Hanchuan Shen, Bing Liu, Hangyu Zhang, Yang Liu, Chenggang Li
Hepatocellular carcinoma (HCC) is the fourth leading cause of cancer death and the sixth in incidence globally. Curative resection is a main treatment for HCC patients, yet the 5-year post-radical resection tumor recurrence rate remains up to 70%. Most high-risk recurrence patients may experience early recurrence within 2 years and have a poor prognosis [1]. Notably, there's still a lack of standardized postoperative treatment globally. A recent study, IMbrave050, found that the postoperative adjuvant use of the combination of bevacizumab and atezolizumab did not extend recurrence-free survival (RFS) when compared to surveillance [2]. Combinations of tyrosine kinase inhibitors (TKIs) and PD-1 inhibitors have shown promise in unresectable HCC, with the efficacy of adjuvant treatment postradical resection yet to be confirmed. Donafenib, a novel TKI, has demonstrated survival benefits over sorafenib in unresectable HCC. Additionally, several studies of donafenib combined with PD-1 inhibitors have shown promising results for unresectable HCC because of synergistic antitumor effects [3, 4]. This retrospective study aims to evaluate the efficacy and safety of adjuvant donafenib combined with PD-1inhibitor sintilimab in preventing tumor recurrence in HCC patients with high-risk recurrence factors (HRRF).
This retrospective study involved patients who underwent radical resection from June 2019 to February 2023. Informed consent was waived due to the retrospective nature of the study. The study adhered to the Helsinki Declaration and was approved by the ethics committee of Chinese PLA General Hospital (Approval no. S2023-737-01). Eligible patients were ≥ 18 years old and had HRRF, including tumor size ≥ 5 cm, tumor number ≥ 2, macrovascular invasion (invasion of portal and hepatic veins), presence of microvascular invasion (MVI), and satellite nodules. Patients receiving adjuvant donafenib (0.1 g twice daily orally) and sintilimab (200 mg every 3 weeks intravenously) initiated treatment 4–8 weeks postsurgery for up to 1 year or until HCC recurrence or serious adverse events. To balance confounding factors, we utilized a 1:1 propensity score matching (PSM) analysis with a caliper width of 0.02, which considered variables such as sex, age, Eastern Co-operative Oncology Group Performance Status, Barcelona Clinic Liver Cancer (BCLC) stage, Child-Pugh score, HBV, tumor diameter, tumor number, macrovascular invasion, MVI, satellite nodules, alpha-fetoprotein (AFP), and tumor differentiation. Imaging was conducted every 12 weeks during the first 2 years and then every 24 weeks until disease recurrence. The outcomes included RFS, overall survival (OS) and safety.
From June 2019 to February 2023, we collected 260 HCC patients with HRRF after radical resection. A total of 101 patients met the inclusion criteria and were ultimately included in the study. The treatment group consisted of 34 patients who received a
肝细胞癌（HCC）是癌症死亡的第四大原因，在全球发病率中排名第六。根治性切除是HCC患者的主要治疗方法，但根治性切除后5年肿瘤复发率仍高达70%。大多数高危复发患者可在2年内早期复发，预后较差。值得注意的是，全球仍缺乏标准化的术后治疗。最近的一项研究IMbrave050发现，与监测bbb相比，术后辅助使用贝伐单抗和阿特唑单抗联合并没有延长无复发生存期（RFS）。酪氨酸激酶抑制剂（TKIs）和PD-1抑制剂联合使用在不可切除的HCC中显示出希望，但术后辅助治疗的效果尚未得到证实。Donafenib是一种新型TKI，在不可切除的HCC中比sorafenib更有利于生存。此外，多纳非尼联合PD-1抑制剂的一些研究显示，由于协同抗肿瘤作用，多纳非尼联合PD-1抑制剂治疗不可切除的HCC有很好的效果[3,4]。本回顾性研究旨在评价佐剂多那非尼联合pd -1抑制剂辛替单抗预防高危复发因素（HRRF） HCC患者肿瘤复发的有效性和安全性。这项回顾性研究涉及2019年6月至2023年2月接受根治性切除术的患者。由于研究的回顾性性质，我们放弃了知情同意。本研究遵循《赫尔辛基宣言》，经中国人民解放军总医院伦理委员会批准(批准号：s2023 - 737 - 01)。符合条件的患者年龄≥18岁，HRRF包括肿瘤大小≥5 cm，肿瘤数≥2，大血管侵犯（门脉和肝静脉侵犯），微血管侵犯（MVI）和卫星结节的存在。接受辅助多纳非尼（0.1 g，每日两次口服）和辛替单抗（200mg，每3周静脉注射）的患者在术后4-8周开始治疗，持续长达1年或直到HCC复发或严重不良事件。为了平衡混杂因素，我们采用了1:1的倾向评分匹配（PSM）分析，卡尺宽度为0.02，考虑了性别、年龄、东部合作肿瘤组的表现状况、巴塞罗那临床肝癌（BCLC）分期、Child-Pugh评分、HBV、肿瘤直径、肿瘤数量、大血管侵袭、MVI、卫星结节、甲胎蛋白（AFP）和肿瘤分化等变量。前2年每12周进行一次影像学检查，之后每24周进行一次影像学检查，直至疾病复发。结果包括RFS、总生存期（OS）和安全性。2019年6月至2023年2月，我们收集了260例根治性切除术后HRRF HCC患者。共有101例患者符合纳入标准，最终被纳入研究。治疗组34例患者接受多纳非尼联合辛替单抗治疗，无术后辅助治疗组（对照组）67例患者。PSM后，52例患者纳入研究（图1A）。PSM匹配前后的基线特征见支持信息：表S1。治疗组中位随访时间为17.7个月，对照组中位随访时间为11.5个月（p = 0.116）。PSM后，治疗组8例，对照组13例出现复发或死亡（图1B）。治疗组的中位RFS不可估计（NE）（95%可信区间[CI]: 13.4 NE），而对照组的中位RFS为11.1个月（95% CI: 8.3 NE）（风险比[HR] = 0.339 [95% CI = 0.138-0.835], p = 0.014，图1C）。值得注意的是，在对照组中，4例患者术后4个月内复发。治疗组在9、12、18个月的RFS率显著优于对照组（支持信息：表S2）。两组均未达到中位OS （p = 0.720，图1C）。两组患者18个月的OS率分别为82.6%和62.7%，且治疗有延长OS的趋势。我们对至少存在两种HRRF的患者进行了额外的分析。治疗组的RFS明显长于对照组(中位数，14.7个月[95% CI: 12.2 ne] vs. 8.3个月[95% CI: 5.1 ne]；Hr = 0.365 [95% ci = 0.136 ~ 0.977]；p = 0.037，支持信息：图S1A)。治疗组的中位OS为NE (95% CI: 12.2-NE)，对照组的中位OS为14.4 （95% CI: 14.4 - NE）个月（HR = 0.724 [95% CI = 0.119-4.390], p = 0.720，支持信息：图S1B）。多因素分析发现辅助治疗（HR = 0.373, p = 0.035）和BCLC分期（HR = 4.225, p = 0.026）是与RFS显著相关的独立预测因子（支持信息：表S3）。 亚组分析显示,治疗组一直在下面的子组优于对照组:男性(HR = 0.316, p = 0.018),孩子普5 (HR = 0.316, p = 0.026),法新社& lt; 400 ng / mL (HR = 0.143, p = 0.005), BCLC阶段C (HR = 0.274, p = 0.017),单一肿瘤(HR = 0.285, p = 0.020),肿瘤直径≥5厘米(HR = 0.184, p = 0.001),没有macrovascular入侵(HR = 0.231, p = 0.014),和没有肿瘤卫星(HR = 0.271, p = 0.023)。(图1 d)。在PSM之前，治疗组中没有患者因不良事件而终止治疗。在治疗组中，没有与治疗相关的死亡，12名患者（35.3%）发生了任何级别的治疗紧急不良事件（TEAE）。最常见的3级TEAE是皮疹（2例，5.9%）。未发生4级或5级不良事件（支持信息：表S4）。在本研究中，我们观察到多纳非尼联合辛替单抗可显著改善高危HCC根治性切除术后的RFS。在单因素和多因素分析中，我们确定了辅助多纳非尼-辛替单抗是RFS的预后因素。虽然OS没有显示出显著差异，但我们相信更长的随访可能会揭示这种辅助方案的OS益处。本研究是专门针对中国患者进行的，虽然结果适用于这一人群，但对其他人群的适用性可能有所不同。高危HCC患者根治后存在残余微转移，常导致复发。TKIs和PD-1抑制剂联合使用可协同靶向这些残留病灶。此外，肿瘤复发受细胞毒性t细胞浸润减少、免疫检查点上调、免疫抑制性细胞积聚等因素的影响。抗血管生成治疗可以调节免疫抑制的肝肿瘤微环境。有证据表明，手术有利于选定的晚期HCC患者，亚洲指南认可手术作为此类患者的一线选择[10]。在我们的研究中，患者肿瘤分期相对较晚，53.8%为BCLC - C，但仍接受手术治疗。亚组分析显示，患者术后辅助治疗后预后较好，无严重不良反应。总之，与主动监测相比，多纳非尼和辛替单抗辅助治疗显著改善了中国HCC根治后HRRF患者的RFS。不良事件是可控的，增强了对辅助治疗的信心。然而，本研究的局限性包括其回顾性、单中心设计和小样本量。一项计划中的多纳非尼联合辛替单抗改善HCC合并HRRF患者RFS的疗效，旨在进一步验证多纳非尼联合辛替单抗改善HRRF患者RFS的疗效。沈汉川：数据策展、形式分析、调查、方法论、软件、可视化、撰写原稿。刘兵：数据策展、形式分析、调查、方法论、软件、可视化、写作——原稿。张杭宇：数据管理、写作、评审、编辑。杨柳：数据策展、项目管理、监督、文审、编辑。李成刚：构思、项目管理、监督、审稿、编辑。所有作者都阅读并批准了最终稿件。中国人民解放军总医院伦理委员会批准了这项研究，并放弃了对这项回顾性分析的知情同意，批准号：s2023 - 737 - 01)。这项研究遵循了《赫尔辛基宣言》。作者声明无利益冲突。
