Pub Date : 2026-01-12DOI: 10.1016/j.tranon.2026.102671
Caiqiang Zhu , Liang Liang , Ning Xue , Dan Mei , Meng Tian , Zhaoyue Zhang , Xinchen Sun , Xiaofeng Ding
Background
Lung adenocarcinoma (LUAD) remains a major clinical challenge in assessment of clinical outcomes and therapeutic response. Although tumor-associated macrophages (TAMs) are known as crucial regulators of tumor progression, their heterogeneity and prognostic relevance in LUAD have not been fully elucidated.
Methods
The heterogeneity of TAMs was detected by integration analyses of single-cell data and spatial transcriptome data. The CTSB+ TAM-related signature (CTRS) was developed by machine learning algorithms across four LUAD datasets. Multi-omics analysis and functional experiments were applied to uncover the potential role and mechanism of CTSB+ TAMs in LUAD.
Results
Single-cell analysis identified CTSB⁺ TAM as a crucial player in LUAD progression with poor prognosis. The spatial co-localization of CTSB⁺ TAMs and tumor cells was confirmed on LUAD slides. Our proposed CTRS was generated and validated in four independent LUAD cohorts, with high scores indicating unfavorable outcomes Furthermore, high CTRS scores were correlated with immunosuppressive status, and poor responses to immune checkpoint blockade. Functional experiments demonstrated the role of CTSB+ TAMs in boosting proliferation and migration in LUAD cells.
Conclusion
Our research develops CTRS with reliable performance in evaluating patient clinical outcomes in LUAD, highlighting its potential utility in clinical decision-making.
{"title":"CTSB-positive tumor-associated macrophages shape prognosis and therapeutic response in lung adenocarcinoma","authors":"Caiqiang Zhu , Liang Liang , Ning Xue , Dan Mei , Meng Tian , Zhaoyue Zhang , Xinchen Sun , Xiaofeng Ding","doi":"10.1016/j.tranon.2026.102671","DOIUrl":"10.1016/j.tranon.2026.102671","url":null,"abstract":"<div><h3>Background</h3><div>Lung adenocarcinoma (LUAD) remains a major clinical challenge in assessment of clinical outcomes and therapeutic response. Although tumor-associated macrophages (TAMs) are known as crucial regulators of tumor progression, their heterogeneity and prognostic relevance in LUAD have not been fully elucidated.</div></div><div><h3>Methods</h3><div>The heterogeneity of TAMs was detected by integration analyses of single-cell data and spatial transcriptome data. The CTSB<sup>+</sup> TAM-related signature (CTRS) was developed by machine learning algorithms across four LUAD datasets. Multi-omics analysis and functional experiments were applied to uncover the potential role and mechanism of CTSB<sup>+</sup> TAMs in LUAD.</div></div><div><h3>Results</h3><div>Single-cell analysis identified CTSB⁺ TAM as a crucial player in LUAD progression with poor prognosis. The spatial co-localization of CTSB⁺ TAMs and tumor cells was confirmed on LUAD slides. Our proposed CTRS was generated and validated in four independent LUAD cohorts, with high scores indicating unfavorable outcomes Furthermore, high CTRS scores were correlated with immunosuppressive status, and poor responses to immune checkpoint blockade. Functional experiments demonstrated the role of CTSB<sup>+</sup> TAMs in boosting proliferation and migration in LUAD cells.</div></div><div><h3>Conclusion</h3><div>Our research develops CTRS with reliable performance in evaluating patient clinical outcomes in LUAD, highlighting its potential utility in clinical decision-making.</div></div>","PeriodicalId":48975,"journal":{"name":"Translational Oncology","volume":"65 ","pages":"Article 102671"},"PeriodicalIF":5.0,"publicationDate":"2026-01-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145947978","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-08DOI: 10.1016/j.tranon.2026.102666
Lulu Li , Jie Xu , Liming Yu , Jingbo Shi , Changnian Li , Jiabao Gu , Yaru Wang , Siyuan Cui
Multiple myeloma (MM) is a hematological malignancy characterized by the clonal proliferation of abnormal plasma cells, with marked heterogeneity and therapeutic refractoriness. Despite the introduction of proteasome inhibitors (PIs), immunomodulatory drugs (IMiDs), monoclonal antibodies (mAbs), and chimeric antigen receptor T-cell (CAR-T) therapy, relapse and drug resistance remain major challenges that urgently need to be addressed. Plant-derived natural products have attracted increasing attention in recent years due to their multi-target synergistic effects, demonstrating unique potential in inducing MM cell apoptosis, reversing drug resistance, and modulating the immune microenvironment—making them a rising focus in translational medicine research. In this structured narrative review, we systematically summarize the anti-myeloma mechanisms of fourteen plant-derived natural products, including plant-derived monomeric compounds (baicalein, artemisinin, curcumin, celastrol, gambogic acid, resveratrol, ginsenosides, icariin, oridonin, plumbagin, formononetin) and standardized plant extracts (Strychnos nux-vomica root extract, dandelion flavonoids, Hedyotis diffusa polysaccharides). This review highlights their multi-target regulatory effects on signaling pathways, cell cycle modulation, and immune regulation, and further discusses their potential translational value in overcoming drug resistance and optimizing combination treatment strategies. Literature was retrieved from PubMed, Web of Science, and CNKI databases, covering studies published up to January 2025. Although plant-derived natural products exhibit promising multi-target regulatory mechanisms in MM therapy, their clinical translation remains limited by poor bioavailability of single compounds and the lack of standardized extracts. Future research should integrate systems pharmacology with clinical studies to elucidate multi-component synergistic networks and develop novel targeted formulations, thereby accelerating the efficient translation of phytochemicals from bench to bedside.
