对fda批准的药物耐药的细胞，如曲妥珠单抗、拉帕替尼、PARP抑制剂和周期蛋白依赖性激酶4和6抑制剂。综上所述，这些发现突出了EphA10-MMAE作为一种有希望的乳腺癌治疗策略，具有克服现有治疗药物耐药性的潜力。

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引用次数: 0