{"title":"Adjuvant Therapy Combining Donafenib and Sintilimab Enhances Recurrence-Free Survival in Hepatocellular Carcinoma Patients With High-Risk Recurrence Factors After Radical Resection: A Retrospective Cohort Study","authors":"Hanchuan Shen, Bing Liu, Hangyu Zhang, Yang Liu, Chenggang Li","doi":"10.1002/mog2.70013","DOIUrl":"https://doi.org/10.1002/mog2.70013","url":null,"abstract":"<p>Hepatocellular carcinoma (HCC) is the fourth leading cause of cancer death and the sixth in incidence globally. Curative resection is a main treatment for HCC patients, yet the 5-year post-radical resection tumor recurrence rate remains up to 70%. Most high-risk recurrence patients may experience early recurrence within 2 years and have a poor prognosis [<span>1</span>]. Notably, there's still a lack of standardized postoperative treatment globally. A recent study, IMbrave050, found that the postoperative adjuvant use of the combination of bevacizumab and atezolizumab did not extend recurrence-free survival (RFS) when compared to surveillance [<span>2</span>]. Combinations of tyrosine kinase inhibitors (TKIs) and PD-1 inhibitors have shown promise in unresectable HCC, with the efficacy of adjuvant treatment postradical resection yet to be confirmed. Donafenib, a novel TKI, has demonstrated survival benefits over sorafenib in unresectable HCC. Additionally, several studies of donafenib combined with PD-1 inhibitors have shown promising results for unresectable HCC because of synergistic antitumor effects [<span>3, 4</span>]. This retrospective study aims to evaluate the efficacy and safety of adjuvant donafenib combined with PD-1inhibitor sintilimab in preventing tumor recurrence in HCC patients with high-risk recurrence factors (HRRF).</p><p>This retrospective study involved patients who underwent radical resection from June 2019 to February 2023. Informed consent was waived due to the retrospective nature of the study. The study adhered to the Helsinki Declaration and was approved by the ethics committee of Chinese PLA General Hospital (Approval no. S2023-737-01). Eligible patients were ≥ 18 years old and had HRRF, including tumor size ≥ 5 cm, tumor number ≥ 2, macrovascular invasion (invasion of portal and hepatic veins), presence of microvascular invasion (MVI), and satellite nodules. Patients receiving adjuvant donafenib (0.1 g twice daily orally) and sintilimab (200 mg every 3 weeks intravenously) initiated treatment 4–8 weeks postsurgery for up to 1 year or until HCC recurrence or serious adverse events. To balance confounding factors, we utilized a 1:1 propensity score matching (PSM) analysis with a caliper width of 0.02, which considered variables such as sex, age, Eastern Co-operative Oncology Group Performance Status, Barcelona Clinic Liver Cancer (BCLC) stage, Child-Pugh score, HBV, tumor diameter, tumor number, macrovascular invasion, MVI, satellite nodules, alpha-fetoprotein (AFP), and tumor differentiation. Imaging was conducted every 12 weeks during the first 2 years and then every 24 weeks until disease recurrence. The outcomes included RFS, overall survival (OS) and safety.</p><p>From June 2019 to February 2023, we collected 260 HCC patients with HRRF after radical resection. A total of 101 patients met the inclusion criteria and were ultimately included in the study. The treatment group consisted of 34 patients who received a","PeriodicalId":100902,"journal":{"name":"MedComm – Oncology","volume":"4 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/mog2.70013","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143554596","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
<p>A recent study published in the journal <i>Cell</i> [<span>1</span>] revealed the critical role of macrophages in the malignant development of brain cancers, particularly glioblastoma. Through a series of in-vivo and in-vitro experiments, the study researched how macrophages provide essential lipids and nutrients to brain cancer cells by mediating the recycling and reuse of myelin, the insulating layer in the nervous system, which in turn promotes growth and invasion of tumor. They explored the heterogeneity of tumor-associated macrophages (TAM) in glioblastoma tumor microenvironment using single-cell and multi-omics analyses and revealed their specific interactions with different glioblastoma subtypes. The study reported the dynamic contexture of the glioblastoma tumor microenvironment at single-cell levels during primary or recurrent tumor progression, revealed the colocated diversity of niche-specific interactions between TAMs and glioblastoma subtypes at spatial transcriptomic levels, evaluated the chromatin landscape changes and immuno-suppressive features associated with the lipid-laden phenotype using multi-omics sequences, addressed the transfer route of lipid flux from myelin to macrophages at last to mesenchymal-like (MES-like) glioblastoma cells, demonstrated the intrinsic lipid traffic in macrophages and the altered metabolic manner in glioblastoma cells using lipidomics analysis and experiments, presented the protumorigenic functions of lipid-laden macrophages (LLMs) in glioblastoma and their relevance to clinical survival or immunotherapeutic response.</p><p>The study found that in the brain tumor microenvironment, macrophages are able to take up and accumulate myelin debris in large quantities. These myelin fragments are converted by macrophages into cholesterol and other lipids, which are then delivered to brain cancer cells to support their growth and malignant transformation. They also found that specific types of macrophages, such as TAMs with high glycoprotein nonmetastatic melanoma protein B (GPNMB) expression, are closely associated with areas of high myelin debris accumulation and exhibit unique patterns of lipid metabolism and inflammatory activity. The study further demonstrated that macrophage-mediated lipid delivery not only provides an energy source for brain cancer cells, but also promotes the invasion and metastasis ability of cancer cells. By interfering with the lipid metabolism pathway of macrophages, the progress of brain cancer can be significantly inhibited. When macrophages take in myelin fragments, their inflammatory activity is suppressed and they shift to an “anti-inflammatory” state. This anti-inflammatory state may help maintain the stability of the tumor microenvironment, thus providing favorable conditions for tumor cell growth. The study was also verified using patient sample data and found similar patterns of macrophage activity in the tumor microenvironment of glioma patients, which suggests that