多发性骨髓瘤（MM）是一种以异常浆细胞克隆增生为特征的血液系统恶性肿瘤，具有明显的异质性和治疗难治性。尽管引入了蛋白酶体抑制剂（pi）、免疫调节药物（IMiDs）、单克隆抗体（mab）和嵌合抗原受体t细胞（CAR-T）治疗，但复发和耐药仍然是迫切需要解决的主要挑战。近年来，植物源性天然产物因其多靶点协同作用而受到越来越多的关注，在诱导MM细胞凋亡、逆转耐药、调节免疫微环境等方面显示出独特的潜力，成为转化医学研究的热点。在这篇结构化的叙述综述中，我们系统地总结了14种植物源性天然产物的抗骨髓瘤机制，包括植物源性单体化合物（黄芩素、青蒿素、姜黄素、celastrol、藤黄酸、白藜芦醇、人参皂苷、淫羊藿苷、冬凌草苷、白桦柄花素）和标准化植物提取物（马钱子根提取物、蒲公英黄酮、白花蛇耳草多糖）。本文综述了它们在信号通路、细胞周期调节和免疫调节等方面的多靶点调控作用，并进一步讨论了它们在克服耐药和优化联合治疗策略方面的潜在翻译价值。文献检索自PubMed、Web of Science和CNKI数据库，涵盖截至2025年1月发表的研究。尽管植物来源的天然产物在多发性骨髓瘤治疗中显示出有希望的多靶点调节机制，但它们的临床转化仍然受到单一化合物生物利用度差和缺乏标准化提取物的限制。未来的研究应将系统药理学与临床研究结合起来，阐明多组分协同网络，开发新的靶向制剂，从而加快植物化学物质从实验室到床边的有效转化。
{"title":"Mechanistic and translational insights into plant-derived natural products in preclinical multiple myeloma research: Current evidence","authors":"Lulu Li , Jie Xu , Liming Yu , Jingbo Shi , Changnian Li , Jiabao Gu , Yaru Wang , Siyuan Cui","doi":"10.1016/j.tranon.2026.102666","DOIUrl":"10.1016/j.tranon.2026.102666","url":null,"abstract":"<div><div>Multiple myeloma (MM) is a hematological malignancy characterized by the clonal proliferation of abnormal plasma cells, with marked heterogeneity and therapeutic refractoriness. Despite the introduction of proteasome inhibitors (PIs), immunomodulatory drugs (IMiDs), monoclonal antibodies (mAbs), and chimeric antigen receptor T-cell (CAR-T) therapy, relapse and drug resistance remain major challenges that urgently need to be addressed. Plant-derived natural products have attracted increasing attention in recent years due to their multi-target synergistic effects, demonstrating unique potential in inducing MM cell apoptosis, reversing drug resistance, and modulating the immune microenvironment—making them a rising focus in translational medicine research. In this structured narrative review, we systematically summarize the anti-myeloma mechanisms of fourteen plant-derived natural products, including plant-derived monomeric compounds (baicalein, artemisinin, curcumin, celastrol, gambogic acid, resveratrol, ginsenosides, icariin, oridonin, plumbagin, formononetin) and standardized plant extracts (<em>Strychnos nux-vomica</em> root extract, dandelion flavonoids, <em>Hedyotis diffusa</em> polysaccharides). This review highlights their multi-target regulatory effects on signaling pathways, cell cycle modulation, and immune regulation, and further discusses their potential translational value in overcoming drug resistance and optimizing combination treatment strategies. Literature was retrieved from PubMed, Web of Science, and CNKI databases, covering studies published up to January 2025. Although plant-derived natural products exhibit promising multi-target regulatory mechanisms in MM therapy, their clinical translation remains limited by poor bioavailability of single compounds and the lack of standardized extracts. Future research should integrate systems pharmacology with clinical studies to elucidate multi-component synergistic networks and develop novel targeted formulations, thereby accelerating the efficient translation of phytochemicals from bench to bedside.</div></div>","PeriodicalId":48975,"journal":{"name":"Translational Oncology","volume":"64 ","pages":"Article 102666"},"PeriodicalIF":5.0,"publicationDate":"2026-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145939212","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-06DOI: 10.1016/j.tranon.2025.102599
Cheng-Huang Shen , PiChe Chen , Chia-Bin Chang , Chih-Chia Chang , Meilin Wang , Lien-Ping Chou , Ya-Yan Lai , Ming-Yang Lee , Shu-Fen Wu
Upper tract urothelial carcinoma (UTUC) is a rare urologic cancer that is more aggressive and has a poorer survival rate compared to bladder cancer. Previously, we linked the UTUC derived factors with tumor-infiltrating immune cells. Macrophages are considered the most abundant immune cell population within tumors and serve as key regulators of the tumor microenvironment. This study aimed to investigate their role in modulating immunosuppression in UTUC tumors. Our results indicated that UTUC patients had higher proportion of M2-type macrophages in the periphery, and that tumor-infiltrating M2 macrophages were inversely correlated with tumor-infiltrating T lymphocytes within UTUC tumors. The supernatants from UTUC tumor tissue, as well as the predominant factor adiponectin, caused upregulation of arginase-1 and CD206 expression in THP-1 differentiated macrophages. Furthermore, macrophages treated with supernatants from UTUC tumor tissue or adiponectin alone inhibited CD4 T cell and CD8 T cell proliferation, along with reduction of effective cytokines produced by T cells. These results suggest that macrophages modulated by adiponectin are associated with T cell suppression in the UTUC tumor microenvironment, highlighting a potential therapeutic target.
