{"title":"The role of NK cells in regulating tumorimmunity: current state, challenges and future strategies.","authors":"Weixiong Zhu, Chuanlei Fan, Yongqing Zhao, Wancheng Li, Jubao Niu, Shi Dong, Zengxi Yang, Wence Zhou","doi":"10.1186/s12935-025-03980-y","DOIUrl":"10.1186/s12935-025-03980-y","url":null,"abstract":"<p><p>Natural killer (NK) cells are lymphocytes of the innate immune system. Their multifaceted cytotoxic mechanisms, coupled with their capacity to modulate immunity through cytokine secretion, underscore their pivotal role in orchestrating the immune microenvironment within tumors. This comprehensive review aims to elucidate the biological properties of NK cells, shedding light on their intricate involvement in tumor immunity. Furthermore, this review provides a comprehensive summary of the crosstalk between NK cell and other cells, and therapeutic strategies that target both T cells and NK cells, thereby offering potential avenues for therapeutic interventions. Finally, we have summarized the current status, advantages, and limitations of CAR-NK cell therapy, providing a reference for future CAR-NK cell engineering designs.</p>","PeriodicalId":9385,"journal":{"name":"Cancer Cell International","volume":"25 1","pages":"360"},"PeriodicalIF":6.0,"publicationDate":"2025-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12535086/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145312485","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Duo Li, Qi Zhong, Di Xiao, Weifan Wang, Lejing Xie, Mei Peng, Cangcang Xu, Huaying Wu, Zhuan Li, Xiaoping Yang
{"title":"Novel combination therapy with phenformin enhances the effects of lenvatinib in hepatocellular carcinoma via AMPK-mediated PDGFRβ degradation.","authors":"Duo Li, Qi Zhong, Di Xiao, Weifan Wang, Lejing Xie, Mei Peng, Cangcang Xu, Huaying Wu, Zhuan Li, Xiaoping Yang","doi":"10.1186/s12935-025-04012-5","DOIUrl":"10.1186/s12935-025-04012-5","url":null,"abstract":"<p><strong>Background: </strong>Hepatocellular carcinoma (HCC) is an invasive malignant tumour for which few effective treatment options are currently available. Lenvatinib is a small-molecule inhibitor of multiple receptor tyrosine kinases used for the treatment of patients with advanced HCC. Although lenvatinib has been proven effective in treating HCC patients, clinical data show that the response rate to lenvatinib is very low and that 76% of HCC patients are insensitive to lenvatinib. Phenformin is a well-known activator of adenosine monophosphate-activated protein kinase (AMPK), which has recently attracted widespread attention because of its anticancer effects. We investigated whether phenformin could enhance the efficacy of lenvatinib in treating HCC and, if so, the underlying mechanisms involved in this process.</p><p><strong>Methods: </strong>The anticancer effects of the combination of phenformin and lenvatinib in HCC cells were assessed in vitro and in vivo. First, colony formation, EdU and MTT assays were conducted to measure the viability of the HCC cells. Flow cytometry was used to assess the cell cycle distribution of HCC cells. Then, western blotting (WB) was performed to detect protein expression in HCC cells after various treatments. Immunoprecipitation-mass spectrometry (IP-MS) and co-immunoprecipitation (Co-IP) assays were used to determine the interaction relationships of proteins. In addition, a xenograft model was used to analyze the effects of the different treatments on the proliferation of HCC cells. Immunohistochemistry and western blot assays were conducted to investigate the expression of related proteins in the tissues of the xenograft model. Haematoxylin and eosin (H&E) staining was used to analyze the toxicity to the livers and kidneys of mice. Western blot assays were used to detect protein expression in human HCC samples.</p><p><strong>Results: </strong>High expression of platelet-derived growth factor receptor β (PDGFRβ) resulted in the insensitivity of HCC cells to lenvatinib, and PDGFRβ knockdown increased the sensitivity of HCC cells to lenvatinib. Phenformin inhibited the proliferation of HCC cells via AMPK-mediated PDGFRβ degradation. Compared with lenvatinib monotherapy, combined treatment with phenformin and lenvatinib considerably enhanced the anticancer effects both in vivo and in vitro. Mechanistic studies showed that AMPK binds PDGFRβ and promotes its degradation via the c-Cbl-mediated lysosomal pathway.</p><p><strong>Conclusions: </strong>Our study reports a novel combined therapy using phenformin and lenvatinib, which can increase the sensitivity of HCC cells to lenvatinib via AMPK-mediated PDGFRβ degradation. Hence, this treatment strategy may provide a personalized approach for treating HCC patients with high PDGFRβ expression and facilitate the development of basic and clinical research on the use of lenvatinib for the treatment of HCC.</p>","PeriodicalId":9385,"journal":{"name":"Cancer Cell International","volume":"25 1","pages":"361"},"PeriodicalIF":6.0,"publicationDate":"2025-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12534998/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145312345","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Luis Silva, Nicholas Skiados, Nikitha Murugavel, Karen Cover, Nastassja Luna, Manish K Gupta, Stephanie C Contreras, Terrence E O'Brien, Wen Cai Zhang
