Molecular Cancer最新文献

{"title":"Reversal of tumour immune evasion via enhanced MHC-Class-I antigen presentation by a dual-functional RNA regulated system","authors":"Chaoyang Meng, Huipeng Zhang, Xuewen Yi, Gangcheng Kong, Xiaoge Zhang, Bei Wang, Yan Xu, Haoxiang Qi, Qing Wu, Ke Zhang, Jiaying Cao, Xiaohan Lin, Huiheng Feng, Jianxiang Chen, Shusen Zheng, Zhen Gu, Hongjun Li, Qi Ling","doi":"10.1186/s12943-025-02480-x","DOIUrl":"https://doi.org/10.1186/s12943-025-02480-x","url":null,"abstract":"Motivating the immune system to target tumour cells plays an increasingly prominent role in the treatment of hepatocellular carcinoma (HCC), but challenges such as low overall response rates persist in current clinical practice. Tumour cell MHC-Class-I (MHC-I) downregulation and antigen loss are typical mechanisms of immune evasion. To this end, a dual-functional RNA-based strategy was conceived for HCC immunotherapy. MHC-I expression on HCC and paratumour tissues from patients was assessed, and the correlations between MHC-I regulators and HCC prognosis were analyzed. Small interfering RNA (siRNA) targeting proprotein convertase subtilisin/kexin type 9 (PCSK9) and mRNA encoding tumour antigens were encapsulated in a fluorinated lipid nanoparticle (LNP), which direct nucleic acids primarily to the liver, making it ideal for HCC treatment. Anti-tumour efficacy was investigated in an orthotopic HCC model, with single-cell RNA sequencing used for in-depth analysis of the tumour microenvironment (TME). A marked downregulation of MHC-I expression was observed in HCC tumour cells from a cohort of patients, with this MHC-I suppression correlating with poor prognosis and diminished responsiveness to immunotherapy. Among the various MHC-I regulators, PCSK9 is the only one that shows a significant correlation with the prognosis of HCC patients. Knockdown of PCSK9 inhibited MHC-I degradation and thus increased the efficiency of antigen presentation by up to sixfold compared to untreated tumour cells. The hybrid RNA LNPs (h-LNP) enhanced Th1-mediated immune responses, reinvigorating and expanding anti-tumour immunity within the TME. Following treatment with h-LNPs, the TME showed a pronounced infiltration of CD8+ T cells and NK cells, coupled with a significant reduction in immune-suppressive populations, such as M2-like macrophages, in contrast to the controls. These changes in the immune landscape were accompanied by a marked inhibition of tumour growth in an orthotopic HCC model as well as melanoma, where this dual-functional RNA-regulated system outperformed the control groups. The present study successfully engineered a dual-functional RNA-regulated system that augments tumour cell antigen presentation and reconfigures the immune landscape within the TME, thereby potentiating the anti-tumour efficacy of the mRNA vaccine.","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":"125 1","pages":""},"PeriodicalIF":37.3,"publicationDate":"2025-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145283322","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":"Turning cold tumors into hot tumors to ignite immunotherapy","authors":"Yuan-Tong Liu, Yun-Long Wang, Shuo Wang, Jia-Jun Li, Wei He, Xin-Juan Fan, Xiang-Bo Wan","doi":"10.1186/s12943-025-02477-6","DOIUrl":"https://doi.org/10.1186/s12943-025-02477-6","url":null,"abstract":"The revolution in cancer immunotherapy, particularly through immune checkpoint inhibitors (ICIs), underscores the significant role of the tumor microenvironment (TME) in determining therapeutic outcomes. At the heart of this is the classification of tumors into “cold” and “hot”, which significantly influences the efficacy of immunotherapy. “Cold” tumors are characterized by scant immune cell infiltration and an immunosuppressive TME, which effectively evades immune detection and resists ICIs. In contrast, “hot” tumors, characterized by abundant immune cells and a proinflammatory environment, are more receptive to immunotherapeutic approaches. This review comprehensively examines the molecular and cellular foundations of the “cold” tumor phenotype, delving into the mechanisms of camouflage (impeding immune priming and infiltration), coercion (suppressing immune functions)​​, and ​​cytoprotection (resisting inflammatory death)​​ that contribute to maintaining immune silence. Furthermore, it critically evaluates emerging strategies for converting “cold” tumors to “hot”, immune-reactive entities, including the role of biomaterials in remodeling the TME to increase the effectiveness of immunotherapy. Through an in-depth exploration of these foundational mechanisms and therapeutic advancements, this review seeks to shed light on the way forward in cancer treatment, framing the transformation of “cold” tumors to “hot” tumors as a crucial approach to enhancing the reach of immunotherapy to a broader array of cancer types.","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":"7 1","pages":""},"PeriodicalIF":37.3,"publicationDate":"2025-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145283328","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":"Harnessing