Cancer letters最新文献_第10页

Application of targeted deep sequencing for management of hepatocellular carcinoma in a real-world setting: prediction of MRD and adjuvant lenvatinib response 靶向深度测序在肝细胞癌治疗中的应用：预测MRD和lenvatinib的辅助反应。

IF 10.1 1区医学 Q1 ONCOLOGY

Cancer letters

Pub Date : 2025-12-08 DOI: 10.1016/j.canlet.2025.218212

Shi-Yu Zhang , De-Zhen Guo , Xin Zhang , Zhu-Jun Gu , Ling Aye , Jia-Yan Yan , Kai Zhu , Xiu-Tao Fu , Shuang-Tao Zhou , Da-Wei Jin , Guo-Huan Yang , Qi-Man Sun , Yi-Feng He , Kang Song , Xiao-Wu Huang , Wei-Ren Liu , Zhen-Bin Ding , Ying-Hong Shi , Xin-Rong Yang , Jia Fan , Ao Huang

Minimal residual disease (MRD) is proposed to drive early recurrence of hepatocellular carcinoma (HCC) after curative treatment, and patients with MRD may benefit from adjuvant treatment. We applied a customized targeted deep sequencing (TDS) to profile tumor genomic alterations in HCC patients undergoing liver transplantation (LT) or hepatectomy, and evaluated their associations with MRD status, recurrence risk, and adjuvant lenvatinib response across multiple independent cohorts. TDS revealed MRD-associated genomic patterns, including increased mutation burden and frequent alterations in TP53 and switch/sucrose non-fermentable (SWI/SNF) genes. Alterations in TP53 and SWI/SNF genes were consistently associated with higher early recurrence rates (48.5 % vs 30.0 %, P = 0.026 for TP53; 56.2 % vs 34.0 %, P = 0.024 for the SWI/SNF genes) and shorter recurrence-free survival (12.2 vs 34.6 months, P = 0.026 for TP53; 9.3 vs 18.6 months, P = 0.018 for the SWI/SNF genes) in the LT cohort, as well as the hepatectomy cohort. Multivariate analysis confirmed these alterations as independent risk factors for MRD. Integrative analysis demonstrated that TP53- and SWI/SNF-altered HCC represent clinically and biologically distinct phenotypes, differing in etiology, differentiation status, mutation burden, and transcriptomic subtypes: TP53 alterations correlated with an epithelial-mesenchymal transition-related subtype, while the SWI/SNF genes alterations related to a MYC-activated subtype. Notably, patients harboring TP53 alterations derived clinical benefit from adjuvant lenvatinib following curative surgery. In conclusion, TDS enables effective identification of MRD-associated genomic alterations and stratifies HCC patients who may benefit from adjuvant lenvatinib, providing a molecular basis for personalized postoperative management.

微小残留病（MRD）被认为是肝细胞癌（HCC）根治后早期复发的驱动因素，MRD患者可能从辅助治疗中获益。我们应用定制的靶向深度测序（TDS）来分析接受肝移植（LT）或肝切除术的HCC患者的肿瘤基因组改变，并在多个独立队列中评估其与MRD状态、复发风险和lenvatinib辅助反应的相关性。TDS揭示了mrd相关的基因组模式，包括突变负担增加和TP53和开关/蔗糖不可发酵（SWI/SNF）基因的频繁改变。在肝切除术和肝切除术队列中，TP53和SWI/SNF基因的改变始终与较高的早期复发率（TP53为48.5%比30.0%，P=0.026； SWI/SNF基因为56.2%比34.0%，P=0.024）和较短的无复发生存期（TP53为12.2比34.6个月，P=0.022； SWI/SNF基因为9.32比18.63个月，P= 0.018）相关。多变量分析证实这些改变是MRD的独立危险因素。综合分析表明，TP53-和SWI/SNF改变的HCC在临床和生物学上代表着不同的表型，在病因、分化状态、突变负担和转录组亚型方面存在差异：TP53的改变与上皮-间充质过渡相关的亚型相关，而SWI/SNF基因的改变与myc激活的亚型相关。值得注意的是，TP53改变的患者在根治性手术后使用lenvatinib获得了临床获益。总之，TDS能够有效识别mrd相关的基因组改变，并对可能受益于lenvatinib辅助治疗的HCC患者进行分层，为个性化术后管理提供分子基础。

{"title":"Application of targeted deep sequencing for management of hepatocellular carcinoma in a real-world setting: prediction of MRD and adjuvant lenvatinib response","authors":"Shi-Yu Zhang , De-Zhen Guo , Xin Zhang , Zhu-Jun Gu , Ling Aye , Jia-Yan Yan , Kai Zhu , Xiu-Tao Fu , Shuang-Tao Zhou , Da-Wei Jin , Guo-Huan Yang , Qi-Man Sun , Yi-Feng He , Kang Song , Xiao-Wu Huang , Wei-Ren Liu , Zhen-Bin Ding , Ying-Hong Shi , Xin-Rong Yang , Jia Fan , Ao Huang","doi":"10.1016/j.canlet.2025.218212","DOIUrl":"10.1016/j.canlet.2025.218212","url":null,"abstract":"<div><div>Minimal residual disease (MRD) is proposed to drive early recurrence of hepatocellular carcinoma (HCC) after curative treatment, and patients with MRD may benefit from adjuvant treatment. We applied a customized targeted deep sequencing (TDS) to profile tumor genomic alterations in HCC patients undergoing liver transplantation (LT) or hepatectomy, and evaluated their associations with MRD status, recurrence risk, and adjuvant lenvatinib response across multiple independent cohorts. TDS revealed MRD-associated genomic patterns, including increased mutation burden and frequent alterations in <em>TP53</em> and switch/sucrose non-fermentable (SWI/SNF) genes. Alterations in <em>TP53</em> and SWI/SNF genes were consistently associated with higher early recurrence rates (48.5 % vs 30.0 %, <em>P</em> = 0.026 for <em>TP53</em>; 56.2 % vs 34.0 %, <em>P</em> = 0.024 for the SWI/SNF genes) and shorter recurrence-free survival (12.2 vs 34.6 months, <em>P</em> = 0.026 for <em>TP53</em>; 9.3 vs 18.6 months, <em>P</em> = 0.018 for the SWI/SNF genes) in the LT cohort, as well as the hepatectomy cohort. Multivariate analysis confirmed these alterations as independent risk factors for MRD. Integrative analysis demonstrated that <em>TP53</em>- and SWI/SNF-altered HCC represent clinically and biologically distinct phenotypes, differing in etiology, differentiation status, mutation burden, and transcriptomic subtypes: <em>TP53</em> alterations correlated with an epithelial-mesenchymal transition-related subtype, while the SWI/SNF genes alterations related to a MYC-activated subtype. Notably, patients harboring <em>TP53</em> alterations derived clinical benefit from adjuvant lenvatinib following curative surgery. In conclusion, TDS enables effective identification of MRD-associated genomic alterations and stratifies HCC patients who may benefit from adjuvant lenvatinib, providing a molecular basis for personalized postoperative management.</div></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"639 ","pages":"Article 218212"},"PeriodicalIF":10.1,"publicationDate":"2025-12-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145721046","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