{"title":"Efficient identification of new small molecules targeting succinate dehydrogenase in non-small cell lung cancer.","authors":"Luis Silva, Nicholas Skiados, Nikitha Murugavel, Karen Cover, Nastassja Luna, Manish K Gupta, Stephanie C Contreras, Terrence E O'Brien, Wen Cai Zhang","doi":"10.1186/s12935-025-04002-7","DOIUrl":"10.1186/s12935-025-04002-7","url":null,"abstract":"<p><strong>Background: </strong>Lung cancer treatment efficacy remains a challenge due to limited therapeutic targets. Succinate dehydrogenase (SDH) enzyme, a crucial enzyme linking the citric acid cycle and the electron transport chain, is implicated in cancer metabolism. While existing compounds target metabolic diseases in vitro, SDH-targeted therapy for lung cancer remains elusive.</p><p><strong>Methods: </strong>We assessed SDH expression levels in non-small cell lung (NSCLC) tissues and cell lines. Leveraging AtomNet® technology for compound identification, coupled with mitochondria- and cell-based enzyme activity assays, we discovered new SDH inhibitors. Using 2D monolayer, 3D organoid culture, and assays for cell viability, migration, mitochondrial reactive oxygen species, oxygen consumption rate, succinate accumulation, and apoptosis, we elucidated their mechanism targeting lung malignancy.</p><p><strong>Results: </strong>SDH subunits were found to be overexpressed in NSCLC tissues compared to tumor-adjacent normal tissues. Two new SDH inhibitors were identified from 96 predicted candidates. Cellular thermal shift assay confirmed direct binding of these small molecules to SDH subunits in lung cancer cells. Mechanistically, treatment increased cellular and mitochondrial reactive oxygen species, succinate accumulation, and induced apoptosis by damaging mitochondria and DNA, while modulating SDH protein expression. Functionally, these molecules reduced growth, migration, and 3D organoid formation in lung cancer cell lines in vitro, both short and long term.</p><p><strong>Conclusions: </strong>Our SDH inhibitors halt tumor growth and migration by targeting key substrate binding sites, showing superior efficacy over existing small molecule antagonists. They also modulate SDH protein expression, suggesting a promising dual-targeting strategy for cancer therapy. This study sheds light on SDH function in cancer-related metabolic dysfunction and underscores the potential of SDH modulation as a therapeutic strategy for lung cancer and beyond.</p>","PeriodicalId":9385,"journal":{"name":"Cancer Cell International","volume":"25 1","pages":"362"},"PeriodicalIF":6.0,"publicationDate":"2025-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12535061/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145312323","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Zhigang Chen, Zhengheng Wu, Tianhan Xu, Fuqian Yu, Dongmei Wang
{"title":"TRPM2: a pivotal player in tumor progression and a promising therapeutic target.","authors":"Zhigang Chen, Zhengheng Wu, Tianhan Xu, Fuqian Yu, Dongmei Wang","doi":"10.1186/s12935-025-03974-w","DOIUrl":"10.1186/s12935-025-03974-w","url":null,"abstract":"<p><p>TRPM2, a member of the TRPM family, is a ubiquitously expressed non-selective cation channel located on cellular membranes. Activated by ADP-ribose (ADPR), this channel is prevalent across various normal tissues and plays a critical role in numerous physiological and pharmacological processes, particularly in maintaining calcium homeostasis. A substantial body of evidence indicates that elevated expression of TRPM2 is associated with various cancer types. Increased TRPM2 expression has been significantly correlated with enhanced cellular proliferation, invasion, and poor prognosis in cancer patients. Furthermore, TRPM2 is pivotal in regulating Ca<sup>2+</sup> levels, maintaining the mitochondrial function, and inducing cell cycle arrest, all contributing to tumor progression. This review examines the significance of the TRPM2 channel in tumor development and highlights its potential as a therapeutic target for inhibiting cell growth, apoptosis, migration, invasion, angiogenesis, and resistance to chemotherapy drugs. The evidence suggests that the targeted modulation of the TRPM2 channel could be invaluable in diagnosing and treating tumors.