{"title":"CircABCA1 promotes ccRCC by reprogramming cholesterol metabolism and facilitating M2 macrophage polarization through IGF2BP3-mediated stabilization of SCARB1 mRNA.","authors":"Hao Ning,Yan Jiang,Binbin Li,Junwu Ren,Cong Wang,Ling Wei,Linfei Li,Ai Ran,Zuozhang Li,Jiao Li,Wei Li,Yongquan Wang,Bin Xiao","doi":"10.1186/s12943-025-02398-4","DOIUrl":"https://doi.org/10.1186/s12943-025-02398-4","url":null,"abstract":"BACKGROUNDThe reliance of clear cell renal cell carcinoma (ccRCC) on exogenous cholesterol import implies a metabolic susceptibility. This susceptibility represents a potential avenue that can be exploited as a novel therapeutic approach for ccRCC. Circular RNAs (circRNAs) are emerging regulators in cancer, yet their roles in ccRCC lipid metabolism and tumor microenvironment remodeling remain unclear. This study investigates the tumor-promoting role of circABCA1 in ccRCC cholesterol homeostasis and M2 macrophage polarization.METHODSThe expression levels of circABCA1, IGF2BP3, SCARB1, autophagy-related proteins, and the IGF1R/PI3K/AKT/mTOR and ABCA1/ABCG1 pathways were measured using RT-qPCR and western blot. Untargeted metabolomics, RNA- sequencing, and MS2 RNA-pulldown were conducted to identify targets. Interaction analyses included RNA immunoprecipitation, RNA pull-down, and RNA fluorescence in situ hybridization (FISH) assays. Lipid raft measurements, cholesterol uptake/efflux assays, and lipophagy assessments were performed. A co-culture system between M2 macrophages and ccRCC cells was established. In vivo tumorigenesis and metastasis were evaluated using xenograft models and a hepatic metastasis model. Statistical analyses involved Student's t-tests and ANOVA; significance set at P < 0.05.RESULTSWe identified a novel lipid metabolism-related circRNA, circABCA1, which was upregulated in ccRCC and positively correlated with tumor stage and distant metastasis. Functionally, circABCA1 enhanced the half-life of SCARB1 mRNA by forming a circABCA1-IGF2BP3-SCARB1 mRNA ternary complex, thereby increasing the expression of SCARB1 and consequent cholesterol uptake. Next, elevated cholesterol caused by circABCA1-SCARB1 axis-maintained lipid rafts, initiated IGF1R/PI3K/AKT/mTOR cascade, and protected lipid droplets from being destructed by lipophagy, leading to decreased cholesterol efflux. CircABCA1 facilitated the proliferation and migration of ccRCC in vitro and in vivo in a SCARB1 depended manner. Moreover, we uncovered that circABCA1 facilitated M2 macrophage polarization and subsequent pro-tumor effect by prompting cholesterol uptake of ccRCC from tumor microenvironment in a SCARB1-dependent manner.CONCLUSIONSCircABCA1 plays a crucial role in promoting ccRCC progression by regulating cholesterol metabolism and facilitating M2 macrophage polarization, representing a potential therapeutic target for ccRCC treatment.","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":"10 1","pages":"199"},"PeriodicalIF":37.3,"publicationDate":"2025-07-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144664182","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Molecular CancerPub Date : 2025-07-17DOI: 10.1186/s12943-025-02401-y
Miriam Sánchez-Ortega, Antonio Garrido, Lorena Sanz, Rafael Torres-Pérez, Carmen Hernandez, Alvaro Gutierrez-Uzquiza, Ming Sound Tsao, Ana Clara Carrera
{"title":"Double vulnerability of active-NRF2 lung squamous cell carcinoma to NRF2 and TRIM24","authors":"Miriam Sánchez-Ortega, Antonio Garrido, Lorena Sanz, Rafael Torres-Pérez, Carmen Hernandez, Alvaro Gutierrez-Uzquiza, Ming Sound Tsao, Ana Clara Carrera","doi":"10.1186/s12943-025-02401-y","DOIUrl":"https://doi.org/10.1186/s12943-025-02401-y","url":null,"abstract":"Lung squamous cell cancer (LUSC) is associated with very poor survival due to the lack of specific treatments. A common genetic alteration in LUSC involves mutations in NFE2L2 (protein named NRF2) or its regulator, KEAP1, resulting in increased activity of the NRF2 transcription factor (TF). This study compares the requirement for active-NRF2 in LUSC cell lines. Although normal-NRF2 cells are more sensitive to oxidative stress, they do not require NRF2 for survival under non-stress conditions, in contrast, LUSC cells with active-NRF2 mutations depend on NRF2 for viability. NRF2 depletion in patient-derived organoid cultures with active-NRF2 as well as in xenografts with active-NRF2 triggers cell death. The focus of this study is to find genes that rescue cell death upon