BMP9 potentiates immunotherapy in triple-negative breast cancer by suppressing Tregs infiltration via the PRKDC-CCL2 axis BMP9通过PRKDC-CCL2轴抑制Tregs浸润增强三阴性乳腺癌的免疫治疗

IF 10.1 1区医学 Q1 ONCOLOGY

Cancer letters

Pub Date : 2025-12-06 DOI: 10.1016/j.canlet.2025.218175

Yiqing You , Lan Wei , Meng Dai , Guozhi Zhao , Kun Fan , Tingting Dang , Haoli Sun , Liang Zhang , Qian Li , Mengxin Sun , Xiaolu Li , Xiran He , Shiyu Yang , Tao Zeng , Jiafeng Tang , Yan Zhang

Immunotherapy represents a pivotal strategy for triple-negative breast cancer (TNBC), yet its efficacy is constrained by the immunosuppressive tumor microenvironment (TME). In this study, we demonstrate that bone morphogenetic protein-9 (BMP9) inhibits tumor growth and reprograms the immune TME in orthotopic TNBC models, primarily by attenuating regulatory T cells (Tregs) infiltration. Tregs depletion abrogates si-BMP9-mediated tumor promotion. Mechanistically, BMP9 suppresses CCL2 expression in an exocrine-independent manner to restrict Tregs recruitment. We identify DNA-dependent protein kinase catalytic subunit (PRKDC) as a BMP9-binding transcriptional regulator. The interaction between PRKDC and BMP9 directly impedes CCL2 transcriptional activation by suppressing PRKDC phosphorylation and indirectly suppresses CCL2 expression via NF-κB pathway remodeling. Critically, BMP9 modulation and CCL2 targeting potentiates immunotherapy efficacy without observable toxicity. Our study unveils the BMP9-PRKDC-CCL2 axis as a master regulatory node for TNBC-Tregs crosstalk, providing a strategy to overcome immunotherapy resistance in TNBC.

免疫治疗是治疗三阴性乳腺癌（TNBC）的关键策略，但其疗效受到免疫抑制肿瘤微环境（TME）的限制。在这项研究中，我们证明骨形态发生蛋白9 （bone morphogenetic protein-9, BMP9）主要通过减弱调节性T细胞（regulatory T cells, Tregs）浸润来抑制原位TNBC模型中的肿瘤生长并重新编程免疫TME。Tregs的缺失消除了bmp9介导的肿瘤抑制。从机制上讲，BMP9以外分泌无关的方式抑制CCL2的表达，从而限制Tregs的募集。我们鉴定出dna依赖性蛋白激酶催化亚基（PRKDC）是一种结合bmp9的转录调节因子。PRKDC与BMP9的相互作用通过抑制PRKDC磷酸化直接抑制CCL2的转录激活，并通过NF-κB通路重塑间接抑制CCL2的表达。关键的是，BMP9调节和CCL2靶向增强了免疫治疗效果，而没有明显的毒性。我们的研究揭示了BMP9-PRKDC-CCL2轴作为TNBC- tregs串扰的主调控节点，提供了克服TNBC免疫治疗耐药的策略。

{"title":"BMP9 potentiates immunotherapy in triple-negative breast cancer by suppressing Tregs infiltration via the PRKDC-CCL2 axis","authors":"Yiqing You , Lan Wei , Meng Dai , Guozhi Zhao , Kun Fan , Tingting Dang , Haoli Sun , Liang Zhang , Qian Li , Mengxin Sun , Xiaolu Li , Xiran He , Shiyu Yang , Tao Zeng , Jiafeng Tang , Yan Zhang","doi":"10.1016/j.canlet.2025.218175","DOIUrl":"10.1016/j.canlet.2025.218175","url":null,"abstract":"<div><div>Immunotherapy represents a pivotal strategy for triple-negative breast cancer (TNBC), yet its efficacy is constrained by the immunosuppressive tumor microenvironment (TME). In this study, we demonstrate that bone morphogenetic protein-9 (BMP9) inhibits tumor growth and reprograms the immune TME in orthotopic TNBC models, primarily by attenuating regulatory T cells (Tregs) infiltration. Tregs depletion abrogates si-BMP9-mediated tumor promotion. Mechanistically, BMP9 suppresses CCL2 expression in an exocrine-independent manner to restrict Tregs recruitment. We identify DNA-dependent protein kinase catalytic subunit (PRKDC) as a BMP9-binding transcriptional regulator. The interaction between PRKDC and BMP9 directly impedes CCL2 transcriptional activation by suppressing PRKDC phosphorylation and indirectly suppresses CCL2 expression via NF-κB pathway remodeling. Critically, BMP9 modulation and CCL2 targeting potentiates immunotherapy efficacy without observable toxicity. Our study unveils the BMP9-PRKDC-CCL2 axis as a master regulatory node for TNBC-Tregs crosstalk, providing a strategy to overcome immunotherapy resistance in TNBC.</div></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"639 ","pages":"Article 218175"},"PeriodicalIF":10.1,"publicationDate":"2025-12-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145707391","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

IF 10.1 1区医学 Q1 ONCOLOGY

Cancer letters

Pub Date : 2025-12-05 DOI: 10.1016/j.canlet.2025.218188

Lina Song , Jialiang Cai , Guiqi Zhu , Peiling Zhang , Shiping Chen , Bing Quan , Junxian Du , Yufan Cai , Lele Song , Jian Zhou , Jia Fan , Tao Li , Lei Yu , Zhi Dai