{"title":"Macrophage-Mediated Myelin Recycling Promotes Malignant Development of Glioblastoma","authors":"Huanhuan Wang, Long Zhang, Feng Xie","doi":"10.1002/mog2.70014","DOIUrl":"https://doi.org/10.1002/mog2.70014","url":null,"abstract":"<p>A recent study published in the journal <i>Cell</i> [<span>1</span>] revealed the critical role of macrophages in the malignant development of brain cancers, particularly glioblastoma. Through a series of in-vivo and in-vitro experiments, the study researched how macrophages provide essential lipids and nutrients to brain cancer cells by mediating the recycling and reuse of myelin, the insulating layer in the nervous system, which in turn promotes growth and invasion of tumor. They explored the heterogeneity of tumor-associated macrophages (TAM) in glioblastoma tumor microenvironment using single-cell and multi-omics analyses and revealed their specific interactions with different glioblastoma subtypes. The study reported the dynamic contexture of the glioblastoma tumor microenvironment at single-cell levels during primary or recurrent tumor progression, revealed the colocated diversity of niche-specific interactions between TAMs and glioblastoma subtypes at spatial transcriptomic levels, evaluated the chromatin landscape changes and immuno-suppressive features associated with the lipid-laden phenotype using multi-omics sequences, addressed the transfer route of lipid flux from myelin to macrophages at last to mesenchymal-like (MES-like) glioblastoma cells, demonstrated the intrinsic lipid traffic in macrophages and the altered metabolic manner in glioblastoma cells using lipidomics analysis and experiments, presented the protumorigenic functions of lipid-laden macrophages (LLMs) in glioblastoma and their relevance to clinical survival or immunotherapeutic response.</p><p>The study found that in the brain tumor microenvironment, macrophages are able to take up and accumulate myelin debris in large quantities. These myelin fragments are converted by macrophages into cholesterol and other lipids, which are then delivered to brain cancer cells to support their growth and malignant transformation. They also found that specific types of macrophages, such as TAMs with high glycoprotein nonmetastatic melanoma protein B (GPNMB) expression, are closely associated with areas of high myelin debris accumulation and exhibit unique patterns of lipid metabolism and inflammatory activity. The study further demonstrated that macrophage-mediated lipid delivery not only provides an energy source for brain cancer cells, but also promotes the invasion and metastasis ability of cancer cells. By interfering with the lipid metabolism pathway of macrophages, the progress of brain cancer can be significantly inhibited. When macrophages take in myelin fragments, their inflammatory activity is suppressed and they shift to an “anti-inflammatory” state. This anti-inflammatory state may help maintain the stability of the tumor microenvironment, thus providing favorable conditions for tumor cell growth. The study was also verified using patient sample data and found similar patterns of macrophage activity in the tumor microenvironment of glioma patients, which suggests that ","PeriodicalId":100902,"journal":{"name":"MedComm – Oncology","volume":"4 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-02-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/mog2.70014","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143481329","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Lin Tang, Shao-Cong Peng, Xiao-Wan Zhuang, Yan He, Yu-Xiang Song, Hao Nie, Can-Can Zheng, Zhen-Yu Pan, Alfred King-Yin Lam, Ming-Liang He, Xing-Yuan Shi, Bin Li, Wen Wen Xu
Metastasis remains a leading cause of cancer-related deaths, defined by a complex, multi-step process in which tumor cells spread and form secondary growths in distant tissues. Despite substantial progress in understanding metastasis, the molecular mechanisms driving this process and the development of effective therapies remain incompletely understood. Elucidating the molecular pathways governing metastasis is essential for the discovery of innovative therapeutic targets. The rapid advancements in sequencing technologies and the expansion of biological databases have significantly deepened our understanding of the molecular drivers of metastasis and associated drug resistance. This review focuses on the molecular drivers of metastasis, particularly the roles of genetic mutations, epigenetic changes, and post-translational modifications in metastasis progression. We also examine how the tumor microenvironment influences metastatic behavior and explore emerging therapeutic strategies, including targeted therapies and immunotherapies. Finally, we discuss future research directions, stressing the importance of novel treatment approaches and personalized strategies to overcome metastasis and improve patient outcomes. By integrating contemporary insights into the molecular basis of metastasis and therapeutic innovation, this review provides a comprehensive framework to guide future research and clinical advancements in metastatic cancer.