NRF2-depletion in active-NRF2 cells. A CRISPRa/dCas9 screening for gene targets capable of rescuing cell survival in these cells identified TRIM24 as a gene whose expression saves cell survival in NRF2-depleted active-NRF2 LUSC cells. Alongside oxidative stress, the lack of TRIM24 selectively contributed to the induction of cell death (apoptosis and ferroptosis) in active-NRF2 LUSC cells. Cells with a high NFE2L2/KEAP1 copy number ratio also undergo cell death. The increase in cell death observed upon TRIM24 depletion involves a reduction of TRIM24/PI3Kα complexes which destabilizes the PI3Kα catalytic subunit. Notably, overexpression of PI3Kα rescues cell survival in TRIM24-depleted active-NRF2 cells. These findings point to novel therapeutic approaches in LUSC.","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":"663 1","pages":""},"PeriodicalIF":37.3,"publicationDate":"2025-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144652141","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Molecular CancerPub Date : 2025-07-17DOI: 10.1186/s12943-025-02402-x
Asra khan, Mengqiu Song, Zigang Dong
{"title":"Chronic stress: a fourth etiology in tumorigenesis?","authors":"Asra khan, Mengqiu Song, Zigang Dong","doi":"10.1186/s12943-025-02402-x","DOIUrl":"https://doi.org/10.1186/s12943-025-02402-x","url":null,"abstract":"Chronic stress, driven by persistent psychological, environmental, or physiological factors, is a prolonged heightened state of stress response that disrupts homeostasis. When unmanaged, it will lead to sustained negative emotions such as depression, loneliness, anxiety, and emotional adversity. This persistent emotional distress not only exacerbates mental health disorders but also poses significant risks to physical health. Increasing evidence suggests a strong link between chronic stress, stress-related hormones, and the rising incidence of malignancies. As a result, chronic stress might be recognized as a potential “fourth etiology” of cancer, alongside physical, chemical, and biological carcinogens. As a potential etiological driver of tumorigenesis, chronic stress-related hormones such as glucocorticoids and catecholamines or neurotransmitters have been implicated in various aspects of tumor initiation, promotion, and progression. Additionally, chronic stress influences tumorigenesis through multiple mechanisms, including tumor microenvironment remodeling, microbial dysbiosis, drug resistance promotion, as well as the regulation of oncogenic signaling pathways. Hence, mitigating the impact of chronic stress could be an effective method of cancer prevention and therapy. However, it remains a significant challenge in the assessment of chronic stress as a cancer etiology. Moreover, the link between stress-associated obesity and cancer offers novel insights into underlying mechanistic pathways in cancer research. Repurposing preventive and therapeutic approaches targeting stress-related tumorigenesis may provide deeper insights into the interplay between chronic stress and cancer, ultimately improving patient outcomes and quality of life.","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":"55 1","pages":""},"PeriodicalIF":37.3,"publicationDate":"2025-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144645313","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Molecular CancerPub Date : 2025-07-15DOI: 10.1186/s12943-025-02403-w
Wanting Zhang, Yuhang Xiang, He Ren, Yilin Liu, Qi Wang, Mengdi Ran, Wanting Zhou, Lu Tian, Xianhui Zheng, Cong Qiao, Yifei Liu, Meisi Yan
{"title":"The tumor microbiome in cancer progression: mechanisms and therapeutic potential","authors":"Wanting Zhang, Yuhang Xiang, He Ren, Yilin Liu, Qi Wang, Mengdi Ran, Wanting Zhou, Lu Tian, Xianhui Zheng, Cong Qiao, Yifei Liu, Meisi Yan","doi":"10.1186/s12943-025-02403-w","DOIUrl":"https://doi.org/10.1186/s12943-025-02403-w","url":null,"abstract":"The tumor microbiome (TM) comprises diverse microbial communities, such as bacteria, fungi, and viruses. Recent advancements in microbial sequencing technologies have improved our understanding of the distribution and functional roles of microbes in solid tumors. The TM is formed through several mechanisms, such as direct invasion of mucosal barriers, diffusion from adjacent normal tissues, metastasis of tumor cells, and dissemination via blood and lymphatic circulation. Microbes play a critical role in the tumor microenvironment (TME), and the TM has a heterogeneous composition in