ovarian cancer ascites for translational science: models, biomarkers, and therapeutics","authors":"Samrita Dogra, Laura Adhikari, Doris M. Benbrook, Jacqueline A. Bohn, Anthony Burgett, Vishal Chandra, Lauren Dockery, Amit Singh, Lacey McNally, Rajani Rai, Zitha Redempta Isingizwe, Debra L. Richardson, Zhibo Yang, Bethany N. Hannafon","doi":"10.1186/s12943-025-02438-z","DOIUrl":"https://doi.org/10.1186/s12943-025-02438-z","url":null,"abstract":"Ovarian cancer is one of the most lethal gynecological malignancies and is often associated with fluid build-up in the peritoneal cavity, known as ascites. Nearly one-third of patients with ovarian cancer present with ascites at the time of initial diagnosis, and more frequently with recurrent ovarian cancer. Ascites is a uniquely valuable tool for research, as it is representative of both the tumor and its microenvironment. Ascites is composed of cells (single cells and multicellular aggregates) and acellular components that contribute to the development of peritoneal metastasis and chemoresistance. Ascites is an underutilized resource that provides an opportunity to improve our understanding of ovarian cancer biology, identify novel drug targets, assess drug responses, and identify diagnostic and/or prognostic biomarkers. This review summarizes the current understanding of ovarian cancer ascites with a focus on, (1) etiology, (2) cytopathological and molecular characterization, (3) the role its cellular and acellular components play in shaping the tumor microenvironment, and (4) its application in translational research for drug development (organoids and patient-derived ascites xenografts) and biomarker discovery. Lastly, options for the treatment of malignant ascites, along with future opportunities to use ascites as a translational research tool to improve our understanding of ovarian cancer biology and to develop new therapeutic strategies, are discussed.","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":"19 1","pages":""},"PeriodicalIF":37.3,"publicationDate":"2025-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145283324","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":"Purine metabolism: a pan-cancer metabolic dysregulation across circulation and tissues","authors":"Mengjie Yu, Cheng Liu, Minmin Cao, Dou Yang, Tongshan Wang, Jing Xu, Danxia Zhu, Guangji Wang, Jiye Aa, Wei Zhu","doi":"10.1186/s12943-025-02482-9","DOIUrl":"https://doi.org/10.1186/s12943-025-02482-9","url":null,"abstract":"Tumors function as organ-like entities within complex ecosystems, interacting with diverse components of their microenvironment, including blood and lymphatic vessels, neurons, immune cells, metabolites, and cytokines, to drive tumorigenesis and progression. Our pan-cancer study investigated the universal tumor hallmarks, integrating metabolite characteristics with molecular mechanisms. Metabolomic profiling on plasma from 2,561 patients across 20 cancer types and 604 healthy controls in two clinical centers, identified three biomarkers in pan cancers: elevated levels of hypoxanthine and reduced levels of cysteine and pyruvic acid. Given the profound significance of hypoxanthine, we further discovered 33 core purine metabolism-related genes in The Cancer Genome Atlas (TCGA) pan-cancer tissues, and their influences on immunomodulation and overall survival. Lastly, candidate therapeutic compounds, intervening purine metabolism, were proposed based on pharmaco-transcriptomics and pharmaco-proteomics analysis. Through interdisciplinary multi-omics investigations, such approaches may enhance insight into antitumor immunotherapy by targeting cancer metabolic reprogramming.","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":"1 1","pages":""},"PeriodicalIF":37.3,"publicationDate":"2025-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145283326","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":"Thyroid hormone receptor beta signaling is a targetable driver of prostate cancer growth","authors":"Aleksandra Fesiuk, Daniel Pölöske, Elvin D. de Araujo, Geordon A. Frere, Timothy B. Wright, Gary Tin, Yasir S. Raouf, Olasunkanmi O. Olaoye, Ji Sung Park, Nicolas Blavet, Boris Tichý, Michaela Schlederer, Sandra Högler, Michael Wolf, Cécile Philippe, Osman Aksoy, Adam Varady, Alejandro Medaglia Mata, Maxim Varenicja, Boglárka Szabó, Theresa Weiss, Gabriel Wasinger, Torben Redmer, Heidi A. Neubauer, Martin Susani, Clemens P. Spielvogel, Jing Ning, Maik Dahlhoff, Martin Schepelmann, Richard Kennedy, Richard Moriggl, Geoffrey Brown, Jenny Persson, Christopher Gerner, Vojtech Bystry, Oldamur Hollóczki, David M. Heery, Patrick T. Gunning, Olaf Merkel, Brigitte Hantusch#, Lukas Kenner","doi":"10.1186/s12943-025-02451-2","DOIUrl":"https://doi.org/10.1186/s12943-025-02451-2","url":null,"abstract":"Thyroid hormone (TH) signaling plays a major role in the development, energy homeostasis, and metabolism of most tissues. Recent studies have identified THs as drivers of prostate cancer (PCa) development and progression. We reported that the T3-scavenger protein µ-crystallin (CRYM) regulates the development and progression of PCa and that this involved crosstalk with androgen receptor (AR) signaling. However, the mechanisms remain incompletely understood. Here, we explored the role of thyroid hormone receptor β (TRβ), which is the main effector of TH signaling, in the context of PCa. The use of the TRβ-selective antagonist NH-3 inhibited PCa cell proliferation in vitro and reduced tumor size in PCa xenograft models in vivo. Notably, NH-3 was highly effective in the engrafted 22Rv1 cell line, a model for castration-resistant PCa (CRPC). Mechanistic studies revealed that NH-3 downregulates AR and the AR target genes Nkx3.1 and KLK3 (PSA). NH-3 was a more effective anticancer agent than enzalutamide, and their combined use was synergistic. Evidence from human datasets corroborates our findings, whereby elevated TRβ expression and mutations in the TH signaling pathway are associated with the onset of PCa. Collectively, these results establish TRβ as a mediator of tumorigenesis in PCa and identify NH-3 as a promising therapeutic agent for targeting AR signaling, particularly in CRPC. ","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":"27 1","pages":""},"PeriodicalIF":37.3,"publicationDate":"2025-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145283325","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":"Harnessing ExDNA for precision exatecan delivery in cancer: a novel antibody-drug conjugate approach.","authors":"Zaira Ianniello,Huimei Lu,Elias Quijano,Daniel A Colón-Ríos,Madison Rackear,Venu Bommireddy,Dale L Ludwig,Zhiyuan Shen,Peter M Glazer","doi":"10.1186/s12943-025-02462-z","DOIUrl":"https://doi.org/10.1186/s12943-025-02462-z","url":null,"abstract":"","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":"136 1","pages":"253"},"PeriodicalIF":37.3,"publicationDate":"2025-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145277202","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":"Medical importance and pharmacokinetics of gold nanoparticles in the human body.","authors":"Priyanka Singh,Abhayraj S Joshi,Hina Singh,Ivan Mijakovic","doi":"10.1186/s12943-025-02418-3","DOIUrl":"https://doi.org/10.1186/s12943-025-02418-3","url":null,"abstract":"","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":"56 1","pages":"252"},"PeriodicalIF":37.3,"publicationDate":"2025-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145254785","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":"Advances in RNA-based cancer therapeutics: pre-clinical and clinical implications","authors":"Yubo Yan, Shuang Liu, Jie Wen, Yunlong He, Chenyang Duan, Noushin Nabavi, Milad Ashrafizadeh, Gautam Sethi, Lubin Liu, Rong Ma","doi":"10.1186/s12943-025-02463-y","DOIUrl":"https://doi.org/10.1186/s12943-025-02463-y","url":null,"abstract":"Cancer therapy has been revolutionised by the emergence of RNA-based therapeutics, providing several strategies and mechanisms to regulate gene expression via messenger RNA (mRNA), small interfering RNA (siRNA), microRNAs (miRNA), antisense oligonucleotides (ASOs), and RNA aptamers. The present review highlights the recent advances in the preclinical development and clinical applications of RNA-based therapeutics, focusing on the delivery strategies, biological targets, and pharmacological optimisation, together with key clinical data. mRNA therapeutics, especially those adapted from vaccine platforms are being developed for the cancer immunotherapy and protein replacement, while siRNAs and ASOs enable highly specific gene silencing and splice correction. miRNA therapies show potential for diverse oncogenic pathway control, despite ongoing challenges in the delivery and specificity. RNA aptamers are obtaining attention as tumor-targeting agents in the drug delivery systems. Progress in lipid nanoparticles, chemical modifications, and tissue-specific delivery has improved the stability and efficacy of these agents. Early-phase clinical trials report encouraging outcomes in both solid tumours and haematologic malignancies, particularly in overcoming resistance and modulating the tumor microenvironment (TME). Although challenges remain in scalability, immune activation, and deep-tumour penetration, RNA-based strategies are advancing towards integration into clinical oncology. Continued refinement of delivery technologies and targeted trial designs will be critical for translating these therapies into effective, personalized cancer treatments. • RNA-based therapies allow for precise intervention at the genetic and molecular levels of cancer. RNA-based therapies enable targeted intervention at the genetic and molecular levels of cancer. • Distinct RNA modalities including mRNA, siRNA, miRNA, ASOs, and aptamers offer provide complementary mechanisms for tumor modulation. • Advances in delivery technologies, particularly lipid nanoparticles (LNPs), have significantly improved RNA stability, targeting, and intracellular uptake. • Clinical trials report