Pub Date : 2025-10-30DOI: 10.1186/s12943-025-02456-x
Zufa Sabeel, Zhao Yang
Breast cancer (BC) presents persistent therapeutic challenges due to tumor heterogeneity, therapy resistance, and immune dysfunction, further compounded by emerging evidence of microbiome involvement in disease progression. Pathogenic bacteria such as Fusobacterium nucleatum have been implicated in modulating immune evasion, remodeling the extracellular matrix, and influencing therapy outcomes. Conventional microbiome-modulating strategies (e.g., antibiotics, probiotics) suffer from non-specificity and potential dysbiosis. Nanomaterial (NM)-based microbiome modulation offers a transformative alternative by enabling: targeted elimination of tumor-associated pathogens (e.g., Gal/GalNAc-functionalized nanoparticles for F. nucleatum), bacterial membrane-coated nanoplatforms for precision antimicrobial delivery, and multifunctional nanosystems that modulate the tumor microenvironment (TME) while preserving beneficial microbiota. This review explores NM-based microbiome modulation across BC contexts, including localized drug delivery, immunomodulation, and microbial niche editing. Highlighted strategies include lipid-based antimicrobial nanoparticles (NP), metallic NPs enhancing therapy sensitivity, and Traditional Chinese Medicine (TCM)-inspired nanoformulations for microbiome balance. Synergies with chemotherapy, immunotherapy, and radiotherapy are evaluated, alongside preclinical findings demonstrating improved tumor control and microbiome resilience. Finally, challenges in clinical translation, including toxicity, immunogenicity, and scalability, are discussed, with future directions emphasizing smart nanosystems capable of microbiome-responsive, biomarker-guided, and immune-integrated interventions in BC therapy.
{"title":"Microbiome-targeted nanoplatforms and engineering approaches in breast cancer therapy","authors":"Zufa Sabeel, Zhao Yang","doi":"10.1186/s12943-025-02456-x","DOIUrl":"https://doi.org/10.1186/s12943-025-02456-x","url":null,"abstract":"Breast cancer (BC) presents persistent therapeutic challenges due to tumor heterogeneity, therapy resistance, and immune dysfunction, further compounded by emerging evidence of microbiome involvement in disease progression. Pathogenic bacteria such as Fusobacterium nucleatum have been implicated in modulating immune evasion, remodeling the extracellular matrix, and influencing therapy outcomes. Conventional microbiome-modulating strategies (e.g., antibiotics, probiotics) suffer from non-specificity and potential dysbiosis. Nanomaterial (NM)-based microbiome modulation offers a transformative alternative by enabling: targeted elimination of tumor-associated pathogens (e.g., Gal/GalNAc-functionalized nanoparticles for F. nucleatum), bacterial membrane-coated nanoplatforms for precision antimicrobial delivery, and multifunctional nanosystems that modulate the tumor microenvironment (TME) while preserving beneficial microbiota. This review explores NM-based microbiome modulation across BC contexts, including localized drug delivery, immunomodulation, and microbial niche editing. Highlighted strategies include lipid-based antimicrobial nanoparticles (NP), metallic NPs enhancing therapy sensitivity, and Traditional Chinese Medicine (TCM)-inspired nanoformulations for microbiome balance. Synergies with chemotherapy, immunotherapy, and radiotherapy are evaluated, alongside preclinical findings demonstrating improved tumor control and microbiome resilience. Finally, challenges in clinical translation, including toxicity, immunogenicity, and scalability, are discussed, with future directions emphasizing smart nanosystems capable of microbiome-responsive, biomarker-guided, and immune-integrated interventions in BC therapy.","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":"108 1","pages":""},"PeriodicalIF":37.3,"publicationDate":"2025-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145397456","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}
Pub Date : 2025-10-30DOI: 10.1186/s12943-025-02495-4
Ainhoa Ruiz-Iglesias, Emma Guilbaud, Lorenzo Galluzzi, Santos Mañes
Type I interferon (IFN) has long been known as a critical component of the molecular machinery that first responds to viral infection in multicellular eukaryotes. More recently, type I IFN signaling has also emerged as a common process in the microenvironment of naturally developing neoplasms, as well as tumors responding to (immuno)therapy. In this setting, robust, acute but ultimately resolving type I IFN responses appear to support natural and therapy-driven cancer immunosurveillance by a number of mechanisms, including an accrued propensity of malignant cells to arrest their proliferation and undergo apoptotic cell death, as well as broad immunostimulatory effects on CD8+ cytotoxic T lymphocytes (CTLs), natural killer (NK) cells, dendritic cells (DCs) and tumor-associated macrophages (TAMs). Conversely, weak, indolent and ultimately non-resolving type I IFN responses de facto facilitate tumor progression, not only by promoting stemness in malignant cells (which is associated with increased metastatic dissemination and resistance to therapy), but also by favoring the establishment of a highly immunosuppressive lymphoid and myeloid tumor microenvironment. Here, we provide a critical discussion of the context-dependent impact of type I IFN signaling on cancer progression and response to treatment, focusing on the tumor-intrinsic and extrinsic factors that may account for such a heterogeneity.