different types of cancer. This heterogeneity affects tumor development, progression, and response to treatment. The TM modulates tumor cell physiology and immune responses via several signaling pathways, such as WNT/β-catenin, NF-κB, toll-like receptors (TLRs), ERK, and stimulator of interferon genes (STING). Extensive studies have characterized the role of TM in tumor progression, revealing the importance of genetic abnormalities, epigenetic changes, metabolic regulation, invasion and metastasis, and chronic inflammatory responses. The role of TM in cancer treatment, especially in immunotherapy, has received increasing attention, demonstrating significant regulatory potential. This review provides an in-depth overview of the development of TM detection technologies, explores its potential origins and heterogeneity, and elucidates the mechanisms by which TM contributes to tumorigenesis or tumor suppression. Furthermore, this review explored how TM can be used in cancer treatment, offering a comprehensive perspective on targeted and personalized approaches.","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":"1 1","pages":""},"PeriodicalIF":37.3,"publicationDate":"2025-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144629664","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Bridging the tumor microenvironment: the pivotal role of cancer-associated fibroblasts in tumor cachexia development","authors":"Guoming Chen, Bonan Chen, Yilin Wu, Hao Nie, Zilan Zhong, Shuyang Yang, Rui Qin, Wei Kang, Cheng Zhang, Ning Wang, Yibin Feng","doi":"10.1186/s12943-025-02379-7","DOIUrl":"https://doi.org/10.1186/s12943-025-02379-7","url":null,"abstract":"Tumor cachexia represents a complex and multifaceted metabolic syndrome that profoundly affects the quality of life and survival rates of individuals. It is highly prevalent in advanced cancer patients and is characterized by severe weight loss, muscle wasting, and systemic inflammation. The tumor microenvironment (TME) is pivotal in cancer formation and progression, where cancer-associated fibroblasts (CAFs) emerge as significant contributors. CAFs are a major component of the TME, and their interactions with tumor cells and other stromal elements contribute to various aspects of cancer biology, including tumor growth, metastasis, and resistance to therapy. Importantly, CAFs have been implicated in the pathogenesis of tumor cachexia through their ability to modulate inflammation, metabolic reprogramming, and immune responses. Given the intricate interplay between the TME, CAFs, and cachexia, understanding the mechanisms underlying these interactions is essential for developing effective therapeutic strategies to mitigate cachexia and improve patient outcomes. This review aims to provide a comprehensive overview of the roles of CAFs within the TME during cancer progression and the development of cachexia, highlighting the potential for targeting CAFs as a novel therapeutic approach.","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":"108 1","pages":""},"PeriodicalIF":37.3,"publicationDate":"2025-07-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144622213","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Molecular CancerPub Date : 2025-07-08DOI: 10.1186/s12943-025-02397-5
Haiqing Jia, Lei Jiang, Xiaoyu Shen, Huinan Ye, Xinguang Li, Liwei Zhang, Yanyan Hu, Dandan Song, Hui Jia, Zhe Wang
{"title":"Post-translational modifications of cancer immune checkpoints: mechanisms and therapeutic strategies","authors":"Haiqing Jia, Lei Jiang, Xiaoyu Shen, Huinan Ye, Xinguang Li, Liwei Zhang, Yanyan Hu, Dandan Song, Hui Jia, Zhe Wang","doi":"10.1186/s12943-025-02397-5","DOIUrl":"https://doi.org/10.1186/s12943-025-02397-5","url":null,"abstract":"Immunotherapies, particularly immune checkpoint inhibitors (ICIs), have revolutionized cancer clinical management, but low response rates and treatment resistance remain challenging. Protein post-translational modifications (PTMs) are critical for governing protein expression, localization, functions, and interactions with other cellular molecules, which notably build up the diversity and complexity of the proteome. A growing body of evidence supports that PTMs influence immunotherapy efficacy and outcomes by post-translationally modulating the expression and functions of immune checkpoints. Therefore, understanding the PTM mechanisms that govern immune checkpoints is paramount for developing novel treatment strategies to improve