{"title":"Tumor Metastasis: Mechanistic Insights and Therapeutic Intervention","authors":"Lin Tang, Shao-Cong Peng, Xiao-Wan Zhuang, Yan He, Yu-Xiang Song, Hao Nie, Can-Can Zheng, Zhen-Yu Pan, Alfred King-Yin Lam, Ming-Liang He, Xing-Yuan Shi, Bin Li, Wen Wen Xu","doi":"10.1002/mog2.70012","DOIUrl":"https://doi.org/10.1002/mog2.70012","url":null,"abstract":"<p>Metastasis remains a leading cause of cancer-related deaths, defined by a complex, multi-step process in which tumor cells spread and form secondary growths in distant tissues. Despite substantial progress in understanding metastasis, the molecular mechanisms driving this process and the development of effective therapies remain incompletely understood. Elucidating the molecular pathways governing metastasis is essential for the discovery of innovative therapeutic targets. The rapid advancements in sequencing technologies and the expansion of biological databases have significantly deepened our understanding of the molecular drivers of metastasis and associated drug resistance. This review focuses on the molecular drivers of metastasis, particularly the roles of genetic mutations, epigenetic changes, and post-translational modifications in metastasis progression. We also examine how the tumor microenvironment influences metastatic behavior and explore emerging therapeutic strategies, including targeted therapies and immunotherapies. Finally, we discuss future research directions, stressing the importance of novel treatment approaches and personalized strategies to overcome metastasis and improve patient outcomes. By integrating contemporary insights into the molecular basis of metastasis and therapeutic innovation, this review provides a comprehensive framework to guide future research and clinical advancements in metastatic cancer.</p>","PeriodicalId":100902,"journal":{"name":"MedComm – Oncology","volume":"4 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/mog2.70012","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143423918","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Xiaohui Du, Congcong Zhang, Ying Li, Peipei He, Jian Wang, Xuena Chen, Han Wang, Qi Wang
Osimertinib resistance remains a significant challenge in the treatment of non-small cell lung cancer (NSCLC). N6-methyladenosine (m6A) modifications are closely linked to various mechanisms of anticancer resistance and autophagy, offering new avenues for targeted therapies. However, the role of m6A-mediated autophagy in osimertinib-resistant NSCLC is still unclear. In this study, we utilized multi-omics sequencing analysis and found that overexpression of the m6A methyltransferase METTL3 contributes to osimertinib resistance in NSCLC. Importantly, we identified that METTL3 positively regulates the expression of the autophagy-related gene ubiquinone-cytochrome C reductase complex assembly factor 2 (UQCC2) through an m6A-dependent mechanism. Further, we confirmed that METTL3 knockdown leads to UQCC2 downregulation and triggers autophagy activation. Interestingly, lomitapide, a cholesterol-lowering drug, was repurposed to enhance the sensitivity of cancer cells to therapy by inhibiting METTL3, which in turn activated autophagy-associated cell death pathways, reversing osimertinib resistance. This study emphasizes the critical role of the METTL3/UQCC2 axis in autophagy-mediated drug resistance and positions lomitapide as a promising METTL3 inhibitor and autophagy inducer with potential therapeutic effects, either alone or in combination with other anticancer agents, in patients with osimertinib-resistant NSCLC.