{"title":"Context-dependent impact of type I interferon signaling in cancer","authors":"Ainhoa Ruiz-Iglesias, Emma Guilbaud, Lorenzo Galluzzi, Santos Mañes","doi":"10.1186/s12943-025-02495-4","DOIUrl":"https://doi.org/10.1186/s12943-025-02495-4","url":null,"abstract":"Type I interferon (IFN) has long been known as a critical component of the molecular machinery that first responds to viral infection in multicellular eukaryotes. More recently, type I IFN signaling has also emerged as a common process in the microenvironment of naturally developing neoplasms, as well as tumors responding to (immuno)therapy. In this setting, robust, acute but ultimately resolving type I IFN responses appear to support natural and therapy-driven cancer immunosurveillance by a number of mechanisms, including an accrued propensity of malignant cells to arrest their proliferation and undergo apoptotic cell death, as well as broad immunostimulatory effects on CD8+ cytotoxic T lymphocytes (CTLs), natural killer (NK) cells, dendritic cells (DCs) and tumor-associated macrophages (TAMs). Conversely, weak, indolent and ultimately non-resolving type I IFN responses de facto facilitate tumor progression, not only by promoting stemness in malignant cells (which is associated with increased metastatic dissemination and resistance to therapy), but also by favoring the establishment of a highly immunosuppressive lymphoid and myeloid tumor microenvironment. Here, we provide a critical discussion of the context-dependent impact of type I IFN signaling on cancer progression and response to treatment, focusing on the tumor-intrinsic and extrinsic factors that may account for such a heterogeneity.","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":"54 1","pages":""},"PeriodicalIF":37.3,"publicationDate":"2025-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145397320","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}
The design and application of microfluidic immune system-on-a-chip (ISOC) technology have played a critical role in cancer immunology and drug discovery over the past decades. The system provides a highly controlled and physiologically relevant platform for studying immune responses and therapeutic interventions. Emerging trends in 3D bioprinting, organoid fusion, and multi-organ systems-on-a-chip further expand the capabilities of ISOC by enabling systemic immune interactions and modeling of the tumor microenvironment. Despite these advances, scalability, standardization, and long-term immune cell viability remain significant challenges that must be addressed to fully harness the potential of ISOC in clinical applications. Overall, ISOC represents a transformative tool in cancer research, offering innovative solutions for immunotherapy trials, biomarker discovery, and precision medicine. Therefore, in this study, the role of ISOC in cancer immunotherapy was investigated, focusing on its ability to recapitulate primary and secondary immune functions, model immune-tumor interactions, and enhance screening and optimization of immune-based therapies. Device design and modeling strategies were also discussed, demonstrating how ISOC platforms simulate dynamic immune cell activity, cytokine signaling, and antigen presentation to improve drug efficacy assessments. The application of ISOC technology in drug discovery and its potential to accelerate clinical trials and develop personalized immunotherapy were further explored.