immunotherapy efficacy and overcome resistance. This review provides an overview of the current comprehension of the regulatory mechanisms by which PTMs (glycosylation, phosphorylation, ubiquitination, acetylation, succinylation, palmitoylation, lactylation, O-GlcNAcylation, UFMylation, and neddylation) modulate immune checkpoints to unveil potential therapeutic targets. Moreover, this review discusses the potential of therapeutic strategies targeting PTMs of immune checkpoints, providing insights into the combination treatment with ICIs in maximizing the benefits of immunotherapy and overcoming resistance.","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":"9 1","pages":""},"PeriodicalIF":37.3,"publicationDate":"2025-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144577991","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Molecular CancerPub Date : 2025-07-08DOI: 10.1186/s12943-025-02399-3
Liqun Ling, Tianqi Hu, Chenkang Zhou, Yingjie Dai, Lijuan Hu, Yuxin Chen, Zhaoting Hu, Kate Huang, Jie Chen, Yumin Wang
{"title":"M6A-Methylated circRAPGEF5 drives lung adenocarcinoma progression and metastasis via IGF2BP2/NUP160-mediated autophagy suppression","authors":"Liqun Ling, Tianqi Hu, Chenkang Zhou, Yingjie Dai, Lijuan Hu, Yuxin Chen, Zhaoting Hu, Kate Huang, Jie Chen, Yumin Wang","doi":"10.1186/s12943-025-02399-3","DOIUrl":"https://doi.org/10.1186/s12943-025-02399-3","url":null,"abstract":"Lung adenocarcinoma (LUAD), the predominant histological subtype of non-small cell lung cancer, demonstrates critical regulatory involvement of RNA-binding proteins (RBPs) and circular RNAs (circRNAs) in tumorigenic processes. Emerging evidence highlights the circRNA-autophagy regulatory axis as a crucial modulator of cancer progression. This study systematically investigates the functional interplay within the RBP-circRNA-autophagy network in LUAD pathogenesis. Employing RNA pull down, mass spectrometry and RNA immunoprecipitation facilitated the exploration of the circRAPGEF5 binding protein. M6A methylation RNA immunoprecipitation-PCR was utilized for m6A analysis. Immunofluorescence (IF) and fluorescence in situ hybridization (FISH) assays were conducted to ascertain the subcellular localization of target genes. Employing mRFP-GFP-LC3 fluorescent lentivirus labelling facilitated the monitoring of autophagy flow levels. Xenografts in mice were instrumental in affirming the role of circRAPGEF5. Through comprehensive molecular profiling, we identified elevated circRAPGEF5 expression in LUAD cells, which significantly suppressed autophagic flux while promoting malignant phenotypes including enhanced proliferation, migration, and invasion. Mechanistic investigations revealed that circRAPGEF5 directly interacts with the KH3-4 functional domain of Insulin-like Growth Factor 2 mRNA-Binding Protein 2 (IGF2BP2), an m6A reader protein. This interaction facilitated IGF2BP2-mediated stabilization of NUP160 mRNA, a nuclear pore complex component. Genetic ablation of NUP160 through RNA interference effectively restored autophagic activity, thereby attenuating the aggressive biological behaviors of LUAD cells. In vivo validation using xenograft models demonstrated that the circRAPGEF5/IGF2BP2/NUP160 signaling axis promotes tumor growth and metastatic dissemination through autophagy suppression. Our findings reveal a novel epigenetic regulatory mechanism wherein m6A-modified circRAPGEF5 orchestrates autophagy inhibition via IGF2BP2-dependent stabilization of NUP160 transcripts, ultimately driving LUAD progression and metastasis. These results establish the circRAPGEF5/IGF2BP2/NUP160 axis as a potential therapeutic target for LUAD intervention.","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":"23 1","pages":""},"PeriodicalIF":37.3,"publicationDate":"2025-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144577992","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Molecular CancerPub Date : 2025-07-07DOI: 10.1186/s12943-025-02386-8
Sarkar Sardar Azeez, Raya Kh. Yashooa, Shukur Wasman Smail, Abbas Salihi, Azhin Saber Ali, Sami Mamand, Christer Janson
