Molecular Cancer最新文献

{"title":"Single-cell multi-omics reveals that FABP1 + renal cell carcinoma drive tumor angiogenesis through the PLG-PLAT axis under fatty acid reprogramming.","authors":"Yiqiu Wang,Yingchun Liang,Min Li,Jiayi Lu,Sian Zhou,Yaoyu Yu,Changwei Yang,Xinhuang Hou","doi":"10.1186/s12943-025-02377-9","DOIUrl":"https://doi.org/10.1186/s12943-025-02377-9","url":null,"abstract":"Renal cell carcinoma is characterized by a poor prognosis. Recently, renal cell carcinoma has been recognized as a metabolic disease associated with fatty acid metabolic reprogramming, although in-depth studies on this topic are still lacking. We found that fatty acid metabolism reprogramming in renal cell carcinoma is primarily characterized by high expression of FABP1. FABP1 + tumors significantly impact survival and display distinct differentiation trajectories compared to other tumor subclusters. They show elevated expression of angiogenesis and cell migration signals, with PLG-PLAT-mediated interactions with endothelial cells notably enhanced. Spatial transcriptomics show a prominent co-localization of FABP1 + tumors with endothelial cells, and their spatial distribution closely aligns with that of PLAT + endothelial cells. FABP1 + tumors exhibit a unique pattern in spatial transcriptomics, enriched in Extracellular Matrix and angiogenesis-related pathways. Through receptor-ligand interaction analysis, a novel PLG-PLAT functional axis was found between tumor epithelial cells and endothelial cells. Based on results of experiments, we infer that FABP1 + tumors can promote plasmin-related tumor angiogenesis by triggering the PLG-PLAT signaling axis. Finally, utilizing preclinical models, we suggest that targeting the FABP1-PLG-PLAT axis may serve as promising strategy enhancing the sensitivity of Tyrosine Kinase Inhibitor therapy.","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":"91 1","pages":"179"},"PeriodicalIF":37.3,"publicationDate":"2025-06-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144295854","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":"Demystifying the cGAS-STING pathway: precision regulation in the tumor immune microenvironment","authors":"Qingyang Wang, Yang Yu, Jing Zhuang, Ruijuan Liu, Changgang Sun","doi":"10.1186/s12943-025-02380-0","DOIUrl":"https://doi.org/10.1186/s12943-025-02380-0","url":null,"abstract":"The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) signaling pathway serves as an immune sentinel for cytosolic DNA, recognizing double-stranded DNA (dsDNA) derived from abnormally localized nuclear DNA or mitochondrial DNA (mtDNA), and plays a pivotal role in innate immune responses and tumor immune surveillance. Conventional antitumor therapies induce genomic instability and mitochondrial stress, leading to the release of nuclear DNA and mtDNA into the cytosol, thereby activating the cGAS-STING pathway. This activation triggers the production of type I interferons (IFN-I) and pro-inflammatory cytokines, which reshape the tumor immune microenvironment (TIME). However, the complexity of TIME reveals a “double-edged sword” effect of cGAS-STING signaling: while it activates antitumor immune responses, it also promotes immune escape and metastasis through the regulation of immunosuppressive cells and stromal components. This review comprehensively delineates the differential regulatory mechanisms of the pathway within TIME constituents, highlighting its multifaceted roles in tumor immunity. Furthermore, it reviews recent advances and challenges in targeting the cGAS-STING pathway for cancer immunotherapy, with the aim of advancing cGAS-STING signaling modulation as a key therapeutic strategy to reprogram TIME and overcome immunosuppression in antitumor treatment.","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":"23 1","pages":""},"PeriodicalIF":37.3,"publicationDate":"2025-06-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144269043","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":"Single-cell transcriptome reveals the reprogramming of immune microenvironment during