Intratumoral heterogeneity (ITH) in hepatocellular carcinoma (HCC), driven by malignant cells plasticity, underlies differential responses to immune checkpoint inhibitors (ICIs). Single-nucleus sequencing revealed that hypoxic stress regulated malignant cellular plasticity, promoting transitions from an innate immune–responsive state to a non-responsive state with elevated lipid metabolism and angiogenesis. Whole-transcriptome sequencing revealed CircARSB was upregulated in responders and indicated better prognosis under ICIs treatment. Mechanistically, under normoxia, CircARSB activated the type I interferon–mediated innate immune pathway, whereas under hypoxia, it underwent m⁶A methylation and interacted with MOV10 to inhibit lipid metabolism. Exosomal CircARSB suppressed angiogenesis and facilitated ICI-responsive Kupffer cell subclusters. In vivo, under tyrosine kinase inhibitor (TKI)-alleviated hypoxia, adeno-associated virus (AAV)-delivered CircARSB remodeled the ICI-responsive tumor microenvironment by promoting CD8⁺ T cell infiltration, M1 macrophage polarization, and IFN-β production. Clinically, an MRI-based radiomics model (Circ-DWI with HIF1A-ADC) was developed to guide personalized treatment ICIs, alone or in combination with TKIs or CircARSB. Collectively, hypoxia-related CircARSB emerges as a promising biomarker for therapeutic response stratification and a potential target to enhance the efficacy of ICIs-based therapy in HCC.

由恶性细胞可塑性驱动的肝细胞癌（HCC）的瘤内异质性（ITH）是免疫检查点抑制剂（ICIs）差异反应的基础。单核测序显示，缺氧应激调节恶性细胞的可塑性，促进从先天免疫应答状态到非应答状态的转变，提高脂质代谢和血管生成。全转录组测序显示CircARSB在应答者中表达上调，表明在ICIs治疗下预后更好。机制上，在常氧条件下，CircARSB激活I型干扰素介导的先天免疫通路，而在缺氧条件下，CircARSB发生m6A甲基化并与MOV10相互作用抑制脂质代谢。外泌体CircARSB抑制血管生成并促进ici响应的Kupffer细胞亚群。在体内，在酪氨酸激酶抑制剂（TKI）缓解的缺氧条件下，腺相关病毒（AAV）递送的CircARSB通过促进CD8+ T细胞浸润、M1巨噬细胞极化和IFN-β的产生，重塑了ci反应性肿瘤微环境。在临床上，基于mri的放射组学模型（Circ-DWI与HIF1A-ADC）被开发用于指导个性化治疗ICIs，单独或与TKIs或CircARSB联合。总之，缺氧相关的CircARSB作为一种有前景的治疗反应分层生物标志物和增强基于icis治疗HCC疗效的潜在靶点。

{"title":"Hypoxia-related CircARSB Modulates lipid metabolism and innate immune crosstalk to influence immune checkpoint inhibitor response in hepatocellular carcinoma","authors":"Lina Song , Jialiang Cai , Guiqi Zhu , Peiling Zhang , Shiping Chen , Bing Quan , Junxian Du , Yufan Cai , Lele Song , Jian Zhou , Jia Fan , Tao Li , Lei Yu , Zhi Dai","doi":"10.1016/j.canlet.2025.218188","DOIUrl":"10.1016/j.canlet.2025.218188","url":null,"abstract":"<div><div>Intratumoral heterogeneity (ITH) in hepatocellular carcinoma (HCC), driven by malignant cells plasticity, underlies differential responses to immune checkpoint inhibitors (ICIs). Single-nucleus sequencing revealed that hypoxic stress regulated malignant cellular plasticity, promoting transitions from an innate immune–responsive state to a non-responsive state with elevated lipid metabolism and angiogenesis. Whole-transcriptome sequencing revealed CircARSB was upregulated in responders and indicated better prognosis under ICIs treatment. Mechanistically, under normoxia, CircARSB activated the type I interferon–mediated innate immune pathway, whereas under hypoxia, it underwent m<sup>6</sup>A methylation and interacted with MOV10 to inhibit lipid metabolism. Exosomal CircARSB suppressed angiogenesis and facilitated ICI-responsive Kupffer cell subclusters. In vivo, under tyrosine kinase inhibitor (TKI)-alleviated hypoxia, adeno-associated virus (AAV)-delivered CircARSB remodeled the ICI-responsive tumor microenvironment by promoting CD8<sup>+</sup> T cell infiltration, M1 macrophage polarization, and IFN-β production. Clinically, an MRI-based radiomics model (Circ-DWI with HIF1A-ADC) was developed to guide personalized treatment ICIs, alone or in combination with TKIs or CircARSB. Collectively, hypoxia-related CircARSB emerges as a promising biomarker for therapeutic response stratification and a potential target to enhance the efficacy of ICIs-based therapy in HCC.</div></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"639 ","pages":"Article 218188"},"PeriodicalIF":10.1,"publicationDate":"2025-12-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145699511","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

Corrigendum to “Bimodal silencing of the acinar cell-specific mRNA translation repressor PAIP2B defines a poor prognostic subgroup within the classical pancreatic tumor type” [Cancer Lett. 632 (2025) 217971] “腺泡细胞特异性mRNA翻译抑制因子PAIP2B的双峰沉默定义了典型胰腺肿瘤类型中的预后不良亚群”的更正[癌症杂志]. 632(2025)217971]。

IF 10.1 1区医学 Q1 ONCOLOGY

Cancer letters

Pub Date : 2025-12-04 DOI: 10.1016/j.canlet.2025.218202

Eulalie Corre , Amandine Alard , Catherine Marbœuf , Charline Lasfargues , Sandra Dailhau , Nicolas Gilbert , Yuna Blum , Rémy Nicolle , Juan Iovanna , Nelson Dusetti , Stéphane Pyronnet

