Molecular Cancer最新文献

{"title":"Orchestrating movement: the role of Caveolin-1 in migration and metastasis.","authors":"Jiri Navratil,Martina Raudenska,Monika Kratochvilova,Jan Balvan,Yoav David Shaul,Michal Masarik","doi":"10.1186/s12943-025-02469-6","DOIUrl":"https://doi.org/10.1186/s12943-025-02469-6","url":null,"abstract":"","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":"54 1","pages":"267"},"PeriodicalIF":37.3,"publicationDate":"2025-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145339187","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":"Efferocytosis: the art of cellular clearance and novel perspectives in disease therapy.","authors":"Gege Li,Jiashuai Xu,Xiaohan Tian,Jingyi Xiao,Junqi Long,Yining Chen,Wenzhi Shen,Shuangtao Zhao","doi":"10.1186/s12943-025-02484-7","DOIUrl":"https://doi.org/10.1186/s12943-025-02484-7","url":null,"abstract":"Efferocytosis, the process of apoptotic cell clearance, is a fundamental biological mechanism for maintaining tissue homeostasis. However, its role in disease pathogenesis is often oversimplified, neglecting a critical knowledge gap: how the single process could drive opposing pathological outcomes. This review provides a comprehensive analysis centered on the functional duality of efferocytosis. By synthesizing evidence across a spectrum of human pathologies-from atherosclerosis and neurodegeneration to cancer-we establish a core paradigm: impaired efferocytosis is a central pathogenic driver in chronic inflammatory and autoimmune diseases, leading to unresolved inflammation. Conversely, the hijacking of efferocytosis by tumors fosters an immunosuppressive microenvironment, facilitating immune evasion. This dichotomy presents a significant therapeutic conundrum, as enhancing efferocytosis benefits inflammatory conditions but exacerbates cancer. By dissecting these context-dependent mechanisms, we argue that the future of efferocytosis-based medicine hinges on developing targeted, disease-specific strategies to safely harness this powerful biological process.","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":"69 1","pages":"268"},"PeriodicalIF":37.3,"publicationDate":"2025-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145339407","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":"Novel molecular mechanisms of FLT3 deregulation: from the acute myeloid leukemia experience to therapeutic insights in acute lymphoblastic leukemia.","authors":"F Lo Schiavo,C Salvesi,M Jandoubi,F Pirini,J Garbetta,G Martinelli,G Simonetti,A Ferrari","doi":"10.1186/s12943-025-02455-y","DOIUrl":"https://doi.org/10.1186/s12943-025-02455-y","url":null,"abstract":"Fms-like tyrosine kinase 3 (FLT3), a class III receptor tyrosine kinase essential for hematopoiesis, is a well-established oncogenic driver in acute myeloid leukemia (AML). Canonical internal tandem duplications (ITD) and tyrosine kinase domain (TKD) mutations inform prognosis and guide targeted therapy. Recent evidence highlights FLT3 as a critical oncogenic hub in acute lymphoblastic leukemia (ALL), where its alterations extend beyond ITD/TKD mutations to include non-canonical mutations with only partially explored functional implications. Moreover, recently discovered regulatory mechanisms, mostly acting on the FLT3 locus, drive FLT3 overexpression in ALL, including transcriptional regulation by rearranged ZNF384, epigenetic modifications, novel circular-RNA URAD::FLT3 fusions, and 13q12.2 deletions leading to enhancer hijacking and topologically associated domain (TAD)-boundary disruptions. The impact of these alterations on leukemogenesis and the possibility to target them in ALL subtypes is discussed here. Data from the Functional Omics Resource of Acute Lymphoblastic Leukemia (FORALL) across B- and T-ALL cell line subtypes drug screening, and from preclinical and clinical evidence reveals a variable efficacy in FLT3-mutated and FLT3-overexpressing ALL subtypes, supporting a molecularly guided treatment approach. Building on the success of FLT3 inhibitors in mutated AML and in light of the emerging results in patients lacking FLT3-ITD and in FLT3-like AML cases, presenting with a gene expression pattern similar to FLT3-mutated ones despite the absence of mutations, we discuss their potential in ALL and we consider novel therapeutic strategies, including