the transition from MASH to HCC","authors":"Yu Huang, Ying Xie, Yuqing Zhang, Zhemian Liu, Weihua Jiang, Yingying Ye, Jiale Tang, Zhenhua Li, Zhinan Yin, Xue-Jia Lin","doi":"10.1186/s12943-025-02370-2","DOIUrl":"https://doi.org/10.1186/s12943-025-02370-2","url":null,"abstract":"The immunological landscape of metabolic dysfunction-associated steatohepatitis (MASH)-driven hepatocellular carcinoma (HCC) is not well understood. Herein, we aim to delineate the immunological landscape in the MASH-to-HCC transition and to identify the critical genes that contribute to the pathogenesis of MASH-related HCC. A well-established MASH-driven HCC mouse model, STAM model, was first constructed. Thereafter, we applied single-cell RNA sequencing (scRNA-seq) analysis of CD45+ cells sorted from livers of mice with normal chow or MASH, as well as paired paracancerous and cancer tissues from mice with HCC. Flow cytometry and multiplexed immunohistochemistry were performed to validate the analysis results of scRNA-seq. Finally, STAM model was applied between apolipoprotein E (ApoE)-deficient mice and wild type controls. We identified 23 major clusters corresponding to nine populations among 31,822 cells. Obviously, immunosuppressive and exhausted CD4+ T (IKZF2+OX40+FOXP3+CD4+ and GZMK+LAG-3+PD-1+CD4+), CD8+ T (LY49I+LY49G+IKZF2+FOXP3−CD8+, IKZF2+FOXP3+CD8+ and GZMK+LAG-3+PD-1+CD8+) and γδ T cells (γδ Treg and exhausted γδ T cells) were induced in the MASH-to-HCC transition. As MASH-related HCC progressed, B cells matured and differentiated into immunosuppressive cells. Natural killer cells (NKs) were found to be strikingly reduced at HCC stage. Particularly, the activation of liver-infiltrated NK cells was inhibited, leading to attenuation of anti-tumor capacity in the MASH-to-HCC transition. Moreover, tumor-associated macrophages were increased in MASH-related HCC. Importantly, multiple immune cells highly expressed ApoE in HCC, and ablation of ApoE impeded MASH-driven hepatocarcinogenesis by disrupting both ApoE-PI3K-AKT-NF-κB and ApoE-PI3K-AKT-c-Jun/c-Fos signaling pathways. We illustrate the profound reprogramming of the liver immune microenvironment in the MASH-to-HCC transition and clarify the role of ApoE in MASH-driven HCC, implying that ApoE may serve as a potential therapeutic target for MASH-related HCC.","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":"8 1","pages":""},"PeriodicalIF":37.3,"publicationDate":"2025-06-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144260484","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":"Enhancing radiotherapy-induced anti-tumor immunity via nanoparticle-mediated STING agonist synergy","authors":"Qian Zeng, Min Liu, Ziqi Wang, Rongrong Zhou, Kelong Ai","doi":"10.1186/s12943-025-02366-y","DOIUrl":"https://doi.org/10.1186/s12943-025-02366-y","url":null,"abstract":"Radiotherapy (RT) remains a cornerstone treatment for over 50% of cancer patients, primarily via ionizing radiation-induced DNA damage to exert therapeutic effects. Notably, emerging studies have revealed its additional capacity to activate systemic anti-tumor immune responses through inducing immunogenic cell death (ICD) and activating the cGAS-STING pathway, further expanding its therapeutic potential. However, its efficacy is often limited by immunosuppressive tumor microenvironment (TME). Additionally, while RT can activate the cGAS-STING pathway, this activation remains transient and suboptimal, failing to sustain robust anti-tumor immunity. Therefore, combining RT with STING agonists may benefit traditional therapy by amplifing tumor immunogenicity and counteracting immune evasion. Despite promising results, challenges such as off-target toxicity, poor cell membrane permeability and poor bioavailability, remain obstacles to clinical translation of conventional STING agonists. Nanomedicine offers a promising approach by enabling targeted delivery of STING agonists and amplifying RT-induced DNA damage through nanoscale radiosensitizers. In this review, we provide a detailed discussion of the immune-stimulatory and