引用次数: 0

G6PD+CSV+ circulating tumor cells associated with portal vein tumor thrombus formation via EMT-ferroptosis crosstalk: a dual biomarker for therapeutic efficacy and prognosis prediction in hepatocellular carcinoma G6PD+CSV+循环肿瘤细胞通过emt -铁下垂串扰与门静脉肿瘤血栓形成相关：肝细胞癌治疗疗效和预后预测的双重生物标志物

IF 10.1 1区医学 Q1 ONCOLOGY

Cancer letters

Pub Date : 2025-12-04 DOI: 10.1016/j.canlet.2025.218205

Lujun Chen , Heming Li , Qiuhua Luo , Haitao Zhou , Haoran Song , Xiaofang Liu , Mingfang Zhao , Tao Han , Kai Li

Portal vein tumor thrombus (PVTT) is a major contributor to recurrence, metastasis, and poor prognosis in hepatocellular carcinoma (HCC). Effective early detection and therapeutic strategies for PVTT are lacking. In our ongoing investigation, we identified cell surface vimentin-positive (CSV⁺) CTCs as a key subpopulation enriched in HCC patients with PVTT, whereas conventional EpCAM⁺ CTCs exhibited limited clinical relevance. Integrated multi-omics analyses further revealed that tumor cells within the primary lesion exhibiting both epithelial-mesenchymal transition (EMT) and ferroptosis-associated signatures are more likely to intravasate and contribute to PVTT formation. Notably, G6PD was identified as a ferroptosis-related marker specifically enriched in this EMT-like tumor cell subset, suggesting its functional involvement in PVTT pathogenesis. Clinically, elevated levels of G6PD⁺CSV⁺ CTCs were associated with poor responses to targeted immunotherapy. Importantly, the identification of CSV also provides a rationale for developing CSV-guided delivery systems, enabling targeted silencing of PVTT-associated molecular drivers such as G6PD. Collectively, our findings highlight G6PD⁺CSV⁺ CTCs as a dual-function biomarker for both PVTT risk stratification and treatment response monitoring, offering a novel strategy for the precision management of advanced HCC with PVTT involvement.

门静脉肿瘤血栓（PVTT）是肝细胞癌（HCC）复发、转移和预后不良的主要因素。目前缺乏有效的早期检测和治疗策略。在我们正在进行的研究中，我们发现细胞表面弧菌素阳性（CSV+） ctc是PVTT HCC患者中富集的关键亚群，而传统的EpCAM+ ctc表现出有限的临床相关性。综合多组学分析进一步显示，原发病变内的肿瘤细胞表现出上皮-间质转化（EMT）和死铁相关特征，更有可能内渗并促进PVTT的形成。值得注意的是，G6PD被鉴定为在这种emt样肿瘤细胞亚群中特异性富集的铁枯相关标志物，提示其功能参与PVTT发病。临床上，G6PD+CSV+ ctc水平升高与靶向免疫治疗的不良反应相关。重要的是，CSV的鉴定也为开发CSV引导的递送系统提供了理论基础，从而能够靶向沉默pvtt相关的分子驱动因子，如G6PD。总之，我们的研究结果强调了G6PD+CSV+ ctc作为PVTT风险分层和治疗反应监测的双重功能生物标志物，为PVTT累及的晚期HCC的精确管理提供了一种新的策略。

{"title":"G6PD+CSV+ circulating tumor cells associated with portal vein tumor thrombus formation via EMT-ferroptosis crosstalk: a dual biomarker for therapeutic efficacy and prognosis prediction in hepatocellular carcinoma","authors":"Lujun Chen , Heming Li , Qiuhua Luo , Haitao Zhou , Haoran Song , Xiaofang Liu , Mingfang Zhao , Tao Han , Kai Li","doi":"10.1016/j.canlet.2025.218205","DOIUrl":"10.1016/j.canlet.2025.218205","url":null,"abstract":"<div><div>Portal vein tumor thrombus (PVTT) is a major contributor to recurrence, metastasis, and poor prognosis in hepatocellular carcinoma (HCC). Effective early detection and therapeutic strategies for PVTT are lacking. In our ongoing investigation, we identified cell surface vimentin-positive (CSV<sup>+</sup>) CTCs as a key subpopulation enriched in HCC patients with PVTT, whereas conventional EpCAM<sup>+</sup> CTCs exhibited limited clinical relevance. Integrated multi-omics analyses further revealed that tumor cells within the primary lesion exhibiting both epithelial-mesenchymal transition (EMT) and ferroptosis-associated signatures are more likely to intravasate and contribute to PVTT formation. Notably, G6PD was identified as a ferroptosis-related marker specifically enriched in this EMT-like tumor cell subset, suggesting its functional involvement in PVTT pathogenesis. Clinically, elevated levels of G6PD<sup>+</sup>CSV<sup>+</sup> CTCs were associated with poor responses to targeted immunotherapy. Importantly, the identification of CSV also provides a rationale for developing CSV-guided delivery systems, enabling targeted silencing of PVTT-associated molecular drivers such as G6PD. Collectively, our findings highlight G6PD<sup>+</sup>CSV<sup>+</sup> CTCs as a dual-function biomarker for both PVTT risk stratification and treatment response monitoring, offering a novel strategy for the precision management of advanced HCC with PVTT involvement.</div></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"639 ","pages":"Article 218205"},"PeriodicalIF":10.1,"publicationDate":"2025-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145696050","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

Strategies to optimize duration of immunotherapy in advanced NSCLC: Current evidence and future directions 优化晚期非小细胞肺癌免疫治疗持续时间的策略：当前证据和未来方向。

IF 10.1 1区医学 Q1 ONCOLOGY

Cancer letters

Pub Date : 2025-12-03 DOI: 10.1016/j.canlet.2025.218203

Xue Dong , Ruyue Li , Xiujing Yao , Ying Li , Wenjie Chen , Hao An , Jiaxuan Chen , Chuankun Han , Yintao Li

Immune checkpoint inhibitors have revolutionized the treatment of advanced non-small cell lung cancer, yet the optimal duration of therapy remains uncertain, raising concerns about cumulative toxicity, economic burden, and potential overtreatment. We analyzed the current evidence comparing fixed-duration regimens (typically capped at 2 years) with continuous treatment until disease progression or unacceptable toxicity, focusing on their impact on long-term survival, disease control, and adverse event risks. Biomarkers, particularly circulating tumor DNA kinetics, play a critical role in guiding individualized treatment duration, providing greater precision in monitoring disease response and tailoring therapy. Additionally, we discuss different approaches for managing patients after treatment discontinuation, such as rechallenging following immune-related adverse events (irAEs).This review summarizes the current evidence on fixed versus indefinite immunotherapy duration and proposes a biomarker-informed, patient-centered framework for optimizing immunotherapy duration, aiming to balance therapeutic efficacy and minimize toxicity.