{"title":"Tumor derived adiponectin induces immunosuppressive macrophages in upper tract urothelial carcinoma","authors":"Cheng-Huang Shen , PiChe Chen , Chia-Bin Chang , Chih-Chia Chang , Meilin Wang , Lien-Ping Chou , Ya-Yan Lai , Ming-Yang Lee , Shu-Fen Wu","doi":"10.1016/j.tranon.2025.102599","DOIUrl":"10.1016/j.tranon.2025.102599","url":null,"abstract":"<div><div>Upper tract urothelial carcinoma (UTUC) is a rare urologic cancer that is more aggressive and has a poorer survival rate compared to bladder cancer. Previously, we linked the UTUC derived factors with tumor-infiltrating immune cells. Macrophages are considered the most abundant immune cell population within tumors and serve as key regulators of the tumor microenvironment. This study aimed to investigate their role in modulating immunosuppression in UTUC tumors. Our results indicated that UTUC patients had higher proportion of M2-type macrophages in the periphery, and that tumor-infiltrating M2 macrophages were inversely correlated with tumor-infiltrating T lymphocytes within UTUC tumors. The supernatants from UTUC tumor tissue, as well as the predominant factor adiponectin, caused upregulation of arginase-1 and CD206 expression in THP-1 differentiated macrophages. Furthermore, macrophages treated with supernatants from UTUC tumor tissue or adiponectin alone inhibited CD4 T cell and CD8 T cell proliferation, along with reduction of effective cytokines produced by T cells. These results suggest that macrophages modulated by adiponectin are associated with T cell suppression in the UTUC tumor microenvironment, highlighting a potential therapeutic target.</div></div>","PeriodicalId":48975,"journal":{"name":"Translational Oncology","volume":"64 ","pages":"Article 102599"},"PeriodicalIF":5.0,"publicationDate":"2026-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145913096","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-06DOI: 10.1016/j.tranon.2025.102616
Claudia Christowitz , Daniel W Olivier , Nicole van der Merwe , Maritha J Kotze , Anna-Mart Engelbrecht
Introduction
Pathology-supported genetic testing (PSGT), a personalized medicine framework established in South Africa, led to the identification of a rare germline tumour suppressor protein 53 (TP53) beta-isoform (β) variant (NM_001126114.3, c.1018A>G, p.N340D) in a family with the Li-Fraumeni-like syndrome. While protein modeling predicted structural alterations consistent with impaired function, its pathogenicity remained unclear.
Aim
To determine the functional impact of the TP53β N340D variant on cell proliferation, cell death, senescence, migration, and anti-tumour activity using a translational ex vivo model.
Methods
Peripheral blood mononuclear cells (PBMCs) were isolated from female controls and breast cancer patients, with or without the TP53β N340D variant. Lipopolysaccharide (LPS)- and phytohemagglutinin-L (PHA-L)-stimulated proliferation was evaluated by a water-soluble tetrazolium 1 (WST-1) assay. Doxorubicin (DXR)-induced cell death was assessed using a WST-1 assay, flow cytometry, and western blotting. A senescence-associated beta-galactosidase assay and western blotting determined senescence. Migration and anti-tumour activity were assessed using a Transwell assay and co-culturing PBMCs with BT-549 spheroids.
Results
The TP53β N340D variant impaired DXR-induced cell death (p < 0.001), supported by reduced late apoptosis and decreased CASP3 and PARP activation. TP53β N340D PBMCs exhibited increased senescence (p < 0.01), potentially contributing to chemoresistance. Reduced LPS- and PHA-L-stimulated proliferation was dependent on cancer status. The variant reduced PBMC migration (p < 0.01), suggesting altered immune recruitment. Although anti-tumour activity appeared reduced in TP53β N340D PBMCs, spheroid size remained unchanged.
Conclusions
This study provides supporting evidence for the pathogenicity of the TP53β N340D variant and highlights the importance of integrating functional genomics into PSGT to enhance medical decision-making.
{"title":"First functional evidence that a rare germline TP53β variant drives senescence-associated immune suppression and impairs apoptosis and cell migration in breast cancer patients","authors":"Claudia Christowitz , Daniel W Olivier , Nicole van der Merwe , Maritha J Kotze , Anna-Mart Engelbrecht","doi":"10.1016/j.tranon.2025.102616","DOIUrl":"10.1016/j.tranon.2025.102616","url":null,"abstract":"<div><h3>Introduction</h3><div>Pathology-supported genetic testing (PSGT), a personalized medicine framework established in South Africa, led to the identification of a rare germline <em>tumour suppressor protein 53</em> (<em>TP53</em>) beta-isoform (β) variant (NM_001126114.3, c.1018A><em>G</em>, p.N340D) in a family with the Li-Fraumeni-like syndrome. While protein modeling predicted structural alterations consistent with impaired function, its pathogenicity remained unclear.</div></div><div><h3>Aim</h3><div>To determine the functional impact of the <em>TP53</em>β N340D variant on cell proliferation, cell death, senescence, migration, and anti-tumour activity using a translational <em>ex vivo</em> model.</div></div><div><h3>Methods</h3><div>Peripheral blood mononuclear cells (PBMCs) were isolated from female controls and breast cancer patients, with or without the <em>TP53</em>β N340D variant. Lipopolysaccharide (LPS)- and phytohemagglutinin-L (PHA-L)-stimulated proliferation was evaluated by a water-soluble tetrazolium 1 (WST-1) assay. Doxorubicin (DXR)-induced cell death was assessed using a WST-1 assay, flow cytometry, and western blotting. A senescence-associated beta-galactosidase assay and western blotting determined senescence. Migration and anti-tumour activity were assessed using a Transwell assay and co-culturing PBMCs with BT-549 spheroids.</div></div><div><h3>Results</h3><div>The <em>TP53</em>β N340D variant impaired DXR-induced cell death (<em>p</em> < 0.001), supported by reduced late apoptosis and decreased CASP3 and PARP activation. <em>TP53</em>β N340D PBMCs exhibited increased senescence (<em>p</em> < 0.01), potentially contributing to chemoresistance. Reduced LPS- and PHA-L-stimulated proliferation was dependent on cancer status. The variant reduced PBMC migration (<em>p</em> < 0.01), suggesting altered immune recruitment. Although anti-tumour activity appeared reduced in <em>TP53</em>β N340D PBMCs, spheroid size remained unchanged.</div></div><div><h3>Conclusions</h3><div>This study provides supporting evidence for the pathogenicity of the <em>TP53</em>β N340D variant and highlights the importance of integrating functional genomics into PSGT to enhance medical decision-making.</div></div>","PeriodicalId":48975,"journal":{"name":"Translational Oncology","volume":"64 ","pages":"Article 102616"},"PeriodicalIF":5.0,"publicationDate":"2026-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145913252","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-06DOI: 10.1016/j.tranon.2025.102654