immune-suppressive effects of RT, as well as the mechanisms and biological effects of selectively activating the cGAS-STING pathway in key TME components. On this basis, we further explore recent advancements in nano-STING agonists-mediated anti-tumor immunity in synergy with RT. This combinatorial approach achieves dual radiosensitization and immunostimulation, ultimately driving immune memory formation and TME reprogramming. Finally, the application prospects and challenges of nano-STING agonists-based immunotherapy are also discussed from the perspective of clinical translation.","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":"24 1","pages":""},"PeriodicalIF":37.3,"publicationDate":"2025-06-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144260485","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":"Anlotinib combined with benmelstobart as a chemo-free first-line treatment in advanced esophageal squamous cell carcinoma: an exploratory multicenter, single-arm phase II clinical trial","authors":"Xiangrui Meng, Xiuli Yang, Yonggui Hong, Wenkang Wang, Zhiye Zhang, Jin Xia, Yunfang Chen, Yue Zhou, Taiying Lu, Min Song, Zhengzheng Shan, Tao Wu, Weilong Wu, Ling Shen, Lulu Guan, Mingying Ma, Lisen Wang, Xi Luo, Dao Xin, Yihui Ma, Guozhong Jiang, Yu Qi, Binghua Jiang, Daoyu Zhang, Biao Hu, Xiaoying Wu, Zuofu Peng, Feng Wang","doi":"10.1186/s12943-025-02376-w","DOIUrl":"https://doi.org/10.1186/s12943-025-02376-w","url":null,"abstract":"No combined antiangiogenic and PD-1/PD-L1 blockade therapy has been investigated as a chemo-free first-line treatment for advanced esophageal squamous cell carcinoma (ESCC). This study evaluates the efficacy and safety of anlotinib combined with benmelstobart as a chemo-free treatment in previously untreated advanced ESCC, and identifies potential predictive biomarkers using next-generation sequencing (NGS). ALTER-E-003, a single-arm, open-label phase II trial, enrolled patients with advanced ESCC across five Chinese centers. Patients received oral anlotinib 12 mg daily on days 1–14 per three-week cycle, with benmelstobart 1200 mg infused on day 1 of each cycle for up to 24 months. Thereafter, patients received anlotinib maintenance therapy. Primary endpoint was objective response rate (ORR). Secondary endpoints included progression-free survival (PFS), overall survival (OS), disease control rate (DCR), duration of response (DOR), and safety. NGS and fluorescent multiplex immunohistochemistry (mIHC) were performed on tumor specimens. Of 53 screened patients, 46 completed the study. The confirmed ORR was 56.5% (95% CI 41.1–71.1), and DCR was 91.3% (95% CI 79.2–97.6). Median PFS was 15.74 months (95% CI 9.03–21.91). Treatment-related adverse events occurred in 93.5% of patients, with 28.3% experiencing grade 3 or higher events. NGS revealed a novel predictive mutational signature (TP53+/FAT1+/NOTCH3-) that was associated with better ORR (65.6% versus 11.1%, P < 0.001), longer median PFS (17.91 versus 5.32 months, P = 0.005) and improved OS (P = 0.006). First-line anlotinib-benmelstobart combination demonstrated durable responses and acceptable safety in ESCC patients. Exploratory biomarker analyses identified a TP53+/FAT1+/NOTCH3- mutational signature potentially associated with improved outcomes, though further validation in randomized trials is warranted. NCT05038813.","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":"36 1","pages":""},"PeriodicalIF":37.3,"publicationDate":"2025-06-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144260486","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":"Correction: Proteogenomic characterization of molecular and cellular targets for treatment‑resistant subtypes in locally advanced cervical cancers","authors":"Do Young Hyeon, Dowoon Nam, Hye‑Jin Shin, Juhee Jeong, Eunsoo Jung, Soo Young Cho, Dong Hoon Shin, Ja‑Lok Ku, Hye Jung Baek, Chong Woo Yoo, Eun‑Kyung Hong, Myong Cheol Lim, Sang‑Jin Lee, Young‑Ki Bae, Jong Kwang Kim, Jingi Bae, Wonyoung Choi, Su‑Jin Kim, Seunghoon Back, Chaewon Kang, Inamul Hasan Madar, Hokeun Kim, Suhwan Kim, Duk