{"title":"Advances in engineering immune-tumor microenvironments on-a-chip: integrative microfluidic platforms for immunotherapy and drug discovery.","authors":"Farnaz Dabbagh Moghaddam,Ali Anvar,Ehsan Ilkhani,Delara Dadgar,Maedeh Rafiee,Najmeh Ranjbaran,Pejman Mortazavi,Seyed Majid Ghoreishian,Yun Suk Huh,Pooyan Makvandi","doi":"10.1186/s12943-025-02479-4","DOIUrl":"https://doi.org/10.1186/s12943-025-02479-4","url":null,"abstract":"The design and application of microfluidic immune system-on-a-chip (ISOC) technology have played a critical role in cancer immunology and drug discovery over the past decades. The system provides a highly controlled and physiologically relevant platform for studying immune responses and therapeutic interventions. Emerging trends in 3D bioprinting, organoid fusion, and multi-organ systems-on-a-chip further expand the capabilities of ISOC by enabling systemic immune interactions and modeling of the tumor microenvironment. Despite these advances, scalability, standardization, and long-term immune cell viability remain significant challenges that must be addressed to fully harness the potential of ISOC in clinical applications. Overall, ISOC represents a transformative tool in cancer research, offering innovative solutions for immunotherapy trials, biomarker discovery, and precision medicine. Therefore, in this study, the role of ISOC in cancer immunotherapy was investigated, focusing on its ability to recapitulate primary and secondary immune functions, model immune-tumor interactions, and enhance screening and optimization of immune-based therapies. Device design and modeling strategies were also discussed, demonstrating how ISOC platforms simulate dynamic immune cell activity, cytokine signaling, and antigen presentation to improve drug efficacy assessments. The application of ISOC technology in drug discovery and its potential to accelerate clinical trials and develop personalized immunotherapy were further explored.","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":"51 1","pages":"271"},"PeriodicalIF":37.3,"publicationDate":"2025-10-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145381074","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}
BACKGROUNDDespite an initial favorable response of EGFR-mutant non-small cell lung cancer (NSCLC) to osimertinib, an EGFR tyrosine kinase inhibitor (TKI), resistance to this drug inevitably develops. Whereas genetic mechanisms for such acquired resistance have been identified, the molecular mediators of resistance induction have remained unclear.METHODSTo identify factors that mediate induction of osimertinib resistance, we studied clinical samples from individuals with EGFR-mutant NSCLC as well as cell lines including PC-9 and H1975. Methods adopted included transcriptomics analysis and immunohistochemistry of pretreatment NSCLC specimens, spatial transcriptomics analysis, a cell viability assay, immunofluorescence and quantitative PCR analysis, RNA sequencing, immunoblot analysis, comprehensive proteomics analysis by mass spectrometry, co-immunoprecipitation and proximity ligation assays, and a mouse xenograft tumor model.RESULTSTranscriptomics analysis of pretreatment clinical specimens identified IFITM3 (interferon-induced transmembrane protein 3) as a gene specifically upregulated in patients with a poor response to osimertinib treatment. Immunohistochemistry confirmed that patients with IFITM3-positive tumors experienced a shorter progression-free survival on osimertinib treatment. Spatial transcriptomics and other analyses further revealed that IFITM3 expression in tumor cells was increased in response to cytokines derived from the tumor microenvironment (TME) during osimertinib treatment. IFITM3 was found to promote the development of osimertinib resistance in NSCLC cell lines through interaction with MET and activation of the AKT signaling pathway. Furthermore, combined treatment with a MET inhibitor suppressed the development of osimertinib resistance in a mouse xenograft tumor model.CONCLUSIONSOur findings reveal that upregulation of IFITM3 driven by TME cytokines represents a previously unrecognized mechanism of osimertinib resistance, and they suggest that targeting of the IFITM3-MET axis may improve EGFR-TKI treatment outcome for EGFR-mutant NSCLC.