new FLT3 inhibitors, antibody-based approaches, FLT3 CAR-T therapy, and synergistic drug combinations, such as FLT3 and BCL2 inhibition. These new insights reviewed here may redefine FLT3 as a pan-leukemic target, with ALL-specific activation mechanisms offering unique therapeutic windows. The implementation of FLT3 expression profiling and full-coding mutation screening in ALL (and in AML) diagnostics could unlock precision medicine approaches. By bridging the AML experience with ALL innovations, this review outlines a roadmap for FLT3-targeted therapies and combination strategies, underscoring the urgency of biomarker-driven clinical trials to optimize FLT3-directed interventions in acute leukemias.","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":"82 1","pages":"266"},"PeriodicalIF":37.3,"publicationDate":"2025-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145339262","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":"Ex vivo modelling of human colorectal cancer liver metastasis by normothermic machine perfusion.","authors":"Manuel Trebo,Thomas Maurer,Felix J Krendl,Stefan Salcher,Agnieszka Martowicz,Theresa Hautz,Sieghart Sopper,Arno Amann,Benno Cardini,Lukas H Poelsler,Anna Mair,Julia Hofmann,Andras T Meszaros,Martin Hermann,Michael Günther,Steffen Ormanns,Zlatko Trajanoski,Stefan Schneeberger,Dominik Wolf,Rupert Oberhuber,Andreas Pircher","doi":"10.1186/s12943-025-02430-7","DOIUrl":"https://doi.org/10.1186/s12943-025-02430-7","url":null,"abstract":"BACKGROUNDColorectal cancer liver metastasis (CRLM) is associated with poor survival, primarily due to acquired therapy resistance. While novel therapies arise, translation is limited by the lack of tumor models accurately representing dynamic microenvironmental interplay. Here, we show that ex vivo normothermic machine perfusion (NMP) offers a novel preclinical framework to study the intratumoral dynamics of CRLM biology.METHODSSix resected metastatic human livers were preserved for two days and subjected to multi-omic profiling of serially sampled adjacent liver and metastatic tissue using single-cell RNA sequencing (scRNA-seq) and spatial transcriptomics (ST). Tissue integrity was assessed and cross-validated by immunofluorescence (IF), high-resolution respirometry (HRR) and flow-cytometry.RESULTSNMP was successfuly applied to metastatic livers with minimal surgical adaptations, preserving both intrinsic hepatic properties and tissue viability over an extended duration. Single-cell and spatial mapping confirmed preservation of CRLM phenotypic properties and demonstrated high clinical translatability by applicability of the intrinsic epithelial consensus molecular subtypes to metastasis. Spatially deconvoluted pathway activities reflected functional tissue-microenvironments. Transcriptomic profiles - including those of tumor-associated myeloid cells - were preserved during NMP. Finally, we demonstrate tumor-associated myeloid cell persistence as a driver of disease progression and poor survival in colorectal cancer.CONCLUSIONOur findings represent the basis for future innovative applications adopting NMP in the context of CRLM, providing a new preclinical tumor model avenue.","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":"101 1","pages":"264"},"PeriodicalIF":37.3,"publicationDate":"2025-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145338655","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 proteostasis for cancer therapy: current advances, challenges, and future perspectives.","authors":"Chenliang Zhang,Jielang Li,Qiulin Tang,Liping Li,Dan Cao","doi":"10.1186/s12943-025-02472-x","DOIUrl":"https://doi.org/10.1186/s12943-025-02472-x","url":null,"abstract":"","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":"23 1","pages":"265"},"PeriodicalIF":37.3,"publicationDate":"2025-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145338658","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":"Integrated multi-omics identifies a CD54+ iCAF-ITGAL+ macrophage niche driving immunosuppression via CXCL8-PDL1 axis in cervical cancer.","authors":"Fanghua Chen,Gaigai Bai,Qinqin Liu,Guangping He,Ziyang Ding,Jiali Liang,Nan Wang,Junjun Qiu,Keqin Hua","doi":"10.1186/s12943-025-02471-y","DOIUrl":"https://doi.org/10.1186/s12943-025-02471-y","url":null,"abstract":"Cervical cancer (CC) remains a formidable clinical challenge, particularly in advanced stages where immune checkpoint blockade yields suboptimal responses. Despite the established role of the tumor microenvironment (TME) in fostering immunosuppression, the precise mechanisms of stroma-immune crosstalk in CC remain elusive. Leveraging single-cell RNA sequencing of 77,221 cells from CC and normal cervical tissues, we uncovered a tumor-enriched subpopulation of inflammatory cancer-associated fibroblasts (iCAFs) marked by elevated CD54 expression (CD54+ iCAFs), which independently predicted adverse clinical outcomes. Systematic dissection of intercellular communication networks revealed a tumor-specific alliance between CD54+ iCAFs and ITGAL+ macrophages, orchestrated through dysregulated ligand-receptor signaling. Spatial multi-omics approaches, including multiplex immunohistochemistry and spatial transcriptomics, confirmed their colocalization within an immunosuppressive niche. Mechanistically, CD54+ iCAFs promote immunosuppression by polarizing ITGAL+ macrophages toward an M2-like phenotype, primarily via CCL2 secretion. These fibroblasts further support immune evasion through two complementary pathways: direct CD54-ITGAL contact-dependent signaling and soluble CCL2-mediated macrophage reprogramming. The resulting macrophage activation stimulates autocrine CXCL8 secretion and subsequent PD-L1 upregulation, which ultimately suppresses CD8+ T cell functions, fostering an immune-tolerant microenvironment in CC. Therapeutic intervention using the CXCL8-CXCR1/2 inhibitor reparixin disrupted the CXCL8-PD-L1 axis, reduced PD-L1+ macrophage abundance and enhanced CD8+ T cell cytotoxicity. Notably, combination therapy with PD-L1 blockade demonstrated synergistic efficacy. Collectively, our findings reveal a stromal-immune checkpoint axis orchestrated by CD54⁺ iCAFs and ITGAL⁺ macrophages that underpins immunosuppression in CC, thereby providing a translational rationale for stroma-directed combination therapies that may overcome resistance to current immunotherapies.","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":"11 1","pages":"262"},"PeriodicalIF":37.3,"publicationDate":"2025-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145338656","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":"Tumor-associated macrophages: untapped molecular targets to improve T cell-based immunotherapy","authors":"Rui M. L. Coelho, Reno Debets, Dora Hammerl","doi":"10.1186/s12943-025-02481-w","DOIUrl":"https://doi.org/10.1186/s12943-025-02481-w","url":null,"abstract":"T cell responses are generally curtailed by suppressive mechanisms within the tumor microenvironment (TME) that prevent T cell infiltration and function. Consequently, T cell-based therapies for solid tumors have yielded limited and often non-durable clinical responses. Tumors develop a hostile TME, where tumor-associated macrophages (TAMs) that initially support T cells are converted into immune suppressive TAMs that facilitate tumor evasion from T cell control. In fact, immune suppressive TAMs represent a dominant fraction of immune cells within the TME and their presence is associated with poor prognosis and resistance to immunotherapy. Often in close contact with effector T cells, TAMs directly suppress CD8+ T cells through mechanisms involving metabolic mediators, co-signaling receptors, their ligands and/or cytokines. Here, we revisit molecular interactions behind TAM-mediated suppression of T cell responses and address the potential targeting of such molecules and pathways to re-boost anti-tumor T cell immunity. This perspective, focusing on molecular interactions between TAM and T cells, may aid the improvement of T cell-based therapies for solid tumors.","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":"31 1","pages":""},"PeriodicalIF":37.3,"publicationDate":"2025-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145295602","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 metalloptosis in tumor therapy: from molecular mechanisms to application of metal nanoparticles","authors":"Jinxiang Wang, Qin Tian, Yuchen Liu, Chao-Yun Cai, Shuying Fu, Jia Li, Yupeng Guan, Xuankai Liao, Danting Su, Tuanwei Sun, Yong Zhang, Rubing Lin, Yuzhi Xu, Jun Pang, Leli Zeng, Yihang