{"title":"Lomitapide: Targeting METTL3 to Overcome Osimertinib Resistance in NSCLC Through Autophagy Activation","authors":"Xiaohui Du, Congcong Zhang, Ying Li, Peipei He, Jian Wang, Xuena Chen, Han Wang, Qi Wang","doi":"10.1002/mog2.70011","DOIUrl":"https://doi.org/10.1002/mog2.70011","url":null,"abstract":"<p>Osimertinib resistance remains a significant challenge in the treatment of non-small cell lung cancer (NSCLC). <i>N</i><sup>6</sup>-methyladenosine (m<sup>6</sup>A) modifications are closely linked to various mechanisms of anticancer resistance and autophagy, offering new avenues for targeted therapies. However, the role of m<sup>6</sup>A-mediated autophagy in osimertinib-resistant NSCLC is still unclear. In this study, we utilized multi-omics sequencing analysis and found that overexpression of the m<sup>6</sup>A methyltransferase METTL3 contributes to osimertinib resistance in NSCLC. Importantly, we identified that METTL3 positively regulates the expression of the autophagy-related gene ubiquinone-cytochrome C reductase complex assembly factor 2 (<i>UQCC2</i>) through an m<sup>6</sup>A-dependent mechanism. Further, we confirmed that <i>METTL3</i> knockdown leads to <i>UQCC2</i> downregulation and triggers autophagy activation. Interestingly, lomitapide, a cholesterol-lowering drug, was repurposed to enhance the sensitivity of cancer cells to therapy by inhibiting METTL3, which in turn activated autophagy-associated cell death pathways, reversing osimertinib resistance. This study emphasizes the critical role of the METTL3/UQCC2 axis in autophagy-mediated drug resistance and positions lomitapide as a promising METTL3 inhibitor and autophagy inducer with potential therapeutic effects, either alone or in combination with other anticancer agents, in patients with osimertinib-resistant NSCLC.</p>","PeriodicalId":100902,"journal":{"name":"MedComm – Oncology","volume":"4 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-01-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/mog2.70011","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143120497","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Nan Liu, Wenwen Wei, Kexing Ren, Dandan Liang, Dong Yang, Weishan Zhang, Beibei Yang, Bin Sun, Jincheng Zhao, Dan Cao, Liqun Zou, Xudong Zhao
Chimeric antigen receptor (CAR) T cells have demonstrated promising results in hematological malignancies; however, challenges remain in treating solid tumors. New CARs with more effectiveness and lower side effects are needed. Ephrin type-A receptor 2 (EphA2) belongs to the Ephrin family of receptor tyrosine kinases, which is overexpressed in several solid malignancies. Compared with some single-chain variable fragment (ScFv) CARs that exhibit excessively high affinity for their targets, natural receptor/ligand-based CARs maintain inherent affinity for their binding partners, potentially balancing cytotoxicity and side effects to better meet clinical needs. Here, we designed a CAR targeting EphA2-positive cancer cells by exploiting the extracellular domain of its natural ligand Ephrin A1 (EFNA1). EFNA1 CAR-T cells exhibited specific cytotoxicity against various cancer cells and cancer stem-like cells in vitro, and significantly suppressed tumor growth in a pancreatic cancer xenograft mouse model. Moreover, although these CAR-T cells specifically targeted mouse EphA2 and killed mouse tumor cell lines in vitro, they did not induce obvious side effects in mice. Additionally, it also showed good safety in rhesus macaques. Collectively, these results validate the therapeutic effectiveness and safety of EFNA1 CAR-T cells for treating solid tumors.
{"title":"Ephrin A1 ligand-based CAR-T cells for immunotherapy of EphA2-positive cancer","authors":"Nan Liu, Wenwen Wei, Kexing Ren, Dandan Liang, Dong Yang, Weishan Zhang, Beibei Yang, Bin Sun, Jincheng Zhao, Dan Cao, Liqun Zou, Xudong Zhao","doi":"10.1002/mog2.70010","DOIUrl":"https://doi.org/10.1002/mog2.70010","url":null,"abstract":"<p>Chimeric antigen receptor (CAR) T cells have demonstrated promising results in hematological malignancies; however, challenges remain in treating solid tumors. New CARs with more effectiveness and lower side effects are needed. Ephrin type-A receptor 2 (EphA2) belongs to the Ephrin family of receptor tyrosine kinases, which is overexpressed in several solid malignancies. Compared with some single-chain variable fragment (ScFv) CARs that exhibit excessively high affinity for their targets, natural receptor/ligand-based CARs maintain inherent affinity for their binding partners, potentially balancing cytotoxicity and side effects to better meet clinical needs. Here, we designed a CAR targeting EphA2-positive cancer cells by exploiting the extracellular domain of its natural ligand Ephrin A1 (EFNA1). EFNA1 CAR-T cells exhibited specific cytotoxicity against various cancer cells and cancer stem-like cells in vitro, and significantly suppressed tumor growth in a pancreatic cancer xenograft mouse model. Moreover, although these CAR-T cells specifically targeted mouse EphA2 and killed mouse tumor cell lines in vitro, they did not induce obvious side effects in mice. Additionally, it also showed good safety in <i>rhesus macaques</i>. Collectively, these results validate the therapeutic effectiveness and safety of EFNA1 CAR-T cells for treating solid tumors.</p>","PeriodicalId":100902,"journal":{"name":"MedComm – Oncology","volume":"4 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-01-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/mog2.70010","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143118772","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Rongli Xie, Yawei Feng, Jiankang Shen, Guohui Xiao, Dan Tan
<p>The incidence of thyroid tumors has been increasing in recent years, and the vast majority of new malignant cases are papillary thyroid micro-carcinoma (PTMC).<span><sup>1</sup></span> For patients with PTMC, comprehensive diagnosis and treatment, led by surgery, is the key to clinical cure. Although the lethality of papillary thyroid carcinoma is very low, tumor proliferation mechanism and surgical method after recurrence are still a hot topic of debate.<span><sup>2-4</sup></span> In this paper, thyroid patients admitted from January 2015 to December 2020 were collected. The inclusion criteria were as follows: (1) age from 18 to 80 years old; (2) the first and subsequent surgeries for thyroid were performed in one single center; (3) the postoperative paraffin pathology confirmed thyroid tumor; and (4) the patient's clinical data were complete. In this study, the gender, age, surgical methods, tumor types, maximum diameter of tumor, metastasis of central neck group and lateral lymph nodes, postoperative complications, and length of hospital stay were collected and recorded. For patients with multiple surgeries, the reason for subsequent surgeries and the interval time between surgeries should be additionally recorded.