Zhenyi Chen , Guozhu Tang , Xuan Lv , Guoqing Ding, Mingyang Huang, Zhe Chen, Shuo Dai, Huilin Liu, Sheng Zhang, Lin Cai
Osteosarcoma (OS) is the most common primary malignant tumor of bone that commonly occurs in adolescents with poor prognosis. Neoadjuvant chemotherapy with the MAP regimen (high-dose methotrexate (Methotrexate), doxorubicin, and cisplatin) is essential for the standardized OS therapeutic, the good response of which critically exceeds the patient survival. However, approximately 30–40 % of patients develop chemoresistance, leading to metastatic disease or recurrence. Understanding the molecular mechanisms underlying chemoresistance is crucial for improving clinical outcomes. In this study, AVIL was identified as a key gene correlated with OS progression and chemoresistance. AVIL overexpression was found to promote OS progression in vitro and in vivo by enhancing cell proliferation, migration, and invasion, while AVIL deficiency exerted the inverse phenotypes. In vivo experiments further confirmed that AVIL overexpression promotes tumor growth and suppresses apoptosis. Mechanistically, AVIL interacts with the ARP2/3 complex, a key regulator of DNA damage repair via actin polymerization and cytoskeletal dynamics. This interaction was confirmed to facilitate cisplatin resistance, with reduced DNA damage response and increased cell survival caused by AVIL overexpression. Furthermore, using patient-derived organoid (PDO) models, we demonstrated that CK666, an ARP2/3 inhibitor, enhanced the chemotherapy efficacy of cisplatin by increasing DNA damage response and reversing AVIL-mediated cisplatin resistance. These findings highlight AVIL as a potential therapeutic target and suggest that targeting the AVIL-ARP2/3 axis could serve as an alternative strategy to overcome chemoresistance during OS treatment.
{"title":"AVIL promotes osteosarcoma progression and cisplatin resistance via ARP2/3-mediated DNA damage repair","authors":"Zhenyi Chen , Guozhu Tang , Xuan Lv , Guoqing Ding, Mingyang Huang, Zhe Chen, Shuo Dai, Huilin Liu, Sheng Zhang, Lin Cai","doi":"10.1016/j.tranon.2025.102654","DOIUrl":"10.1016/j.tranon.2025.102654","url":null,"abstract":"<div><div>Osteosarcoma (OS) is the most common primary malignant tumor of bone that commonly occurs in adolescents with poor prognosis. Neoadjuvant chemotherapy with the MAP regimen (high-dose methotrexate (Methotrexate), doxorubicin, and cisplatin) is essential for the standardized OS therapeutic, the good response of which critically exceeds the patient survival. However, approximately 30–40 % of patients develop chemoresistance, leading to metastatic disease or recurrence. Understanding the molecular mechanisms underlying chemoresistance is crucial for improving clinical outcomes. In this study, AVIL was identified as a key gene correlated with OS progression and chemoresistance. AVIL overexpression was found to promote OS progression <em>in vitro</em> and <em>in vivo</em> by enhancing cell proliferation, migration, and invasion, while AVIL deficiency exerted the inverse phenotypes. <em>In vivo</em> experiments further confirmed that AVIL overexpression promotes tumor growth and suppresses apoptosis. Mechanistically, AVIL interacts with the ARP2/3 complex, a key regulator of DNA damage repair via actin polymerization and cytoskeletal dynamics. This interaction was confirmed to facilitate cisplatin resistance, with reduced DNA damage response and increased cell survival caused by AVIL overexpression. Furthermore, using patient-derived organoid (PDO) models, we demonstrated that CK666, an ARP2/3 inhibitor, enhanced the chemotherapy efficacy of cisplatin by increasing DNA damage response and reversing AVIL-mediated cisplatin resistance. These findings highlight AVIL as a potential therapeutic target and suggest that targeting the AVIL-ARP2/3 axis could serve as an alternative strategy to overcome chemoresistance during OS treatment.</div></div>","PeriodicalId":48975,"journal":{"name":"Translational Oncology","volume":"64 ","pages":"Article 102654"},"PeriodicalIF":5.0,"publicationDate":"2026-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145913261","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-06DOI: 10.1016/j.tranon.2025.102635
Jingda Xu , Guanzheng Wu , Lu Wang , Qingfeng Zhang , Periyannan Velu , Annamalai Vijayalakshmi , Gang Chen
Nasopharyngeal carcinoma (NPC) occurs frequently, and NPC poses a significant risk to public health in areas where it is endemic. Better care is needed because NPC is associated with considerable morbidity and mortality. A natural anticancer substance called scutellarin fights cancer by acting on a variety of signalling pathways. Nevertheless, little is known about the underlying apoptotic and anti-proliferative actions of scutellarin. The current study aimed to determine the molecular effects of in vitro scutellarin on CNE1 human NPC cells through mechanisms such as cell proliferation, anti-inflammatory, and anti-apoptotic effects. NPC cells were exposed to scutellarin (20 and 30 μM/ml), and their proliferation and apoptosis were evaluated using the MTT assay, AO/EB, Rh-123, DCFH-DA, DAPI, and PI staining, cell adhesion, cell migration, and western blot analysis. We evaluated putative molecular pathways, MAPKs/NF-κB signaling, MMP, and intracellular ROS, cell proliferation regulatory proteins. By generating intracellular ROS, causing MMP loss and inducing apoptosis via the signalling pathways of TNF-α, COX-2, iNOS, and IL-6, pRB, cyclin-D1, CDK4/CDK6, and MAPKs/NF-κB, it has been found that scutellarin may reduce the proliferative, inflammatory, migratory, and invasive capacity of NPC cells. Our research supports the MAPKs/NF-κB pathway as a therapeutic target and suggests that it may play a key role in mediating the scutellarin actions against nasopharyngeal cancer malignancy. In summary, scutellarin may be an effective conventional therapeutic drug in preventing the progression of NPC.