encouraging promising efficacy and tolerability stability of RNA therapeutics in both solid tumours and haematologic malignancies. • Novel approaches such as self-amplifying RNA (saRNA) and synthetic lethality are emerging as precision strategies to address tumour heterogeneity and drug resistance. Questions • How do different types of RNA therapeutics function in cancer treatment? • What are the major challenges in delivering the delivery of RNA molecules effectively to tumor sites? • How do chemical modifications improve the performance of RNA-based drugs? • What clinical evidence supports the use of RNA therapeutics in oncology? • In what ways can RNA therapies be integrated into personalized cancer care strategies?","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":"22 1","pages":""},"PeriodicalIF":37.3,"publicationDate":"2025-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145246765","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":"Exosome-mediated metabolic reprogramming: effects on thyroid cancer progression and tumor microenvironment remodeling.","authors":"Shouhua Li,Hengtong Han,Kaili Yang,Xiaoxiao Li,Libin Ma,Ze Yang,Yong-Xun Zhao","doi":"10.1186/s12943-025-02470-z","DOIUrl":"https://doi.org/10.1186/s12943-025-02470-z","url":null,"abstract":"Metabolic reprogramming is one of the fundamental characteristics of thyroid cancer (TC), which meets its energy and biosynthetic demands through mitochondrial dysfunction, glycolysis activation, lipid metabolism imbalance, and glutamine dependency, thereby promoting metastasis and reshaping the immune microenvironment. Exosomes, as extracellular vesicles, play a crucial role in TC by delivering bioactive molecules such as proteins, lipids, and nucleic acids. In the tumor microenvironment (TME) of TC, exosomes secreted by both tumor and non-tumor cells interact with each other, driving metabolic reprogramming and forming a bidirectional regulatory network. This significantly alters the biological characteristics of TC cells, including proliferation, invasion, metastasis, angiogenesis, and the acquisition of drug resistance and immune tolerance, ultimately influencing the process of immune escape in TC. This review systematically summarizes how exosomes in the TME of TC promote tumor progression through metabolic reprogramming, providing new diagnostic and therapeutic strategies for patients with locally advanced, radioiodine-refractory TC.","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":"9 1","pages":"247"},"PeriodicalIF":37.3,"publicationDate":"2025-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145240902","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":"Overcoming resistance to anti-PD-L1 immunotherapy: mechanisms, combination strategies, and future directions.","authors":"Kartik Mandal,Ganesh Kumar Barik,Manas Kumar Santra","doi":"10.1186/s12943-025-02400-z","DOIUrl":"https://doi.org/10.1186/s12943-025-02400-z","url":null,"abstract":"Cancer cells express high levels of programmed cell death-ligand 1 (PD-L1) to evade immune surveillance. PD-L1 interacts with PD-1 on T cells to make them non-functional. Thus, PD-L1 and PD-1 are pivotal targets in cancer immunotherapy. While anti-PD-1/PD-L1 therapies have offered renewed hope for many patients, their modest efficacy remains a critical concern. This underscores the urgent need to unravel the intricate mechanisms that govern both therapeutic responses as well as resistance to immunotherapy. This review explores the multifaceted nature of PD-L1, including factors that regulate its expression, tumor-immune interactions, and the resistance mechanisms associated with anti-PD-L1 immunotherapy. Several promising strategies have been explored to overcome these challenges, such as combination therapies, modulation of the tumor microenvironment, neoantigen targeting, and dynamic biomarker monitoring. Outcomes of these approaches, integrating advanced technologies like high-resolution imaging, machine learning, multi-omics profiling, and liquid biopsy for soluble PD-L1 detection emerge as a powerful means to refine patient stratification. Together, these innovations pave the way toward more precise and personalized immunotherapy, maximizing clinical benefits for cancer patients. Additionally, the evolving landscape of clinical trials involving anti-PD-1/PD-L1 monoclonal antibodies has been explored, emphasizing the integration of immune checkpoint therapies with chemotherapy, radiotherapy, targeted therapy, CAR-T, and metabolic immunotherapy to overcome resistance in refractory cancers. By embarking on these challenges and leveraging novel therapeutic strategies, this review intends to advance the understanding of more effective, personalized cancer immunotherapies, ultimately improving outcomes for a broader range of patients.","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":"33 1","pages":"246"},"PeriodicalIF":37.3,"publicationDate":"2025-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145240894","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}