{"title":"IFITM3-MET interaction drives osimertinib resistance through AKT pathway activation in EGFR-mutant non-small cell lung cancer.","authors":"Ritsu Ibusuki,Eiji Iwama,Atsushi Shimauchi,Hiromu Kawano,Shun Mizusaki,Satoshi Nakamura,Yui Miyazaki,Yu Inutsuka,Mikiko Hashisako,Taishi Harada,Yuko Tsuchiya-Kawano,Hirono Tsutsumi,Takayuki Nakanishi,Noriaki Nakagaki,Yuichiro Koga,Shinichi Kimura,Shun Mashimoto,Daisuke Shibahara,Kohei Otsubo,Yasuto Yoneshima,Kentaro Tanaka,Yoshinao Oda,Isamu Okamoto","doi":"10.1186/s12943-025-02493-6","DOIUrl":"https://doi.org/10.1186/s12943-025-02493-6","url":null,"abstract":"BACKGROUNDDespite an initial favorable response of EGFR-mutant non-small cell lung cancer (NSCLC) to osimertinib, an EGFR tyrosine kinase inhibitor (TKI), resistance to this drug inevitably develops. Whereas genetic mechanisms for such acquired resistance have been identified, the molecular mediators of resistance induction have remained unclear.METHODSTo identify factors that mediate induction of osimertinib resistance, we studied clinical samples from individuals with EGFR-mutant NSCLC as well as cell lines including PC-9 and H1975. Methods adopted included transcriptomics analysis and immunohistochemistry of pretreatment NSCLC specimens, spatial transcriptomics analysis, a cell viability assay, immunofluorescence and quantitative PCR analysis, RNA sequencing, immunoblot analysis, comprehensive proteomics analysis by mass spectrometry, co-immunoprecipitation and proximity ligation assays, and a mouse xenograft tumor model.RESULTSTranscriptomics analysis of pretreatment clinical specimens identified IFITM3 (interferon-induced transmembrane protein 3) as a gene specifically upregulated in patients with a poor response to osimertinib treatment. Immunohistochemistry confirmed that patients with IFITM3-positive tumors experienced a shorter progression-free survival on osimertinib treatment. Spatial transcriptomics and other analyses further revealed that IFITM3 expression in tumor cells was increased in response to cytokines derived from the tumor microenvironment (TME) during osimertinib treatment. IFITM3 was found to promote the development of osimertinib resistance in NSCLC cell lines through interaction with MET and activation of the AKT signaling pathway. Furthermore, combined treatment with a MET inhibitor suppressed the development of osimertinib resistance in a mouse xenograft tumor model.CONCLUSIONSOur findings reveal that upregulation of IFITM3 driven by TME cytokines represents a previously unrecognized mechanism of osimertinib resistance, and they suggest that targeting of the IFITM3-MET axis may improve EGFR-TKI treatment outcome for EGFR-mutant NSCLC.","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":"21 1","pages":"272"},"PeriodicalIF":37.3,"publicationDate":"2025-10-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145381075","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}
Pub Date : 2025-10-27DOI: 10.1186/s12943-025-02444-1
András Füredi,Szilárd Tóth,Kristóf Hegedüs,Pál T Szabó,Anikó Gaál,Gergő Barta,Lívia N Naszályi,Krisztina Kiss,Kata Bölcskei,Zoltán Szeltner,Eszter Bajtai,Balázs Gombos,Dániel Kiss,Mihály T Cserepes,Attila Kiss,Peter Pokreisz,Lukas Kenner,Sandra Högler,Csaba Magyar,Jamie D Cowles,Agnes Csiszar,József Tóvári,Dávid Szüts,Zsuzsanna Helyes,Zoltán Varga,Gábor Mező,Gergely Szakács
BACKGROUNDChemotherapy remains the cornerstone of cancer treatment despite its well-documented challenges, including toxic side effects and drug resistance. Here, we demonstrate that a novel, highly toxic, daunosamine-modified derivative of daunorubicin (2-pyrrolino-daunorubicin, PyDau) can be safely administered to mice when encapsulated in liposome.METHODSPyDau was synthesized from daunorubicin in a one-step reaction. Its increased in vitro cytotoxicity was confirmed across 42 human cell lines representing 12 cancer types, including multidrug resistant cells. The activity profile of this new derivative was analyzed in the context of 13 commonly used cancer drugs across a panel of lymphoblast cell lines missing individual components of DNA-repair enzymes. To enable in vivo application, PyDau was encapsulated in pegylated liposome, resulting in liposomal PyDau (LiPyDau). In vivo efficacy of LiPyDau was evaluated in three allograft models (melanoma, breast, lung), a xenograft model (uterine sarcoma), a patient-derived xenograft model (lung), and a genetically engineered mouse model of mammary cancer, including two models of drug resistance.RESULTSWhile PyDau exhibited up to 1000-fold greater cytotoxicity than daunomycin and doxorubicin against cancer cell lines, its in vivo application was hindered by an extremely narrow therapeutic window. Liposomal nanoformulation mitigated the limiting toxicity, allowing LiPyDau to be tested in preclinical allograft and xenograft mouse models. LiPyDau demonstrated robust efficacy across all models including multidrug-resistant cancer, completely eradicating tumors in a genetically engineered mouse model of triple-negative breast cancer. LiPyDau exerts its anticancer effect through a unique mechanism involving the crosslinking of complementary DNA strands, resulting in irreversible DNA damage.CONCLUSIONLiposomal formulations of extremely cytotoxic anthracycline analogs, such as LiPyDau, represent a promising and highly effective therapeutic approach for combating drug resistant cancer.