{"title":"Scutellarin regulates MAPK/ERK signalling in nasopharyngeal cancer via the apoptotic and ROS induced DNA damage","authors":"Jingda Xu , Guanzheng Wu , Lu Wang , Qingfeng Zhang , Periyannan Velu , Annamalai Vijayalakshmi , Gang Chen","doi":"10.1016/j.tranon.2025.102635","DOIUrl":"10.1016/j.tranon.2025.102635","url":null,"abstract":"<div><div>Nasopharyngeal carcinoma (NPC) occurs frequently, and NPC poses a significant risk to public health in areas where it is endemic. Better care is needed because NPC is associated with considerable morbidity and mortality. A natural anticancer substance called scutellarin fights cancer by acting on a variety of signalling pathways. Nevertheless, little is known about the underlying apoptotic and anti-proliferative actions of scutellarin. The current study aimed to determine the molecular effects of <em>in vitro</em> scutellarin on CNE1 human NPC cells through mechanisms such as cell proliferation, anti-inflammatory, and anti-apoptotic effects. NPC cells were exposed to scutellarin (20 and 30 μM/ml), and their proliferation and apoptosis were evaluated using the MTT assay, AO/EB, Rh-123, DCFH-DA, DAPI, and PI staining, cell adhesion, cell migration, and western blot analysis. We evaluated putative molecular pathways, MAPKs/NF-κB signaling, MMP, and intracellular ROS, cell proliferation regulatory proteins. By generating intracellular ROS, causing MMP loss and inducing apoptosis via the signalling pathways of TNF-α, COX-2, iNOS, and IL-6, pRB, cyclin-D1, CDK4/CDK6, and MAPKs/NF-κB, it has been found that scutellarin may reduce the proliferative, inflammatory, migratory, and invasive capacity of NPC cells. Our research supports the MAPKs/NF-κB pathway as a therapeutic target and suggests that it may play a key role in mediating the scutellarin actions against nasopharyngeal cancer malignancy. In summary, scutellarin may be an effective conventional therapeutic drug in preventing the progression of NPC.</div></div>","PeriodicalId":48975,"journal":{"name":"Translational Oncology","volume":"64 ","pages":"Article 102635"},"PeriodicalIF":5.0,"publicationDate":"2026-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145912790","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-06DOI: 10.1016/j.tranon.2025.102658
Jinxi He , Bo Yu , Xuyang Song , Tong Zhang, Zhixiong Qiao, Jing Li
Lung cancer (LC) remains a significant global health challenge, characterized by rapid progression and limited therapeutic options. Zeaxanthin (Zea), a natural carotenoid, exhibits promising antioxidant, anti-inflammatory, and anti-tumor activities; however, its precise mechanisms in LC are largely unexplored. Here, we demonstrate that Zea and DNA topoisomerase II A (TOP2A) significantly suppresses the viability, proliferation, and migration of LC cells while promoting apoptosis in vitro. Mechanistically, transcriptome analysis identified TOP2A as a critical downstream target. Molecular docking and cellular thermal shift assays further confirmed a direct interaction between Zea and TOP2A, suggesting Zea enhances TOP2A protein stability. We found that Zea inhibits TOP2A expression, which subsequently disrupts MAPK/ERK signaling and enhances autophagic activity, evidenced by increased autophagosome and autolysosome formation. Western blot and immunofluorescence analyses corroborated the modulation of key autophagy-related proteins. In vivo studies using an orthotopic LC model revealed that Zea treatment markedly reduced tumor growth, accompanied by decreased TOP2A and Ki67 expression. Collectively, our findings establish Zea as a potent LC therapeutic agent that suppresses tumor progression by targeting TOP2A, inhibiting the MAPK/ERK pathway, and ultimately modulating autophagy.