</p>","PeriodicalId":9385,"journal":{"name":"Cancer Cell International","volume":"25 1","pages":"356"},"PeriodicalIF":6.0,"publicationDate":"2025-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12522950/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145298663","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Ang-2 modulates VEGFR3-induced lymphangiogenesis in peritumoral adipose tissue of metastatic head and neck cancer.","authors":"Li-Yun Yang, Jian-Wei Zhang, An Hu","doi":"10.1186/s12935-025-03990-w","DOIUrl":"10.1186/s12935-025-03990-w","url":null,"abstract":"","PeriodicalId":9385,"journal":{"name":"Cancer Cell International","volume":"25 1","pages":"354"},"PeriodicalIF":6.0,"publicationDate":"2025-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12522992/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145298509","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Green-synthesized MnFe₂O₄/GO nanocomposites: structural characterization, cytotoxicity, and potential for targeted cervical cancer therapy.","authors":"Amany I Almars","doi":"10.1186/s12935-025-03953-1","DOIUrl":"10.1186/s12935-025-03953-1","url":null,"abstract":"<p><p>Cervical cancer remains a major global health challenge, with high mortality rates particularly in developing countries, and is often associated with poor prognosis in advanced stages. The limitations of conventional chemotherapeutics, such as systemic toxicity, poor targeting efficiency, and drug resistance, have prompted the exploration of nanotechnology-based therapeutic strategies. In this study, manganese ferrite (MnFe₂O₄) nanoparticles were synthesized via both chemical co-precipitation and a green hydrothermal method employing Urtica (nettle) extract as a natural reducing and stabilizing agent. Graphene oxide (GO) nanosheets were prepared through a modified Hummers method and integrated with MnFe₂O₄ to form MnFe₂O₄/GO nanocomposites. Physicochemical characterization using FT-IR, XRD, SEM-EDX, TEM, and DLS confirmed the successful synthesis of pure, crystalline spinel MnFe₂O₄ and its stable incorporation into GO matrices, with particle sizes in the nanoscale range and negative zeta potentials supporting colloidal stability. Magnetic measurements revealed superparamagnetic behavior for all samples, with saturation magnetization (Ms) values of 55 emu/g for pristine MnFe₂O₄, 40 emu/g for green-synthesized MnFe₂O₄, and 25 emu/g for MnFe₂O₄/GO, remaining within ranges suitable for magnetic targeting and hyperthermia. In vitro cytotoxicity against HeLa cells demonstrated enhanced anticancer activity for the MnFe₂O₄/GO composite (IC₅₀ = 120.7 µg/mL) compared to MnFe₂O₄ (IC₅₀ = 200.7 µg/mL) and GO (IC₅₀ = 1202 µg/mL), indicating a synergistic effect. qPCR analysis showed significant upregulation of pro-apoptotic genes (BAX, Caspase-3) and downregulation of the anti-apoptotic gene (Bcl-2), confirming apoptosis induction as a key mechanism of action. The results highlight MnFe₂O₄/GO nanocomposites as promising multifunctional platforms for targeted cervical cancer therapy, with combined magnetic responsiveness, structural stability, and potent pro-apoptotic activity.</p>","PeriodicalId":9385,"journal":{"name":"Cancer Cell International","volume":"25 1","pages":"355"},"PeriodicalIF":6.0,"publicationDate":"2025-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12523175/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145298533","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Establishment and characteristic analysis of a novel patient derived cell line of intrahepatic cholangiocarcinoma.","authors":"Shuangshuang Dou, Minghui Gao, Quanwei Li, Mengyin Chai, Buxin Kou, Xiaoni Liu","doi":"10.1186/s12935-025-03989-3","DOIUrl":"10.1186/s12935-025-03989-3","url":null,"abstract":"<p><strong>Background: </strong>Intrahepatic cholangiocarcinoma (ICC) is a primary malignant tumor of the liver, second only to hepatocellular carcinoma. The scarcity of appropriate cell lines has impeded ICC-related research. This study aims to establish a novel patient-derived ICC cell line and systematically evaluate its biological characteristics, thereby providing a valuable cellular tool for ICC research.</p><p><strong>Methods: </strong>A cell line named LPHC-6 of ICC was established using a patient-derived xenograft (PDX) tumor model. We comprehensively characterized this novel cell line through a series of techniques, including cell morphology observation, short tandem repeat (STR) analysis, karyotype analysis, cell proliferation, cell migration assays, western blot analysis, immunofluorescence staining, flow cytometry, gene mutation detection, spheroid formation assays, drug sensitivity testing, and xenograft tumor formation in nude mice.