免疫检查点抑制剂已经彻底改变了晚期非小细胞肺癌的治疗，但最佳治疗持续时间仍不确定，引起了对累积毒性、经济负担和潜在过度治疗的担忧。我们分析了目前的证据，比较了固定时间方案（通常上限为2年）和持续治疗直到疾病进展或不可接受的毒性，重点关注它们对长期生存、疾病控制和不良事件风险的影响。生物标志物，特别是循环肿瘤DNA动力学，在指导个体化治疗持续时间方面发挥着关键作用，为监测疾病反应和定制治疗提供了更高的精度。此外，我们讨论了治疗停药后管理患者的不同方法，如免疫相关不良事件（irAEs）后的重新挑战。这篇综述总结了目前关于固定和无限期免疫治疗持续时间的证据，并提出了一个生物标志物信息，以患者为中心的优化免疫治疗持续时间的框架，旨在平衡治疗效果和最小化毒性。

{"title":"Strategies to optimize duration of immunotherapy in advanced NSCLC: Current evidence and future directions","authors":"Xue Dong , Ruyue Li , Xiujing Yao , Ying Li , Wenjie Chen , Hao An , Jiaxuan Chen , Chuankun Han , Yintao Li","doi":"10.1016/j.canlet.2025.218203","DOIUrl":"10.1016/j.canlet.2025.218203","url":null,"abstract":"<div><div>Immune checkpoint inhibitors have revolutionized the treatment of advanced non-small cell lung cancer, yet the optimal duration of therapy remains uncertain, raising concerns about cumulative toxicity, economic burden, and potential overtreatment. We analyzed the current evidence comparing fixed-duration regimens (typically capped at 2 years) with continuous treatment until disease progression or unacceptable toxicity, focusing on their impact on long-term survival, disease control, and adverse event risks. Biomarkers, particularly circulating tumor DNA kinetics, play a critical role in guiding individualized treatment duration, providing greater precision in monitoring disease response and tailoring therapy. Additionally, we discuss different approaches for managing patients after treatment discontinuation, such as rechallenging following immune-related adverse events (irAEs).This review summarizes the current evidence on fixed versus indefinite immunotherapy duration and proposes a biomarker-informed, patient-centered framework for optimizing immunotherapy duration, aiming to balance therapeutic efficacy and minimize toxicity.</div></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"639 ","pages":"Article 218203"},"PeriodicalIF":10.1,"publicationDate":"2025-12-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145687048","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

SRC at the crossroads of KRAS inhibitor resistance: Mechanisms and therapeutic opportunities SRC处于KRAS抑制剂耐药的十字路口：机制和治疗机会

IF 10.1 1区医学 Q1 ONCOLOGY

Cancer letters

Pub Date : 2025-12-02 DOI: 10.1016/j.canlet.2025.218194

Hui Tian , Dan Zhao , Zhuan Zhou , Alex Kim , Huocong Huang , Yong J. Lee , Zhaoxia Qu , Rui Kang , Herbert J. Zeh , Kenneth D. Westover , Xinxin Song

Kirsten rat sarcoma (KRAS) mutations are among the most common oncogenic drivers in human cancers, particularly in non-small cell lung cancer (NSCLC), colorectal cancer (CRC), and pancreatic ductal adenocarcinoma (PDAC). The development of allele-specific KRAS inhibitors, especially those targeting the KRAS^G12C variant, represents a landmark achievement in precision oncology. Yet their therapeutic benefit is often transient, as tumors rapidly develop seemingly heterogeneous resistance mechanisms. Increasing evidence implicates SRC, a non-receptor tyrosine kinase frequently hyperactivated in KRAS-mutant cancers, as a central regulator of resistance. This review integrates current evidence supporting SRC's role in mediating diverse resistance pathways, including mitogen-activated protein kinase (MAPK) reactivation, transcriptional/epigenetic reprogramming, metabolic adaptation, multidrug resistance, cell death evasion, and remodeling of the tumor microenvironment. We also critically examine the shortcomings of early-generation SRC inhibitors in solid tumors and highlight emerging therapeutic avenues such as next-generation inhibitors, proteolysis-targeting chimera (PROTAC) degraders, and biomarker-guided combination strategies. By connecting molecular insights with preclinical and clinical findings, this review positions SRC as a therapeutically actionable vulnerability in KRAS-driven cancers and outlines a translational framework for overcoming drug resistance.

Kirsten大鼠肉瘤（KRAS）突变是人类癌症中最常见的致癌驱动因素之一，特别是在非小细胞肺癌（NSCLC）、结直肠癌（CRC）和胰腺导管腺癌（PDAC）中。等位基因特异性KRAS抑制剂的开发，特别是靶向KRASG12C变体的抑制剂，代表了精准肿瘤学的里程碑式成就。然而，它们的治疗效果往往是短暂的，因为肿瘤迅速发展出看似异质的耐药机制。越来越多的证据表明，SRC是一种非受体酪氨酸激酶，在kras突变型癌症中经常过度激活，是耐药性的中心调节因子。本综述整合了目前支持SRC介导多种耐药途径的证据，包括丝裂原活化蛋白激酶（MAPK）再激活、转录/表观遗传重编程、代谢适应、多药耐药、细胞死亡逃避和肿瘤微环境重塑。我们还严格检查了早期SRC抑制剂在实体肿瘤中的缺点，并强调了新兴的治疗途径，如下一代抑制剂、靶向蛋白水解嵌合体（PROTAC）降解剂和生物标志物引导的联合策略。通过将分子见解与临床前和临床研究结果联系起来，本综述将SRC定位为kras驱动的癌症中可治疗的易感性，并概述了克服耐药性的翻译框架。