肺癌（LC）仍然是一个重大的全球健康挑战，其特点是快速进展和有限的治疗选择。玉米黄质（Zea）是一种天然类胡萝卜素，具有良好的抗氧化、抗炎和抗肿瘤活性；然而，其在LC中的确切机制在很大程度上尚未被探索。在这里，我们证明了玉米和DNA拓扑异构酶II A （TOP2A）在体外显著抑制LC细胞的活力、增殖和迁移，同时促进细胞凋亡。从机制上讲，转录组分析确定TOP2A是一个关键的下游靶标。分子对接和细胞热移实验进一步证实了Zea与TOP2A之间的直接相互作用，表明Zea增强了TOP2A蛋白的稳定性。我们发现，Zea抑制TOP2A的表达，进而破坏MAPK/ERK信号通路，增强自噬活性，自噬体和自噬酶体的形成增加。Western blot和免疫荧光分析证实了关键自噬相关蛋白的调节。原位LC模型的体内研究显示，Zea处理显著降低肿瘤生长，同时降低TOP2A和Ki67的表达。总的来说，我们的研究结果表明Zea是一种有效的LC治疗剂，通过靶向TOP2A，抑制MAPK/ERK通路，最终调节自噬来抑制肿瘤进展。
{"title":"Zeaxanthin targets TOP2A to regulate autophagy and suppress lung cancer progression via the MAPK/ERK pathway","authors":"Jinxi He , Bo Yu , Xuyang Song , Tong Zhang, Zhixiong Qiao, Jing Li","doi":"10.1016/j.tranon.2025.102658","DOIUrl":"10.1016/j.tranon.2025.102658","url":null,"abstract":"<div><div>Lung cancer (LC) remains a significant global health challenge, characterized by rapid progression and limited therapeutic options. Zeaxanthin (Zea), a natural carotenoid, exhibits promising antioxidant, anti-inflammatory, and anti-tumor activities; however, its precise mechanisms in LC are largely unexplored. Here, we demonstrate that Zea and DNA topoisomerase II A (TOP2A) significantly suppresses the viability, proliferation, and migration of LC cells while promoting apoptosis <em>in vitro</em>. Mechanistically, transcriptome analysis identified TOP2A as a critical downstream target. Molecular docking and cellular thermal shift assays further confirmed a direct interaction between Zea and TOP2A, suggesting Zea enhances TOP2A protein stability. We found that Zea inhibits TOP2A expression, which subsequently disrupts MAPK/ERK signaling and enhances autophagic activity, evidenced by increased autophagosome and autolysosome formation. Western blot and immunofluorescence analyses corroborated the modulation of key autophagy-related proteins. <em>In vivo</em> studies using an orthotopic LC model revealed that Zea treatment markedly reduced tumor growth, accompanied by decreased TOP2A and Ki67 expression. Collectively, our findings establish Zea as a potent LC therapeutic agent that suppresses tumor progression by targeting TOP2A, inhibiting the MAPK/ERK pathway, and ultimately modulating autophagy.</div></div>","PeriodicalId":48975,"journal":{"name":"Translational Oncology","volume":"64 ","pages":"Article 102658"},"PeriodicalIF":5.0,"publicationDate":"2026-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145913148","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-06DOI: 10.1016/j.tranon.2025.102634
Fang-Zheng Chen , Ying Deng , Wen-Jing Yin , Meng-Yao Wang , Fang Yang , Zhi-Huan Yang , Li-Ping Zhou , Si-Da Chen , Jie-Ling Chen , Xi-Zhen Jiang , Ao-Xiong Zhou , Yu-Meng Ou , Jin-Quan Liu , Dong-Ping Chen , Bin Qi
Purpose
To evaluate the efficacy of nedaplatin in induction chemotherapy and concurrent chemoradiotherapy for locoregionally advanced nasopharyngeal carcinoma.
Methods
In this prospective, single-arm, open-label phase II trial, patients with newly diagnosed stage III-IVa (except T3–4N0) nasopharyngeal carcinoma were enrolled. Participants received three cycles of induction chemotherapy with docetaxel (60 mg/m² IV on days 1, 22, and 43), nedaplatin (60 mg/m² IV on days 1, 22, and 43), and fluorouracil (600 mg/m²/day as a continuous 120 h infusion on days 1–5, 22–26, and 43–47). This was followed by intensity-modulated radiotherapy with concurrent nedaplatin (100 mg/m² IV on days 1, 22, and/or 43) for two or three cycles. The primary endpoint was the objective response rate (ORR). Secondary endpoints included overall survival (OS), progression-free survival (PFS), and toxicity profile.
Results
From March 2020 to November 2021, 32 patients were enrolled. With a median follow-up of 42.4 months (IQR, 35.4–45.2), 32 patients (100 %) achieved ORR at 12 weeks post-treatment. The 36-month PFS was 87.5 % (95 % CI, 76.1 %-98.8 %), and the 36-month OS was 100 %. The most common grade 3 or 4 adverse events during induction chemotherapy were neutropenia (9.4 %), diarrhea (9.4 %), leukopenia (6.2 %), fatigue (3.1 %) and hepatotoxicity (3.1 %). Mucositis (9.4 %) was the most common adverse events during concurrent chemoradiotherapy, followed by leukopenia (3.1 %), neutropenia (3.1 %), and thrombocytopenia (3.1 %). All adverse events were manageable.
Conclusion
Induction chemotherapy with nedaplatin, docetaxel, and 5-fluorouracil, followed by concurrent nedaplatin with intensity-modulated radiotherapy, demonstrated promising antitumor activity and manageable toxicities in locoregionally advanced nasopharyngeal carcinoma patients.
Trial registration
This trial was registered with ClinicalTrials.gov identifier: NCT04834206.