{"title":"Advancing CAR-based cell therapies for solid tumours: challenges, therapeutic strategies, and perspectives","authors":"Sarkar Sardar Azeez, Raya Kh. Yashooa, Shukur Wasman Smail, Abbas Salihi, Azhin Saber Ali, Sami Mamand, Christer Janson","doi":"10.1186/s12943-025-02386-8","DOIUrl":"https://doi.org/10.1186/s12943-025-02386-8","url":null,"abstract":"Chimeric antigen receptor-cell therapies have demonstrated remarkable success in haematological malignancies but face significant hurdles in solid tumours. The hostile tumour microenvironment, antigen heterogeneity, limited tumour infiltration, and CAR-cell exhaustion contribute to reduced efficacy. Additionally, toxicity, off-target effects, and manufacturing challenges limit widespread clinical adoption. Overcoming these barriers requires a multifaceted approach that enhances CAR-cell persistence, trafficking, and tumour-specific targeting. Recent advancements in alternative cellular therapies, such as CAR-natural killer cells, CAR-macrophages, gamma delta CAR-T cells, and CAR-natural killer T cells, provide promising avenues for improving efficacy. These strategies leverage distinct immune cell properties to enhance tumour recognition and persistence. Furthermore, combination therapies, including chemotherapy, radiotherapy, antibodies, small molecule inhibitors, cancer vaccines, oncolytic viruses, and multi-CAR cell combination therapy, offer synergistic potential by modulating the TME and improving CAR-cell functionality. This review explores the challenges of CAR-based cellular therapies in solid tumours and highlights emerging strategies to overcome therapeutic limitations. By integrating novel cellular platforms and combination approaches, we seek to provide insights into optimising CAR-cell therapies for durable responses in solid malignancies.","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":"151 1","pages":""},"PeriodicalIF":37.3,"publicationDate":"2025-07-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144568755","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Targeting CD30L in B-cell non-Hodgkin lymphoma: novel peptide conjugates and their therapeutic potential.","authors":"Chaowen Shi, Tianzheng Lan, Yufeng Gao, Zhiquan Liang, Yafei Zhang, Yanbei Tu, Hanqing Liu, Zhigang Tu","doi":"10.1186/s12943-025-02393-9","DOIUrl":"10.1186/s12943-025-02393-9","url":null,"abstract":"<p><strong>Background: </strong>B-cell non-Hodgkin lymphoma (B-NHL) constitutes the majority of NHL cases. Patients with B-NHL often experience multiple recurrences, necessitating several lines of antitumor therapy, and develop drug resistance. The recent success of therapeutic strategies targeting CD19 and CD20 highlights the therapeutic potential of identifying unique molecular markers in B-NHL for precision medicine, although challenges like immunogenicity and limited tumor penetration persist.</p><p><strong>Methods: </strong>In this study, whole-cell phage display was employed to identify the specific binding peptide TG-1 towards B-NHL cells which was confirmed in vitro and in vivo, and its corresponding target CD30 ligand (CD30L) was identified by mass spectrometry and validated by functional assays, molecular docking, bioinformational analyses, knockdown, and rescue experiments. Additionally, the effects of TG-1 and functional roles of CD30L in B-NHL cells were investigated by exploring the molecular mechanisms of CD30/CD30L interactions. Furthermore, TG-1 peptide and doxorubicin co-functionalized gold nanoparticles (AuNPs) were characterized, and their effects on B-NHL cell proliferation were studied both in vitro and in vivo.</p><p><strong>Results: </strong>Here, we identified and validated the CD30L as a novel target on B-NHL cells, along with its highly specific binding peptide TG-1, using whole-cell phage display. TG-1 binds CD30L, impairing lymphoma cell viability by disrupting the CD30-CD30L signaling axis, which is crucial for B-NHL cell survival. It demonstrates strong inhibitory effects on lymphoma cell proliferation both in vitro and in vivo. Additionally, the peptide and doxorubicin co-functionalized AuNPs demonstrated significant inhibitory effects on B-NHL cell proliferation, highlighting their potential as a promising therapeutic strategy.</p><p><strong>Conclusions: </strong>In summary, our findings underscore the potential of CD30L as a novel target for B-NHL treatment and demonstrate the promise of CD30L-targeted peptides in advancing precision medicine for B-NHL, paving the way for future clinical developments.</p>","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":"24 1","pages":"189"},"PeriodicalIF":27.7,"publicationDate":"2025-07-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12228221/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144564978","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}