</p><p>A total of 58 patients undergoing thyroid surgeries (1 patient with laparoscopic surgery was excluded) were collected in this study, as shown in Table 1. Fifteen patients in the observation group underwent central lymph node dissection and 26 patients in the lateral lymph node dissection, while only 1 patient in the control group underwent cervical lateral lymph node dissection, and there was a statistically significant difference in the overall surgical method between the two groups (<i>p</i> < 0.01).</p><p>In the control group, 4 cases of benign tumors and 21 cases of papillary carcinoma were confirmed by pathology after the surgery. However, 55 cases of postoperative pathology confirmed malignant tumors in the observation group, including 52 cases of papillary carcinoma, 2 cases of follicular carcinoma, and 1 case of medullary carcinoma. In patients with confirmed papillary carcinoma, the mean tumor size was 1.33 ± 0.14 cm (<i>p</i> < 0.001). The rate of lymph node metastasis in the central group was 27 out of 118 (<i>p</i> < 0.0001) and the rate of lateral lymph node metastasis was 162 out of 241 (<i>p</i> < 0.01), as shown in Table 1.</p><p>The average length of hospital stay in the observation group was 5.64 ± 0.30 days (<i>p</i> < 0.05). There were five cases of adverse reactions (<i>p</i> > 0.05) after the operation, including four cases of hoarseness, one case of choking cough (with hoarseness), and one case of hemorrhage. The average length of hospitalization in the control group was 4.44 ± 0.38 days, and no patients had obvious adverse reactions (Table S1).</p><p>Out of 58 patients who underwent multiple surgeries, 51 patients underwent two surgeries, and 7 patients underwent three surgeries. Am
{"title":"Analysis of reoperational reason of patients with thyroid cancer and strategies for its diagnosis and treatment: A 6-year single-center retrospective study","authors":"Rongli Xie, Yawei Feng, Jiankang Shen, Guohui Xiao, Dan Tan","doi":"10.1002/mog2.70008","DOIUrl":"https://doi.org/10.1002/mog2.70008","url":null,"abstract":"<p>The incidence of thyroid tumors has been increasing in recent years, and the vast majority of new malignant cases are papillary thyroid micro-carcinoma (PTMC).<span><sup>1</sup></span> For patients with PTMC, comprehensive diagnosis and treatment, led by surgery, is the key to clinical cure. Although the lethality of papillary thyroid carcinoma is very low, tumor proliferation mechanism and surgical method after recurrence are still a hot topic of debate.<span><sup>2-4</sup></span> In this paper, thyroid patients admitted from January 2015 to December 2020 were collected. The inclusion criteria were as follows: (1) age from 18 to 80 years old; (2) the first and subsequent surgeries for thyroid were performed in one single center; (3) the postoperative paraffin pathology confirmed thyroid tumor; and (4) the patient's clinical data were complete. In this study, the gender, age, surgical methods, tumor types, maximum diameter of tumor, metastasis of central neck group and lateral lymph nodes, postoperative complications, and length of hospital stay were collected and recorded. For patients with multiple surgeries, the reason for subsequent surgeries and the interval time between surgeries should be additionally recorded.</p><p>A total of 58 patients undergoing thyroid surgeries (1 patient with laparoscopic surgery was excluded) were collected in this study, as shown in Table 1. Fifteen patients in the observation group underwent central lymph node dissection and 26 patients in the lateral lymph node dissection, while only 1 patient in the control group underwent cervical lateral lymph node dissection, and there was a statistically significant difference in the overall surgical method between the two groups (<i>p</i> < 0.01).</p><p>In the control group, 4 cases of benign tumors and 21 cases of papillary carcinoma were confirmed by pathology after the surgery. However, 55 cases of postoperative pathology confirmed malignant tumors in the observation group, including 52 cases of papillary carcinoma, 2 cases of follicular carcinoma, and 1 case of medullary carcinoma. In patients with confirmed papillary carcinoma, the mean tumor size was 1.33 ± 0.14 cm (<i>p</i> < 0.001). The rate of lymph node metastasis in the central group was 27 out of 118 (<i>p</i> < 0.0001) and the rate of lateral lymph node metastasis was 162 out of 241 (<i>p</i> < 0.01), as shown in Table 1.</p><p>The average length of hospital stay in the observation group was 5.64 ± 0.30 days (<i>p</i> < 0.05). There were five cases of adverse reactions (<i>p</i> > 0.05) after the operation, including four cases of hoarseness, one case of choking cough (with hoarseness), and one case of hemorrhage. The average length of hospitalization in the control group was 4.44 ± 0.38 days, and no patients had obvious adverse reactions (Table S1).</p><p>Out of 58 patients who underwent multiple surgeries, 51 patients underwent two surgeries, and 7 patients underwent three surgeries. Am","PeriodicalId":100902,"journal":{"name":"MedComm – Oncology","volume":"4 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-01-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/mog2.70008","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143114800","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Yunhan Tan, Siyuan Qin, Zhe Zhang, Yongen Liu, Li Zhou, Bowen Li, Edouard C. Nice, Yuanyuan Zhang, Jing Jing
The success of cancer therapy has been significantly hampered by various mechanisms of therapeutic resistance. Chief among these mechanisms is the presence of clonal heterogeneity within an individual tumor mass. The introduction of the concept of cancer stem cells (CSCs)—a rare and immature subpopulation with tumorigenic potential that contributes to intratumoral heterogeneity—has deepened our understanding of drug resistance. Given the characteristics of CSCs, such as increased drug-efflux activity, enhanced DNA-repair capacity, high metabolic plasticity, adaptability to oxidative stress, and/or upregulated detoxifying aldehyde dehydrogenase (ALDH) enzymes, CSCs have been recognized as a theoretical reservoir for resistant diseases. Implicit in this recognition is the possibility that CSC-targeted therapeutic strategies might offer a breakthrough in overcoming drug resistance in cancer patients. Herein, we summarize the generation of CSCs and our current understanding of the mechanisms underlying CSC-mediated therapeutic resistance. This extended knowledge has progressively been translated into novel anticancer therapeutic strategies and significantly enriched the available options for combination treatments, all of which are anticipated to improve clinical outcomes for patients experiencing CSC-related relapse.