{"title":"SRC at the crossroads of KRAS inhibitor resistance: Mechanisms and therapeutic opportunities","authors":"Hui Tian , Dan Zhao , Zhuan Zhou , Alex Kim , Huocong Huang , Yong J. Lee , Zhaoxia Qu , Rui Kang , Herbert J. Zeh , Kenneth D. Westover , Xinxin Song","doi":"10.1016/j.canlet.2025.218194","DOIUrl":"10.1016/j.canlet.2025.218194","url":null,"abstract":"<div><div>Kirsten rat sarcoma (KRAS) mutations are among the most common oncogenic drivers in human cancers, particularly in non-small cell lung cancer (NSCLC), colorectal cancer (CRC), and pancreatic ductal adenocarcinoma (PDAC). The development of allele-specific KRAS inhibitors, especially those targeting the KRAS<sup>G12C</sup> variant, represents a landmark achievement in precision oncology. Yet their therapeutic benefit is often transient, as tumors rapidly develop seemingly heterogeneous resistance mechanisms. Increasing evidence implicates SRC, a non-receptor tyrosine kinase frequently hyperactivated in KRAS-mutant cancers, as a central regulator of resistance. This review integrates current evidence supporting SRC's role in mediating diverse resistance pathways, including mitogen-activated protein kinase (MAPK) reactivation, transcriptional/epigenetic reprogramming, metabolic adaptation, multidrug resistance, cell death evasion, and remodeling of the tumor microenvironment. We also critically examine the shortcomings of early-generation SRC inhibitors in solid tumors and highlight emerging therapeutic avenues such as next-generation inhibitors, proteolysis-targeting chimera (PROTAC) degraders, and biomarker-guided combination strategies. By connecting molecular insights with preclinical and clinical findings, this review positions SRC as a therapeutically actionable vulnerability in KRAS-driven cancers and outlines a translational framework for overcoming drug resistance.</div></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"639 ","pages":"Article 218194"},"PeriodicalIF":10.1,"publicationDate":"2025-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145658694","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

Updated clinical practice guidelines for the management of adult diffuse gliomas 成人弥漫性胶质瘤治疗的最新临床实践指南。

IF 10.1 1区医学 Q1 ONCOLOGY

Cancer letters

Pub Date : 2025-12-01 DOI: 10.1016/j.canlet.2025.218185

Tao Jiang , Do-Hyun Nam , Zvi Ram , Wai-sang Poo , Jiguang Wang , Damdindorj Boldbaatar , Ying Mao , Wenbin Ma , Qing Mao , Yongping You , Chuanlu Jiang , Xuejun Yang , Vinay Tergaonkar , Wei Zhang , Zheng Wang , Chunsheng Kang , Xiaoguang Qiu , Shaowu Li , Ling Chen , Xuejun Li , Yu Wang

It has been five years since the last version of the clinical practice guidelines for the management of adult diffuse gliomas was published by the Asian Glioma Genome Atlas (AGGA). Significant progress and revisions have occurred in the diagnosis and treatment of adult diffuse gliomas in recent years. In response to these updates, the joint guideline committee of the Chinese Glioma Cooperative Group (CGCG), the Society for Neuro-Oncology of China (SNO-China), and the Chinese Brain Cancer Association (CBCA) has revised the clinical practice guidelines. This updated guideline emphasizes molecular and pathological diagnostics, as well as the primary treatment modalities of surgery, radiotherapy, chemotherapy, and targeted therapy. Additionally, we have incorporated findings from recent clinical trials of new therapies to align with cutting-edge treatment strategies. This guideline is designed to serve as a practical resource for all professionals involved in managing adult diffuse glioma patients, while also providing valuable information for insurance companies and other institutions responsible for regulating cancer care costs in China and beyond.

自亚洲胶质瘤基因组图谱（AGGA）发布成人弥漫性胶质瘤的临床实践指南以来，已经过去了五年。近年来，成人弥漫性胶质瘤的诊断和治疗取得了重大进展和改进。针对这些更新，中国胶质瘤合作小组（CGCG）、中国神经肿瘤学会（SNO-China）和中国脑癌协会（CBCA）联合指南委员会修订了临床实践指南。这一更新的指南强调分子和病理诊断，以及手术、放疗、化疗和靶向治疗的主要治疗方式。此外，我们还结合了最近新疗法的临床试验结果，以配合尖端的治疗策略。本指南旨在为所有参与成人弥漫性胶质瘤患者管理的专业人员提供实用的资源，同时也为保险公司和其他负责监管中国及其他地区癌症治疗费用的机构提供有价值的信息。

{"title":"Updated clinical practice guidelines for the management of adult diffuse gliomas","authors":"Tao Jiang , Do-Hyun Nam , Zvi Ram , Wai-sang Poo , Jiguang Wang , Damdindorj Boldbaatar , Ying Mao , Wenbin Ma , Qing Mao , Yongping You , Chuanlu Jiang , Xuejun Yang , Vinay Tergaonkar , Wei Zhang , Zheng Wang , Chunsheng Kang , Xiaoguang Qiu , Shaowu Li , Ling Chen , Xuejun Li , Yu Wang","doi":"10.1016/j.canlet.2025.218185","DOIUrl":"10.1016/j.canlet.2025.218185","url":null,"abstract":"<div><div>It has been five years since the last version of the clinical practice guidelines for the management of adult diffuse gliomas was published by the Asian Glioma Genome Atlas (AGGA). Significant progress and revisions have occurred in the diagnosis and treatment of adult diffuse gliomas in recent years. In response to these updates, the joint guideline committee of the Chinese Glioma Cooperative Group (CGCG), the Society for Neuro-Oncology of China (SNO-China), and the Chinese Brain Cancer Association (CBCA) has revised the clinical practice guidelines. This updated guideline emphasizes molecular and pathological diagnostics, as well as the primary treatment modalities of surgery, radiotherapy, chemotherapy, and targeted therapy. Additionally, we have incorporated findings from recent clinical trials of new therapies to align with cutting-edge treatment strategies. This guideline is designed to serve as a practical resource for all professionals involved in managing adult diffuse glioma patients, while also providing valuable information for insurance companies and other institutions responsible for regulating cancer care costs in China and beyond.</div></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"640 ","pages":"Article 218185"},"PeriodicalIF":10.1,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145667132","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