{"title":"Induction chemotherapy with nedaplatin, docetaxel and 5-fluorouracil followed by concurrent nedaplatin and radiotherapy in locoregionally advanced nasopharyngeal carcinoma: A single arm, open label, phase II clinical trial","authors":"Fang-Zheng Chen , Ying Deng , Wen-Jing Yin , Meng-Yao Wang , Fang Yang , Zhi-Huan Yang , Li-Ping Zhou , Si-Da Chen , Jie-Ling Chen , Xi-Zhen Jiang , Ao-Xiong Zhou , Yu-Meng Ou , Jin-Quan Liu , Dong-Ping Chen , Bin Qi","doi":"10.1016/j.tranon.2025.102634","DOIUrl":"10.1016/j.tranon.2025.102634","url":null,"abstract":"<div><h3>Purpose</h3><div>To evaluate the efficacy of nedaplatin in induction chemotherapy and concurrent chemoradiotherapy for locoregionally advanced nasopharyngeal carcinoma.</div></div><div><h3>Methods</h3><div>In this prospective, single-arm, open-label phase II trial, patients with newly diagnosed stage III-IVa (except T3–4N0) nasopharyngeal carcinoma were enrolled. Participants received three cycles of induction chemotherapy with docetaxel (60 mg/m² IV on days 1, 22, and 43), nedaplatin (60 mg/m² IV on days 1, 22, and 43), and fluorouracil (600 mg/m²/day as a continuous 120 h infusion on days 1–5, 22–26, and 43–47). This was followed by intensity-modulated radiotherapy with concurrent nedaplatin (100 mg/m² IV on days 1, 22, and/or 43) for two or three cycles. The primary endpoint was the objective response rate (ORR). Secondary endpoints included overall survival (OS), progression-free survival (PFS), and toxicity profile.</div></div><div><h3>Results</h3><div>From March 2020 to November 2021, 32 patients were enrolled. With a median follow-up of 42.4 months (IQR, 35.4–45.2), 32 patients (100 %) achieved ORR at 12 weeks post-treatment. The 36-month PFS was 87.5 % (95 % CI, 76.1 %-98.8 %), and the 36-month OS was 100 %. The most common grade 3 or 4 adverse events during induction chemotherapy were neutropenia (9.4 %), diarrhea (9.4 %), leukopenia (6.2 %), fatigue (3.1 %) and hepatotoxicity (3.1 %). Mucositis (9.4 %) was the most common adverse events during concurrent chemoradiotherapy, followed by leukopenia (3.1 %), neutropenia (3.1 %), and thrombocytopenia (3.1 %). All adverse events were manageable.</div></div><div><h3>Conclusion</h3><div>Induction chemotherapy with nedaplatin, docetaxel, and 5-fluorouracil, followed by concurrent nedaplatin with intensity-modulated radiotherapy, demonstrated promising antitumor activity and manageable toxicities in locoregionally advanced nasopharyngeal carcinoma patients.</div></div><div><h3>Trial registration</h3><div>This trial was registered with ClinicalTrials.gov identifier: NCT04834206.</div></div>","PeriodicalId":48975,"journal":{"name":"Translational Oncology","volume":"64 ","pages":"Article 102634"},"PeriodicalIF":5.0,"publicationDate":"2026-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145913185","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-06DOI: 10.1016/j.tranon.2025.102630
Wei Gan , Guo-Qiang Sun , Jin-Long Huang , Bao-Ye Sun , Zhu-Tao Wang , Zhang-Fu Yang , Cheng Zhou , Yong Yi , Shuang-Jian Qiu
Background
A growing number of therapeutic strategies against hepatocellular carcinoma (HCC) have emerged. However, their efficacy remains limited. This study investigated the mechanism of interleukin-35 (IL-35) in the progression of HCC and its potential application in HCC treatment.
Methods
The expression of IL-35,Gp130 ,IL12-Rβ2, CCL3,etc. in HCC tissues was detected by immunohistochemistry(IHC), and the expression of IL-35 in HCC cell lines was detected by fluorescence assay. Kaplan-Meier survival analysis of IL-35 and its receptor in relation to overall survival(OS) and recurrence free survival(RFS) in patients with HCC. The mouse subcutaneous tumor models to study the effects of IL-35 on HCC growth and immune cells. Western blot were used to detect the expression IL-35, CCL3, FGF2, and flow cytometric plot were performed to explore the immune cells infiltration in the tumor tissue.
Results
High expression of IL-35 in patients with HCC was associated with poor prognosis. Furthermore, IL-35 could facilitate tumor progression by affecting neutrophil infiltration, angiogenesis, and CD8+ T-cell infiltration. Additionally, CCL3 was a key factor mediating the recruitment of neutrophils by IL-35. FGF2 derived from neutrophils stimulated by IL-35 promoted intratumoral angiogenesis. IL-35 also facilitated the adhesion of tumors to endothelial cells, with neutrophils further enhancing this effect both. Anti-IL-35 antibody combined with anti-PD1 antibody significantly enhanced which therapeutic effect in HCC.
Conclusions
Our data show that the high expression of IL-35 in patients with HCC is an important tumor promoter. Combined treatment with anti-IL-35 and anti-PD1 antibodies have potential therapeutic effect against HCC.