{"title":"Unraveling the underlying mechanisms of cancer stem cells in therapeutic resistance for optimizing treatment strategies","authors":"Yunhan Tan, Siyuan Qin, Zhe Zhang, Yongen Liu, Li Zhou, Bowen Li, Edouard C. Nice, Yuanyuan Zhang, Jing Jing","doi":"10.1002/mog2.70009","DOIUrl":"https://doi.org/10.1002/mog2.70009","url":null,"abstract":"<p>The success of cancer therapy has been significantly hampered by various mechanisms of therapeutic resistance. Chief among these mechanisms is the presence of clonal heterogeneity within an individual tumor mass. The introduction of the concept of cancer stem cells (CSCs)—a rare and immature subpopulation with tumorigenic potential that contributes to intratumoral heterogeneity—has deepened our understanding of drug resistance. Given the characteristics of CSCs, such as increased drug-efflux activity, enhanced DNA-repair capacity, high metabolic plasticity, adaptability to oxidative stress, and/or upregulated detoxifying aldehyde dehydrogenase (ALDH) enzymes, CSCs have been recognized as a theoretical reservoir for resistant diseases. Implicit in this recognition is the possibility that CSC-targeted therapeutic strategies might offer a breakthrough in overcoming drug resistance in cancer patients. Herein, we summarize the generation of CSCs and our current understanding of the mechanisms underlying CSC-mediated therapeutic resistance. This extended knowledge has progressively been translated into novel anticancer therapeutic strategies and significantly enriched the available options for combination treatments, all of which are anticipated to improve clinical outcomes for patients experiencing CSC-related relapse.</p>","PeriodicalId":100902,"journal":{"name":"MedComm – Oncology","volume":"4 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-01-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/mog2.70009","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143113766","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Ping Jin, Xu-Dong Feng, Cheng-Shuang Huang, Jia Li, Hui Wang, Xian-Mei Wang, Lei Li, Lan-Qing Ma
Oxidative stress results from an imbalance between the production and neutralization of reactive oxygen species. It induces oxidative damage to cellular components including proteins, lipids, nucleic acids, and membranes, therefore intrinsically linking to aging-related diseases such as cancer, cardiovascular disease, and neurological disorders. Emerging evidence suggests that oxidative stress may promote tumor development by influencing various aspects of cellular senescence, such as its onset, pro-inflammatory secretion, and alteration of cellular function and structure. Modulating oxidative stress to target cellular senescence offers a novel strategy for cancer prevention and treatment. However, a thorough grasp of the specific mechanisms at play is lacking. This review will present the association between oxidative stress and cellular senescence and their regulatory role in tumor progression and treatment, with emphasis on senescence-associated secretory phenotype, immunosenescence and therapy-induced senescence. Current agents and strategies that remove side effects of cellular senescence via killing senescent cancer cells or modulating oxidative stress to improve antitumor efficacy will be summarized. This review will help readers better understand the complex relationship between oxidative stress and senescence in cancer, and will also provide a basis for further research in this area.
{"title":"Oxidative stress and cellular senescence: Roles in tumor progression and therapeutic opportunities","authors":"Ping Jin, Xu-Dong Feng, Cheng-Shuang Huang, Jia Li, Hui Wang, Xian-Mei Wang, Lei Li, Lan-Qing Ma","doi":"10.1002/mog2.70007","DOIUrl":"https://doi.org/10.1002/mog2.70007","url":null,"abstract":"<p>Oxidative stress results from an imbalance between the production and neutralization of reactive oxygen species. It induces oxidative damage to cellular components including proteins, lipids, nucleic acids, and membranes, therefore intrinsically linking to aging-related diseases such as cancer, cardiovascular disease, and neurological disorders. Emerging evidence suggests that oxidative stress may promote tumor development by influencing various aspects of cellular senescence, such as its onset, pro-inflammatory secretion, and alteration of cellular function and structure. Modulating oxidative stress to target cellular senescence offers a novel strategy for cancer prevention and treatment. However, a thorough grasp of the specific mechanisms at play is lacking. This review will present the association between oxidative stress and cellular senescence and their regulatory role in tumor progression and treatment, with emphasis on senescence-associated secretory phenotype, immunosenescence and therapy-induced senescence. Current agents and strategies that remove side effects of cellular senescence via killing senescent cancer cells or modulating oxidative stress to improve antitumor efficacy will be summarized. This review will help readers better understand the complex relationship between oxidative stress and senescence in cancer, and will also provide a basis for further research in this area.</p>","PeriodicalId":100902,"journal":{"name":"MedComm – Oncology","volume":"3 4","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-12-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/mog2.70007","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143119011","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cancer stem cells (CSCs) are a small group of tumor cells with the capacity to undergo self-renewal and differentiation. These cells not only initiate and maintain tumor growth, but also confer resistance to current cancer therapies. CSCs display a high degree of plasticity and can be generated under therapeutic stress via dedifferentiation from non-stem-like tumor cells, suggesting the necessity simultaneously targeting CSCs and bulk tumor cells to achieve the best therapeutic effect. Despite the findings that therapeutic stress induces CSC plasticity, the mechanisms underpinning CSC formation and therapeutic resistance are not fully defined. Tumor cells display elevated levels of reactive oxygen species (ROS), contributed by rapid proliferation, enhanced metabolic demands and oncogenic signaling. CSCs achieve redox homeostasis partly by regulating redox-sensitive transcription factors (TFs), including NRF2, HIF-1α, BACH1, NF-kB, FOXOs, AP-1, and others. This review aims to summarize the roles and underlying mechanisms of these TFs in regulation of CSCs and tumor progression from the perspectives of stem cell maintenance, metabolic reprogramming, epithelial–mesenchymal transition (EMT) and angiogenesis. We also discuss the potentials of utilizing specific inhibitors for these TFs in suppressing drug resistance and metastasis by repressing CSC activity, an approach that may provide new targeted therapies for advanced cancer and improve patient outcome.