Ki Kim, Jihyung Kang, Geon Woo Park, Ki Seok Park, Yourae Shin, Sang Soo Kim, Keehoon Jung, Daehee Hwang, Sang‑Won Lee, Joo‑Young Kim","doi":"10.1186/s12943-025-02373-z","DOIUrl":"https://doi.org/10.1186/s12943-025-02373-z","url":null,"abstract":"&lt;p&gt;&lt;b&gt;Correction: Mol Cancer 24&lt;/b&gt;,&lt;b&gt; 77 (2025)&lt;/b&gt;&lt;/p&gt;&lt;p&gt;&lt;b&gt;https://doi.org/10.1186/s12943-025-02256-3&lt;/b&gt;&lt;/p&gt;&lt;p&gt;Following the publication of the original article [1], the authors, during their post-publication review, have noted that the standard acknowledgment required by the International Cancer Proteogenome Consortium (ICPC) was inadvertently omitted. Because the study was conducted under the auspices of ICPC, inclusion of this language is essential for proper attribution and for the consortium’s ongoing efforts to catalogue and promote ICPC-supported research. They therefore respectfully request the publication of an article correction note to address the change in Acknowledgements section. The incorrect and correct Acknowledgements are provided below.&lt;/p&gt;&lt;p&gt; Incorrect Acknowledgements:&lt;/p&gt;&lt;p&gt;This work was supported by grants from the Proteogenomic Research Project of National Cancer Center, Korea (NCC-1810861, NCC-1810862, NCC-1711260, NCC-2210490), the Basic Science Research Program through the National Research Foundation (NRF) funded by the Ministry of Education, Korea.&lt;/p&gt;&lt;p&gt;(2018R1D1A1A09084250, 2021R1F1A1052407, RS-2023-00208004, RS-2023-00217571), and the NAVER Corporation (Grant No. 3720230110). This work was also supported by the Korea Basic Science Institute (KBSI) National Research Facilities &amp; Equipment Center (NFEC) grant funded by the Korean government (Ministry of Education) (2019R1A6C1010028) and by the NRF funded by the Korean government (Ministry of Science and ICT) (NRF-2022M3H9A2086450).&lt;/p&gt;&lt;p&gt; Correct Acknowledgements:&lt;/p&gt;&lt;p&gt;This work was supported by grants from the Proteogenomic Research Project of National Cancer Center, Korea (NCC-1810861, NCC-1810862, NCC-1711260, NCC-2210490), the Basic Science Research Program through the National Research Foundation (NRF) funded by the Ministry of Education, Korea (2018R1D1A1A09084250, 2021R1F1A1052407, RS-2023-00208004, RS-2023-00217571), and the NAVER Corporation (Grant No. 3720230110). This work was also supported by the Korea Basic Science Institute (KBSI) National Research Facilities &amp; Equipment Center (NFEC) grant funded by the Korean government (Ministry of Education) (2019R1A6C1010028) and by the NRF funded by the Korean government (Ministry of Science and ICT) (NRF-2022M3H9A2086450). This work was done under the auspices of a Memorandum of Understanding between Korea University and the U.S. National Cancer Institute’s International Cancer Proteogenome Consortium (ICPC). ICPC encourages international cooperation among institutions and nations in proteogenomic cancer research in which proteogenomic datasets are made available to the public. This work was also done in collaboration with the U.S. National Cancer Institute’s Clinical Proteomic Tumor Analysis Consortium (CPTAC).&lt;/p&gt;&lt;ol data-track-component=\"outbound reference\" data-track-context=\"references section\"&gt;&lt;li data-counter=\"1.\"&gt;&lt;p&gt;Hyeon DY, Nam D, Shin HJ, et al. Proteogenomic characterization of molecula","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":"11 1","pages":""},"PeriodicalIF":37.3,"publicationDate":"2025-06-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144260175","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":"Wnt/β-catenin mediated signaling pathways in cancer: recent advances, and applications in cancer therapy","authors":"Xiuzhu Wu, Haiying Que, Qingfang Li, Xiawei Wei","doi":"10.1186/s12943-025-02363-1","DOIUrl":"https://doi.org/10.1186/s12943-025-02363-1","url":null,"abstract":"The Wnt/β-catenin signaling pathway is a highly conserved signaling pathway closely linked to cancer development through various biological processes, including oncogenic