Cytoplasmic SIRT1 enhances the stemness of polyploid giant cancer cells by promoting β-catenin protein stability and nuclear accumulation in ovarian carcinoma upon neoadjuvant chemotherapy 细胞质SIRT1通过促进卵巢癌新辅助化疗后β-catenin蛋白的稳定性和核积累，增强多倍体巨癌细胞的干性。

IF 10.1 1区医学 Q1 ONCOLOGY

Cancer letters

Pub Date : 2025-12-01 DOI: 10.1016/j.canlet.2025.218193

Hong Xu , Shujun Zeng , Minmin Wang , Yinmei Wang , Yixin Cao , Yuling Qu , XinYi Huang , Xia Li , Qing Qiao , Jing Zhang

Epithelial ovarian carcinoma, the deadliest gynecological malignancy, frequently develops treatment resistance through polyploid giant cancer cells (PGCCs) that typically emerge after carboplatin-paclitaxel chemotherapy. Accumulating evidence suggests that PGCCs exhibit traits similar to those of cancer stem cells (CSCs), including expression of stemness markers, self-renewal, and resistance to treatment. Although Wnt/β-catenin signaling is a major driver of stemness and chemoresistance in ovarian carcinoma, the specific mechanisms by which it activates cancer stemness of PGCCs remain unclear. This study investigates the role of SIRT1-mediated deacetylation of β-catenin in PGCC stemness, with a specific focus on SIRT1's subcellular localization. Immunohistochemical analysis of ovarian carcinoma samples from patients receiving neoadjuvant chemotherapy revealed that nuclear β-catenin staining in PGCCs correlated with SOX2-positive expression. Comparative proteomics further demonstrated the enrichment of differentially expressed proteins related to the Wnt pathway and stem cell programs in PGCCs compared to diploid tumor cells, highlighting the role of the Wnt/β-catenin pathway in the cancer stemness of PGCCs. Critically, PGCCs with overexpressed cytoplasmic SIRT1 (SIRT1^NLSmt) showed increased CSC marker expression, chemoresistance, colony and spheroid formation abilities, and hyperactivation of the Wnt/β-catenin pathway, compared to PGCCs overexpressing the nuclear-predominant wild-type SIRT1 (SIRT1^WT). Mechanistically, cytoplasmic retention of SIRT1 in PGCCs stabilizes β-catenin, facilitates its nuclear accumulation, and decreases its deacetylation of nuclear β-catenin through post-translational modification. Our findings establish that the cytoplasmic SIRT1/β-catenin axis contributes to PGCC stemness, elucidating a novel mechanism underlying chemoresistance. Therefore, targeting cytoplasmic SIRT1 represents a promising therapeutic strategy to overcome PGCC-mediated resistance in this lethal carcinoma.

上皮性卵巢癌是最致命的妇科恶性肿瘤，通常在卡铂-紫杉醇化疗后通过多倍体巨癌细胞（pgcc）产生治疗耐药性。越来越多的证据表明，pgcc表现出与癌症干细胞（CSCs）相似的特征，包括干细胞标志物的表达、自我更新和对治疗的抵抗力。尽管Wnt/β-catenin信号是卵巢癌干细胞和化疗耐药的主要驱动因素，但其激活pgcc癌症干细胞的具体机制尚不清楚。本研究探讨了SIRT1介导的β-catenin去乙酰化在PGCC干细胞中的作用，并特别关注SIRT1的亚细胞定位。对接受新辅助化疗患者的卵巢癌样本进行免疫组化分析，发现核β-catenin染色与sox2阳性表达相关。比较蛋白质组学进一步证实，与二倍体肿瘤细胞相比，pgcc中Wnt通路和干细胞程序相关的差异表达蛋白富集，突出了Wnt/β-catenin通路在pgcc癌变中的作用。关键的是，与过表达核优势野生型SIRT1 （SIRT1WT）的pgcc相比，胞质SIRT1过表达的pgcc （SIRT1NLSmt）表现出CSC标记物表达增加、耐药、集落和球体形成能力以及Wnt/β-catenin通路的过度激活。从机制上讲，pgcc细胞质中SIRT1的保留稳定了β-catenin，促进了其核积累，并通过翻译后修饰减少了核β-catenin的去乙酰化。我们的研究结果证实细胞质SIRT1/β-catenin轴有助于PGCC的干性，阐明了化学耐药的新机制。因此，靶向细胞质SIRT1是一种很有前景的治疗策略，可以克服这种致命癌症中pgcc介导的耐药。

{"title":"Cytoplasmic SIRT1 enhances the stemness of polyploid giant cancer cells by promoting β-catenin protein stability and nuclear accumulation in ovarian carcinoma upon neoadjuvant chemotherapy","authors":"Hong Xu , Shujun Zeng , Minmin Wang , Yinmei Wang , Yixin Cao , Yuling Qu , XinYi Huang , Xia Li , Qing Qiao , Jing Zhang","doi":"10.1016/j.canlet.2025.218193","DOIUrl":"10.1016/j.canlet.2025.218193","url":null,"abstract":"<div><div>Epithelial ovarian carcinoma, the deadliest gynecological malignancy, frequently develops treatment resistance through polyploid giant cancer cells (PGCCs) that typically emerge after carboplatin-paclitaxel chemotherapy. Accumulating evidence suggests that PGCCs exhibit traits similar to those of cancer stem cells (CSCs), including expression of stemness markers, self-renewal, and resistance to treatment. Although Wnt/β-catenin signaling is a major driver of stemness and chemoresistance in ovarian carcinoma, the specific mechanisms by which it activates cancer stemness of PGCCs remain unclear. This study investigates the role of SIRT1-mediated deacetylation of β-catenin in PGCC stemness, with a specific focus on SIRT1's subcellular localization. Immunohistochemical analysis of ovarian carcinoma samples from patients receiving neoadjuvant chemotherapy revealed that nuclear β-catenin staining in PGCCs correlated with SOX2-positive expression. Comparative proteomics further demonstrated the enrichment of differentially expressed proteins related to the Wnt pathway and stem cell programs in PGCCs compared to diploid tumor cells, highlighting the role of the Wnt/β-catenin pathway in the cancer stemness of PGCCs. Critically, PGCCs with overexpressed cytoplasmic SIRT1 (SIRT1<sup>NLSmt</sup>) showed increased CSC marker expression, chemoresistance, colony and spheroid formation abilities, and hyperactivation of the Wnt/β-catenin pathway, compared to PGCCs overexpressing the nuclear-predominant wild-type SIRT1 (SIRT1<sup>WT</sup>). Mechanistically, cytoplasmic retention of SIRT1 in PGCCs stabilizes β-catenin, facilitates its nuclear accumulation, and decreases its deacetylation of nuclear β-catenin through post-translational modification. Our findings establish that the cytoplasmic SIRT1/β-catenin axis contributes to PGCC stemness, elucidating a novel mechanism underlying chemoresistance. Therefore, targeting cytoplasmic SIRT1 represents a promising therapeutic strategy to overcome PGCC-mediated resistance in this lethal carcinoma.</div></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"639 ","pages":"Article 218193"},"PeriodicalIF":10.1,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145667191","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