{"title":"Redox regulation of cancer stem cells: Biology and therapeutic implications","authors":"Min Du, Jian Zhang, Max S. Wicha, Ming Luo","doi":"10.1002/mog2.70005","DOIUrl":"https://doi.org/10.1002/mog2.70005","url":null,"abstract":"<p>Cancer stem cells (CSCs) are a small group of tumor cells with the capacity to undergo self-renewal and differentiation. These cells not only initiate and maintain tumor growth, but also confer resistance to current cancer therapies. CSCs display a high degree of plasticity and can be generated under therapeutic stress via dedifferentiation from non-stem-like tumor cells, suggesting the necessity simultaneously targeting CSCs and bulk tumor cells to achieve the best therapeutic effect. Despite the findings that therapeutic stress induces CSC plasticity, the mechanisms underpinning CSC formation and therapeutic resistance are not fully defined. Tumor cells display elevated levels of reactive oxygen species (ROS), contributed by rapid proliferation, enhanced metabolic demands and oncogenic signaling. CSCs achieve redox homeostasis partly by regulating redox-sensitive transcription factors (TFs), including NRF2, HIF-1α, BACH1, NF-kB, FOXOs, AP-1, and others. This review aims to summarize the roles and underlying mechanisms of these TFs in regulation of CSCs and tumor progression from the perspectives of stem cell maintenance, metabolic reprogramming, epithelial–mesenchymal transition (EMT) and angiogenesis. We also discuss the potentials of utilizing specific inhibitors for these TFs in suppressing drug resistance and metastasis by repressing CSC activity, an approach that may provide new targeted therapies for advanced cancer and improve patient outcome.</p>","PeriodicalId":100902,"journal":{"name":"MedComm – Oncology","volume":"3 4","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-12-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/mog2.70005","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142861114","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
<p>In a recent study published in <i>Nature Nanotechnology</i>, the research teams of Professor Siwen Li and Professor Yueqing Gu introduced a bispecific bone marrow-targeted nanosystem, CSF@E-Hn, based on hematopoietic stem cell (HSC) nanovesicles (Hn).<span><sup>1</sup></span> The system uses Hn vesicles, decorated with natural killer (NK) cell-activating ligands (aNKG2D) and tumor-targeting antibodies (aPD-L1), encapsulating colony-stimulating factor (CSF) to treat hematological malignancies. Experimental results confirmed the system's therapeutic efficacy in mouse models of acute myelogenous leukemia (AML) and multiple myeloma (MM) and demonstrated its ability to prevent tumor recurrence long-term.</p><p>Most malignant hematological tumors arise from uncontrolled clonal expansion of tumor cells within the bone marrow, leading to high mortality and recurrence rates. Although current treatments, including chemotherapy, immunotherapy, and cell therapy, have improved overall survival in patients with hematological malignancies, these strategies still face significant challenges. Targeting bone marrow tumor cells specifically, reducing toxic side effects, and preventing recurrence remain major hurdles due to the lack of effective bone marrow-targeting technologies and the difficulty in reversing the diseased bone marrow microenvironment.<span><sup>2, 3</sup></span> The unique physiological structure of the bone marrow also acts as a formidable barrier, severely limiting the development of in vivo targeting technologies. In this context, Hn shows great potential for overcoming these challenges. As an ideal carrier, Hn has several advantages: it mirrors the characteristics of parent cells, features a drug-loaded bilayer structure, has a small size, and exhibits low immunogenicity.<span><sup>4, 5</sup></span> However, how to translate these significant advantages into clinical treatment remains a critical issue in current research.</p><p>To address these challenges, the bone marrow-targeted nanosystem CSF@E-Hn, developed by the team of Professor Li and Professor Gu, innovatively fuses nanotechnology with immunotherapy. This system accomplishes precise bone marrow-targeted treatment by capitalizing on the natural bone marrow hematopoietic stem cells and the generation of memory T cells, thus remodeling the bone marrow microenvironment and augmenting the immune response. Additionally, the system possesses excellent biocompatibility and sustained release properties, guaranteeing favorable safety (Figure 1).</p><p>The research team conducted a comprehensive evaluation of CSF@E-Hn's performance and efficacy. In vitro experiments demonstrated that the nanosystem, after antibody modification of HSC cells, maintained stable size distribution in phosphate-buffered saline (PBS) and serum. CSF@E-Hn remained stable for up to 14 days under low-temperature storage and thawing at −80°C. When NK cells were isolated from the bone marrow of C57BL/6J mice, CSF@E-Hn eff
{"title":"CSF@E-Hn: A bone marrow-targeted nanosystem for advanced treatment of hematological malignancies","authors":"Yinyan Jiang, Jianqiao Shentu, Yalu Chen","doi":"10.1002/mog2.70006","DOIUrl":"https://doi.org/10.1002/mog2.70006","url":null,"abstract":"<p>In a recent study published in <i>Nature Nanotechnology</i>, the research teams of Professor Siwen Li and Professor Yueqing Gu introduced a bispecific bone marrow-targeted nanosystem, CSF@E-Hn, based on hematopoietic stem cell (HSC) nanovesicles (Hn).<span><sup>1</sup></span> The system uses Hn vesicles, decorated with natural killer (NK) cell-activating ligands (aNKG2D) and tumor-targeting antibodies (aPD-L1), encapsulating colony-stimulating factor (CSF) to treat hematological malignancies. Experimental results confirmed the system's therapeutic efficacy in mouse models of acute myelogenous leukemia (AML) and multiple myeloma (MM) and demonstrated its ability to prevent tumor recurrence long-term.</p><p>Most malignant hematological tumors arise from uncontrolled clonal expansion of tumor cells within the bone marrow, leading to high mortality and recurrence rates. Although current treatments, including chemotherapy, immunotherapy, and cell therapy, have improved overall survival in patients with hematological malignancies, these strategies still face significant challenges. Targeting bone marrow tumor cells specifically, reducing toxic side effects, and preventing recurrence remain major hurdles due to the lack of effective bone marrow-targeting technologies and the difficulty in reversing the diseased bone marrow microenvironment.<span><sup>2, 3</sup></span> The unique physiological structure of the bone marrow also acts as a formidable barrier, severely limiting the development of in vivo targeting technologies. In this context, Hn shows great potential for overcoming these challenges. As an ideal carrier, Hn has several advantages: it mirrors the characteristics of parent cells, features a drug-loaded bilayer structure, has a small size, and exhibits low immunogenicity.<span><sup>4, 5</sup></span> However, how to translate these significant advantages into clinical treatment remains a critical issue in current research.</p><p>To address these challenges, the bone marrow-targeted nanosystem CSF@E-Hn, developed by the team of Professor Li and Professor Gu, innovatively fuses nanotechnology with immunotherapy. This system accomplishes precise bone marrow-targeted treatment by capitalizing on the natural bone marrow hematopoietic stem cells and the generation of memory T cells, thus remodeling the bone marrow microenvironment and augmenting the immune response. Additionally, the system possesses excellent biocompatibility and sustained release properties, guaranteeing favorable safety (Figure 1).</p><p>The research team conducted a comprehensive evaluation of CSF@E-Hn's performance and efficacy. In vitro experiments demonstrated that the nanosystem, after antibody modification of HSC cells, maintained stable size distribution in phosphate-buffered saline (PBS) and serum. CSF@E-Hn remained stable for up to 14 days under low-temperature storage and thawing at −80°C. When NK cells were isolated from the bone marrow of C57BL/6J mice, CSF@E-Hn eff","PeriodicalId":100902,"journal":{"name":"MedComm – Oncology","volume":"3 4","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-12-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/mog2.70006","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142861158","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","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