{"title":"Safe delivery of a highly toxic anthracycline derivative through liposomal nanoformulation achieves complete cancer regression.","authors":"András Füredi,Szilárd Tóth,Kristóf Hegedüs,Pál T Szabó,Anikó Gaál,Gergő Barta,Lívia N Naszályi,Krisztina Kiss,Kata Bölcskei,Zoltán Szeltner,Eszter Bajtai,Balázs Gombos,Dániel Kiss,Mihály T Cserepes,Attila Kiss,Peter Pokreisz,Lukas Kenner,Sandra Högler,Csaba Magyar,Jamie D Cowles,Agnes Csiszar,József Tóvári,Dávid Szüts,Zsuzsanna Helyes,Zoltán Varga,Gábor Mező,Gergely Szakács","doi":"10.1186/s12943-025-02444-1","DOIUrl":"https://doi.org/10.1186/s12943-025-02444-1","url":null,"abstract":"BACKGROUNDChemotherapy remains the cornerstone of cancer treatment despite its well-documented challenges, including toxic side effects and drug resistance. Here, we demonstrate that a novel, highly toxic, daunosamine-modified derivative of daunorubicin (2-pyrrolino-daunorubicin, PyDau) can be safely administered to mice when encapsulated in liposome.METHODSPyDau was synthesized from daunorubicin in a one-step reaction. Its increased in vitro cytotoxicity was confirmed across 42 human cell lines representing 12 cancer types, including multidrug resistant cells. The activity profile of this new derivative was analyzed in the context of 13 commonly used cancer drugs across a panel of lymphoblast cell lines missing individual components of DNA-repair enzymes. To enable in vivo application, PyDau was encapsulated in pegylated liposome, resulting in liposomal PyDau (LiPyDau). In vivo efficacy of LiPyDau was evaluated in three allograft models (melanoma, breast, lung), a xenograft model (uterine sarcoma), a patient-derived xenograft model (lung), and a genetically engineered mouse model of mammary cancer, including two models of drug resistance.RESULTSWhile PyDau exhibited up to 1000-fold greater cytotoxicity than daunomycin and doxorubicin against cancer cell lines, its in vivo application was hindered by an extremely narrow therapeutic window. Liposomal nanoformulation mitigated the limiting toxicity, allowing LiPyDau to be tested in preclinical allograft and xenograft mouse models. LiPyDau demonstrated robust efficacy across all models including multidrug-resistant cancer, completely eradicating tumors in a genetically engineered mouse model of triple-negative breast cancer. LiPyDau exerts its anticancer effect through a unique mechanism involving the crosslinking of complementary DNA strands, resulting in irreversible DNA damage.CONCLUSIONLiposomal formulations of extremely cytotoxic anthracycline analogs, such as LiPyDau, represent a promising and highly effective therapeutic approach for combating drug resistant cancer.","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":"57 1","pages":"269"},"PeriodicalIF":37.3,"publicationDate":"2025-10-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145374017","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}
Pub Date : 2025-10-23DOI: 10.1186/s12943-025-02469-6
Jiri Navratil,Martina Raudenska,Monika Kratochvilova,Jan Balvan,Yoav David Shaul,Michal Masarik
{"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}
Pub Date : 2025-10-23DOI: 10.1186/s12943-025-02484-7
Gege Li,Jiashuai Xu,Xiaohan Tian,Jingyi Xiao,Junqi Long,Yining Chen,Wenzhi Shen,Shuangtao Zhao
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.
{"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}
Pub Date : 2025-10-22DOI: 10.1186/s12943-025-02455-y
F Lo Schiavo,C Salvesi,M Jandoubi,F Pirini,J Garbetta,G Martinelli,G Simonetti,A Ferrari
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.
{"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}
Pub Date : 2025-10-21DOI: 10.1186/s12943-025-02430-7
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
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.
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