Copper orchestrates triple-negative breast cancer progression via the STEAP3-dependent CDK16-JAK1 activation 铜通过steap3依赖性CDK16-JAK1激活调控三阴性乳腺癌的进展

IF 10.1 1区医学 Q1 ONCOLOGY

Cancer letters

Pub Date : 2025-12-01 DOI: 10.1016/j.canlet.2025.218192

Fangfang Duan , Chao Zhang , Zichao Wu , Lan Zhuang , Yutian Zou , Xudong Wang , Lingrui Liu , Wenkuan Chen , Xiumei Wang , Hailin Tang

Triple-negative breast cancer (TNBC) is the most aggressive breast cancer subtype, characterized by high recurrence rates and limited treatments beyond chemotherapy. The interplay between tumor cells and the tumor microenvironment plays a critical role in TNBC progression, with copper homeostasis emerging as a key regulator of this dynamic niche. Our previous study indicated elevated serum copper as a predictor of poor prognosis for TNBC patients, but its specific role and underlying mechanisms remains to be elucidated. Herein, notable upregulation of STEAP3 was found in high-copper TNBC patients and significantly associated with poor prognosis. The intracellular copper level markedly increased upon STEAP3 overexpression and decreased following STEAP3 knockdown. Through comprehensive in vitro and in vivo experiments, we proved that copper facilitated cell proliferation, migration, xenograft tumor growth and lung metastasis, which were inhibited by copper chelator tetrathiomolybdate. Mechanistically, copper directly bound to CDK16 kinase, leading to its activation, in turn enhanced CDK16 binding and subsequently activating JAK1 kinase to upregulate transcription of c-Myc and cyclin D1. Critically, targeted knockdown of STEAP3 remarkably inhibited TNBC cells proliferation, migration and xenograft tumor growth. These findings unveil a critical pro-tumorigenic copper-driven pathway-distinct from cuproptosis-operating through STEAP3/copper/CDK16/JAK1 axis, and highlight STEAP3 as a promising therapeutic target for TNBC.

三阴性乳腺癌（TNBC）是最具侵袭性的乳腺癌亚型，其特点是高复发率和化疗以外的治疗有限。肿瘤细胞和肿瘤微环境之间的相互作用在TNBC的进展中起着关键作用，铜稳态是这一动态生态位的关键调节因子。我们之前的研究表明，血清铜升高是TNBC患者预后不良的一个预测因素，但其具体作用和潜在机制仍有待阐明。本研究发现，STEAP3在高铜TNBC患者中显著上调，并与不良预后显著相关。细胞内铜水平在STEAP3过表达时显著升高，在STEAP3敲低后显著降低。通过全面的体外和体内实验，我们证明了铜对细胞增殖、迁移、异种移植肿瘤生长和肺转移有促进作用，而铜螯合剂四硫钼酸盐对这些作用有抑制作用。从机制上讲，铜直接与CDK16激酶结合，导致其活化，进而增强CDK16的结合，随后激活JAK1激酶，上调c-Myc和cyclin D1的转录。重要的是，靶向敲除STEAP3显著抑制TNBC细胞增殖、迁移和异种移植肿瘤生长。这些发现揭示了一个关键的促肿瘤铜驱动途径-不同于铜增殖-通过STEAP3/copper/CDK16/JAK1轴运作，并突出了STEAP3作为TNBC的一个有希望的治疗靶点。

{"title":"Copper orchestrates triple-negative breast cancer progression via the STEAP3-dependent CDK16-JAK1 activation","authors":"Fangfang Duan , Chao Zhang , Zichao Wu , Lan Zhuang , Yutian Zou , Xudong Wang , Lingrui Liu , Wenkuan Chen , Xiumei Wang , Hailin Tang","doi":"10.1016/j.canlet.2025.218192","DOIUrl":"10.1016/j.canlet.2025.218192","url":null,"abstract":"<div><div>Triple-negative breast cancer (TNBC) is the most aggressive breast cancer subtype, characterized by high recurrence rates and limited treatments beyond chemotherapy. The interplay between tumor cells and the tumor microenvironment plays a critical role in TNBC progression, with copper homeostasis emerging as a key regulator of this dynamic niche. Our previous study indicated elevated serum copper as a predictor of poor prognosis for TNBC patients, but its specific role and underlying mechanisms remains to be elucidated. Herein, notable upregulation of STEAP3 was found in high-copper TNBC patients and significantly associated with poor prognosis. The intracellular copper level markedly increased upon STEAP3 overexpression and decreased following STEAP3 knockdown. Through comprehensive in vitro and in vivo experiments, we proved that copper facilitated cell proliferation, migration, xenograft tumor growth and lung metastasis, which were inhibited by copper chelator tetrathiomolybdate. Mechanistically, copper directly bound to CDK16 kinase, leading to its activation, in turn enhanced CDK16 binding and subsequently activating JAK1 kinase to upregulate transcription of c-Myc and cyclin D1. Critically, targeted knockdown of STEAP3 remarkably inhibited TNBC cells proliferation, migration and xenograft tumor growth. These findings unveil a critical pro-tumorigenic copper-driven pathway-distinct from cuproptosis-operating through STEAP3/copper/CDK16/JAK1 axis, and highlight STEAP3 as a promising therapeutic target for TNBC.</div></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"639 ","pages":"Article 218192"},"PeriodicalIF":10.1,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145658695","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