transformation, genomic instability, cancer cell proliferation, stemness, metabolism, cell death, immune regulation, and metastasis. Notably, its activation plays a crucial role in drug resistance to chemotherapy, targeted therapy and immunotherapy. Recent advances in drug development have identified several targeted inhibitors acting at key nodal points of this pathway, with some demonstrating synergistic efficacy when combined with immunotherapeutic agents. This review provides a comprehensive analysis of current understanding regarding the Wnt/β-catenin pathway in malignancy, emphasizing its multifaceted roles in tumor initiation, therapeutic resistance, and immune regulation. Additionally, we summarized the clinical performance of combination therapies targeting the Wnt/β-catenin pathway in conjunction with chemotherapy, targeted therapy, and immunotherapy. Although clinical development remains at a relatively early stage, pharmacological modulation of Wnt/β-catenin signaling offers considerable potential as a novel therapeutic paradigm in precision oncology.","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":"58 1","pages":""},"PeriodicalIF":37.3,"publicationDate":"2025-06-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144252010","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":"Differential susceptibility and role for senescence in CART cells based on costimulatory domains","authors":"Ismail Can, Elizabeth L. Siegler, Olivia L. Sirpilla, Claudia Manriquez-Roman, Kun Yun, Carli M. Stewart, Jennifer M. Feigin, Makena L. Rodriguez, Omar L. Gutierrez-Ruiz, Ekene J. Ogbodo, Truc N. Huynh, Brooke L. Kimball, Long K. Mai, Mehrdad Hefazi, Lionel Kankeu Fonkoua, Hong Xia, Imene Hamaidi, Berke Alkan, Fatih Sezer, H. Atakan Ekiz, R. Leo Sakemura, Saad S. Kenderian","doi":"10.1186/s12943-025-02371-1","DOIUrl":"https://doi.org/10.1186/s12943-025-02371-1","url":null,"abstract":"Despite the success of chimeric antigen receptor T (CART) cell therapy in hematological malignancies, durable remissions remain low. Here, we report CART senescence as a potential resistance mechanism in 41BB-costimulated CART cell therapy. To mimic cancer relapse, we utilized an in vitro model with repeated CART cell activation cycles followed by rest periods. Using CD19-targeted CART cells with costimulation via 4-1BB-CD3ζ (BBζ) or CD28-CD3ζ (28ζ), we showed that CART cells undergo functional, phenotypical, and transcriptomic changes of senescence, which is more prominent in BBζ. We then utilized two additional independent strategies to induce senescence through MYC activation and irradiation. Induction of senescence impaired BBζ activity but improved 28ζ activity in preclinical studies. These findings were supported by analyses of independent patient data sets; senescence signatures in CART cell products were associated with non-response to BBζ but with improved clinical outcomes in 28ζ treatment. In summary, our study identifies senescence as a potential mechanism of failure predominantly in 41BB-costimulated CART cells. We identified senescence as a cause of failure in CART cell therapy, predominantly in 4-1BB-costimulated CART cells.","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":"31 1","pages":""},"PeriodicalIF":37.3,"publicationDate":"2025-06-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144252009","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":"CREPT is required for the metastasis of triple-negative breast cancer through a co-operational-chromatin loop-based gene regulation","authors":"Jianghua Li, Lu Xu, Jiayu Wang, Xuning Wang, Yuting Lin, Alex Yutian Zou, Fangli Ren, Yinyin Wang, Jun Li, Zhijie Chang","doi":"10.1186/s12943-025-02361-3","DOIUrl":"https://doi.org/10.1186/s12943-025-02361-3","url":null,"abstract":"Triple-negative breast cancer (TNBC) is recognized for its aggressiveness, yet the mechanism underlying metastasis remains unclear. Here, we report that CREPT/RPRD1B, which exhibits somatic gene copy-number amplifications and elevated expression, correlates with poor patient survival and drives TNBC