{"title":"Interleukin 35 promotes progression of hepatocellular carcinoma by recruiting neutrophils","authors":"Wei Gan , Guo-Qiang Sun , Jin-Long Huang , Bao-Ye Sun , Zhu-Tao Wang , Zhang-Fu Yang , Cheng Zhou , Yong Yi , Shuang-Jian Qiu","doi":"10.1016/j.tranon.2025.102630","DOIUrl":"10.1016/j.tranon.2025.102630","url":null,"abstract":"<div><h3>Background</h3><div>A growing number of therapeutic strategies against hepatocellular carcinoma (HCC) have emerged. However, their efficacy remains limited. This study investigated the mechanism of interleukin-35 (IL-35) in the progression of HCC and its potential application in HCC treatment.</div></div><div><h3>Methods</h3><div>The expression of IL-35,Gp130 ,IL12-Rβ2, CCL3,etc. in HCC tissues was detected by immunohistochemistry(IHC), and the expression of IL-35 in HCC cell lines was detected by fluorescence assay. Kaplan-Meier survival analysis of IL-35 and its receptor in relation to overall survival(OS) and recurrence free survival(RFS) in patients with HCC. The mouse subcutaneous tumor models to study the effects of IL-35 on HCC growth and immune cells. Western blot were used to detect the expression IL-35, CCL3, FGF2, and flow cytometric plot were performed to explore the immune cells infiltration in the tumor tissue.</div></div><div><h3>Results</h3><div>High expression of IL-35 in patients with HCC was associated with poor prognosis. Furthermore, IL-35 could facilitate tumor progression by affecting neutrophil infiltration, angiogenesis, and CD8+ T-cell infiltration. Additionally, CCL3 was a key factor mediating the recruitment of neutrophils by IL-35. FGF2 derived from neutrophils stimulated by IL-35 promoted intratumoral angiogenesis. IL-35 also facilitated the adhesion of tumors to endothelial cells, with neutrophils further enhancing this effect both. Anti-IL-35 antibody combined with anti-PD1 antibody significantly enhanced which therapeutic effect in HCC.</div></div><div><h3>Conclusions</h3><div>Our data show that the high expression of IL-35 in patients with HCC is an important tumor promoter. Combined treatment with anti-IL-35 and anti-PD1 antibodies have potential therapeutic effect against HCC.</div></div>","PeriodicalId":48975,"journal":{"name":"Translational Oncology","volume":"64 ","pages":"Article 102630"},"PeriodicalIF":5.0,"publicationDate":"2026-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145912731","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-06DOI: 10.1016/j.tranon.2025.102655
Rongrong Cui , Yuanyuan Wang , Yao Yao , Xiaojuan Ren , Yuchen Zhang , Daxu Li , Peng Hou , Meiju Ji , Yiping Qu
Lung adenocarcinoma (LUAD) is the most prevalent histological subtype of lung cancer, and the development of chemoresistance often leads to tumor recurrence and metastasis. Neurotrophic receptor tyrosine kinase 2 (NTRK2) has been implicated in tumorigenesis and chemotherapy resistance, but its precise role in LUAD and contribution to paclitaxel resistance remain unclear. In this study, we found that NTRK2 expression was significantly upregulated in LUADs compared with paired noncancerous tissues and was further elevated in samples from patients who experienced recurrence following paclitaxel-based chemotherapy. Functional assays demonstrated that NTRK2 knockdown markedly inhibited the malignant phenotypes of LUAD cells in vitro and significantly restored the sensitivity of LUAD cells to paclitaxel. Conversely, NTRK2 overexpression promoted cell proliferation, colony formation, and reduced responsiveness to paclitaxel. Consistently, in vivo xenograft experiments revealed that NTRK2 knockdown suppressed tumor growth and enhanced the antitumor efficacy of paclitaxel. Mechanistically, NTRK2 activated the MAPK/ERK and PI3K/AKT signaling pathways, leading to the upregulation of MYC, which in turn directly activated the transcription of ATP-binding cassette subfamily F member 1 (ABCF1), thereby promoting LUAD progression and paclitaxel resistance. Collectively, our findings identify NTRK2 as a critical oncogenic driver that confers chemoresistance by activating the NTRK2/MYC/ABCF1 signaling axis. This study provides new mechanistic insights into the regulation of paclitaxel resistance in LUAD and highlights NTRK2 and its downstream effectors as promising therapeutic targets for overcoming chemoresistance.
{"title":"NTRK2 promotes malignant progression and paclitaxel resistance of lung adenocarcinoma through targeting MYC/ABCF1 axis","authors":"Rongrong Cui , Yuanyuan Wang , Yao Yao , Xiaojuan Ren , Yuchen Zhang , Daxu Li , Peng Hou , Meiju Ji , Yiping Qu","doi":"10.1016/j.tranon.2025.102655","DOIUrl":"10.1016/j.tranon.2025.102655","url":null,"abstract":"<div><div>Lung adenocarcinoma (LUAD) is the most prevalent histological subtype of lung cancer, and the development of chemoresistance often leads to tumor recurrence and metastasis. Neurotrophic receptor tyrosine kinase 2 (NTRK2) has been implicated in tumorigenesis and chemotherapy resistance, but its precise role in LUAD and contribution to paclitaxel resistance remain unclear. In this study, we found that NTRK2 expression was significantly upregulated in LUADs compared with paired noncancerous tissues and was further elevated in samples from patients who experienced recurrence following paclitaxel-based chemotherapy. Functional assays demonstrated that <em>NTRK2</em> knockdown markedly inhibited the malignant phenotypes of LUAD cells <em>in vitro</em> and significantly restored the sensitivity of LUAD cells to paclitaxel. Conversely, <em>NTRK2</em> overexpression promoted cell proliferation, colony formation, and reduced responsiveness to paclitaxel. Consistently, <em>in vivo</em> xenograft experiments revealed that <em>NTRK2</em> knockdown suppressed tumor growth and enhanced the antitumor efficacy of paclitaxel. Mechanistically, NTRK2 activated the MAPK/ERK and PI3K/AKT signaling pathways, leading to the upregulation of MYC, which in turn directly activated the transcription of ATP-binding cassette subfamily F member 1 (<em>ABCF1</em>), thereby promoting LUAD progression and paclitaxel resistance. Collectively, our findings identify NTRK2 as a critical oncogenic driver that confers chemoresistance by activating the NTRK2/MYC/ABCF1 signaling axis. This study provides new mechanistic insights into the regulation of paclitaxel resistance in LUAD and highlights NTRK2 and its downstream effectors as promising therapeutic targets for overcoming chemoresistance.</div></div>","PeriodicalId":48975,"journal":{"name":"Translational Oncology","volume":"64 ","pages":"Article 102655"},"PeriodicalIF":5.0,"publicationDate":"2026-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145912842","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
扫码关注我们
求助内容：
应助结果提醒方式：
京公网安备 11010802042870号