</p><p><strong>Results: </strong>LPHC-6 cells exhibited typical characteristics of malignant epithelial cells, demonstrating robust proliferation and migration capabilities. These cells possessed a structurally complex triploid karyotype, which was confirmed to be free from cross-contamination with other human cell lines. Tumor biomarker analysis revealed positive expression of AFP and negative expression of GPC3. Additionally, LPHC-6 cells showed high expression levels of stem cell markers CD133 and CD44. The biliary epithelial cell marker CK19 was positive, whereas the hepatocyte marker Hep Par1 was negative. Genomic analysis identified an exon mutation in TP53, copy number loss in PTEN and RAD51, and copy number gain in NTRK1, PDCD1LG2, and VEGFA. Investigations confirmed that LPHC-6 cells exhibited excellent sphere formation ability and tumorigenic potential. Furthermore, LPHC-6 cells demonstrated sensitivity to Sorafenib, Lenvatinib, 5-fluorouracil, Oxaliplatin and Atezolizumab in both 2D and 3D culture system.</p><p><strong>Conclusion: </strong>A novel intrahepatic cholangiocarcinoma cell line LPHC-6 has been successfully established, which provides a powerful cell tool for the research related to intrahepatic cholangiocarcinoma.</p>","PeriodicalId":9385,"journal":{"name":"Cancer Cell International","volume":"25 1","pages":"357"},"PeriodicalIF":6.0,"publicationDate":"2025-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12522666/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145298507","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Construction of a lipid metabolism-based prognostic gene signature in cervical squamous cell carcinoma and validation of LIPG's oncogenic role.","authors":"Gaigai Bai, Fanghua Chen, Junjun Qiu, Keqin Hua","doi":"10.1186/s12935-025-03991-9","DOIUrl":"10.1186/s12935-025-03991-9","url":null,"abstract":"<p><strong>Background: </strong>Cervical cancer, in which cervical squamous cell carcinoma (CSCC) accounts for 60-70% of cases, has a poor prognosis and poses a significant health threat to global patients. Lipid metabolism reprogramming is a key driver of tumor progression and tumor microenvironment (TME) regulation, making it a promising target for improving the efficacy of immunotherapy. This study aimed to construct a lipid metabolism prognostic signature (LMPS) in CSCC and identify key genes involved in tumor progression.</p><p><strong>Methods: </strong>Through RNA-sequencing and clinical data from TCGA and GTEx databases, we identified differentially expressed lipid metabolism-related genes (DLMGs) and constructed the LMPS using machine learning algorithms. Next, the value of the LMPS was validated using the HTMCP database and the GEO database. Furthermore, the relationship between the LMPS and the TME was analyzed, including immune cell infiltration, immune checkpoint gene expression, and drug sensitivity. The key gene lipase G (LIPG) was identified through machine learning methods and validated through cellular and molecular biology experiments.</p><p><strong>Results: </strong>A total of 60 DLMGs were identified, with 9 DLMGs showing prognostic value. The LMPS was constructed using 6 genes (ACOT4, PLA2G2D, GAL3ST1, ALOX12B, PLA2G3, and LIPG), which effectively predicted patients' survival (AUC: 0.76, 0.75, 0.68 at 1, 3, 5 years, respectively). High LMPS was correlated with an immune-suppressive TME, reduced immune cell infiltration, lower human leukocyte antigen (HLA) and immune checkpoint gene expression, and higher IC50 values for common chemotherapy drugs. LIPG was identified as a key gene, showing higher expression in advanced cancer stages. As revealed by functional experiments, LIPG promoted lipid accumulation and phosphatidylcholine (PC) hydrolysis in CSCC cells. Additionally, LIPG facilitated tumor progression through activation of the MAPK-p38 signaling pathway.</p><p><strong>Conclusions: </strong>The LMPS was a valuable prognostic tool and was correlated with the TME and drug sensitivity. LIPG was a key regulator of lipid metabolism and facilitated CSCC development by hydrolyzing PC into lysophosphatidylcholine (LPC) and activating the MAPK-p38 signaling pathway. These findings may highlight the potential of targeting lipid metabolism for therapeutic intervention in CSCC.</p>","PeriodicalId":9385,"journal":{"name":"Cancer Cell International","volume":"25 1","pages":"349"},"PeriodicalIF":6.0,"publicationDate":"2025-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12522510/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145291286","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}