Pan","doi":"10.1186/s12943-025-02414-7","DOIUrl":"https://doi.org/10.1186/s12943-025-02414-7","url":null,"abstract":"Metal ions-based regulated cell death (RCD), a form of cell death involving metal ions and controlled by one or more cascade signaling pathways, has recently been termed “metalloptosis”. Given the rapid advances in understanding metalloptosis in malignant progression and nanotherapeutics, this review elucidates the latest progress in metalloptosis, focusing on the roles of various metal ions and the targeting of metalloptosis in cancer therapy and nanomedicine. We briefly describe the essential discoveries of RCD and comprehensively summarize the current major regulatory signaling pathways of emerging metalloptosis forms, including ferroptosis, cuproptosis, lysozincrosis, manganism, calcicoptosis, and necrosis by sodium overload (NECSO). Additionally, we demonstrated the effects of metalloptosis on malignant neoplastic progression and the tumor microenvironment (TME). Furthermore, we discuss the feasibility of targeting metalloptosis pathways using metal nanoparticles (MNPs) for cancer therapy and overcoming drug resistance in cancer cells. We hope that this review will provide both fundamental insights and translational outlooks for harnessing metalloptosis in precision oncology. ","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":"102 1","pages":""},"PeriodicalIF":37.3,"publicationDate":"2025-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145295604","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":"Exploring personalized prediction of clinical chemotherapy efficacy and revealing tumor heterogeneity using patient-derived 3D bioprinting gastric cancer models","authors":"Liwei Du, Zicheng Zheng, Kai Zhang, Hang Sun, Yuce Lu, Minghao Sun, Mingchang Pang, Shangze Jiang, Yixuan He, Shunda Du, Haitao Zhao, Yilei Mao, Weiming Kang, Penglei Ge, Huayu Yang","doi":"10.1186/s12943-025-02466-9","DOIUrl":"https://doi.org/10.1186/s12943-025-02466-9","url":null,"abstract":"The pronounced chemotherapeutic heterogeneity observed in gastric cancer (GC) poses significant challenges to personalized treatment strategies, with current approaches lacking reliable predictive modalities for chemotherapy efficacy and postoperative prognosis. While patient-derived organoid (PDO) and xenograft (PDX) models serve as established three-dimensional platforms, their prohibitive costs and inherent batch effect limit faithful replication of native tumor extracellular matrix (ECM) complexity. We utilized patient-derived GC tissues to construct individualized 3D bioprinting (3DP)-GC models. After screening bioinks for optimal mechanical properties and biocompatibility, we successfully and efficiently constructed 3DP-GC models of 33 patients, and performed histopathological and genomic analyses to determine that the 3DP-GC model effectively preserved the histological architecture, biomarker expression abundance and genetic mutation profiles of the parental tumors. Drug screening on the 3DP-GC models was conducted using clinical gastric cancer therapies. Retrospective analysis of patients’ post-neoadjuvant therapy and follow-up of those post-adjuvant therapies were performed to evaluate the model’s potential in predicting and selecting chemotherapeutic agents for gastric cancer patients. In this study, we successfully and efficiently constructed 3D in vitro models of 33 GC patients using 3D bioprinting technology, and performed histopathological and genomic validation to find that the 3DP-GC model well preserved the expression abundance and mutation profiles of markers in the parental tumors. A significant correlation was observed in drug sensitivity between the 3DP-GC platform and the actual clinical efficacy observed in patients. Our study establishes a robust and stable 3DP-GC model. Crucially, drug testing of 3DP-GC model can accurately predict the clinical chemotherapy of patients in a shorter time and at a lower cost, offering a promising tool for high-throughput drug screening and personalized treatment decision-making.","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":"119 1","pages":""},"PeriodicalIF":37.3,"publicationDate":"2025-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145283323","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":"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}