metastasis. We demonstrate that CREPT alters three-dimensional genome structures in topologically-associating domain (TAD) status and chromatin loops via occupying promoters and enhancers. Specifically, CREPT mediates 1082 co-operational chromatin loops configured by enhancer-promoter and promoter-termination loops, which are validated by HiChIP analyses and visualized by Tn5-FISH experiments. These loops orchestrate RNAPII loading and recycling to enhance the metastatic gene expression. Disruption of these co-operational loops using CRISPR-dCas9 suppresses TNBC metastasis in vivo. Furthermore, depletion of CREPT using an AAV-based shRNA blocks TNBC metastasis in both preventative and therapeutic mouse models. We propose that targeting CREPT to disrupt the co-operational chromatin loop structures represents a promising therapeutic strategy for metastatic TNBC. • Somatic CREPT gene copy-number amplifications with elevated expression occur in the metastatic triple-negative breast cancer (TNBC) and correlate with poor patient survival • CREPT mediates 1082 co-operational chromatin loops configured by enhancer-promoter and promoter-termination loops • CREPT-mediated co-operational chromatin loops regulate metastatic genes during the metastasis of TNBC • Depleting CREPT by adeno-associated virus (AAV) blocks TNBC metastasis in preventative and therapeutic mouse models","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":"23 6 1","pages":""},"PeriodicalIF":37.3,"publicationDate":"2025-06-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144252011","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":"The tumor microenvironment in hepatocellular carcinoma: mechanistic insights and therapeutic potential of traditional Chinese medicine","authors":"Xiaojun Su, Xiuli Yan, Hui Zhang","doi":"10.1186/s12943-025-02378-8","DOIUrl":"https://doi.org/10.1186/s12943-025-02378-8","url":null,"abstract":"Hepatocellular carcinoma (HCC) progression and therapeutic resistance are profoundly influenced by the dynamic interplay within the tumor microenvironment (TME). The HCC TME comprises a complex network of cellular components, including cancer-associated fibroblasts, tumor-associated macrophages, and infiltrating immune cells, alongside non-cellular factors such as extracellular matrix proteins, cytokines, and angiogenic mediators. These elements collectively promote immune evasion, stromal remodeling, and neovascularization, driving tumor aggressiveness and treatment resistance. Emerging evidence suggests that traditional Chinese medicine (TCM) may offer a promising strategy to reprogram the immunosuppressive HCC TME through multimodal mechanisms, such as immunomodulation to enhance anti-tumor immunity and deplete regulatory cell populations, stromal normalization to attenuate fibroblast activation and pathological matrix deposition, and anti-angiogenic effects to restrict tumor vascularization. Notably, TCM compounds exhibit synergistic potential when combined with conventional therapies, including immune checkpoint inhibitors, tyrosine kinase inhibitors, and cytotoxic regimens, potentially enhancing efficacy while mitigating adverse effects. However, key challenges persist, such as intratumoral heterogeneity, pharmacokinetic variability of herbal formulations, and the need for rigorous preclinical-to-clinical translation. Future investigations should prioritize systems-level dissection of TCM-mediated TME modulation using omics technologies, rational design of TCM-based combination therapies guided by mechanistic studies, and standardization of clinically translatable TCM regimens. This review synthesizes current understanding of TME-driven HCC pathogenesis and highlights the emerging paradigm of TCM as a complementary modality to recalibrate the tumor-immune-stroma axis for improved therapeutic outcomes.","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":"18 1","pages":""},"PeriodicalIF":37.3,"publicationDate":"2025-06-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144252008","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}