Ferroptosis is a non-apoptotic form of regulated cell death driven by iron dependent lipid peroxidation. It sits at the intersection of several hallmarks of metastatic cancer, including metabolic rewiring, membrane remodeling, epithelial mesenchymal plasticity, immune editing, and adaptation to distant niches. In this review, we integrate biochemical mechanisms with single cell, spatial, and in vivo data to map how ferroptotic pressure changes as tumor cells invade, travel through vessels, extravasate, enter dormancy, and re-awaken to form overt metastases. We highlight that these dynamics are strongly shaped by organ context. Lymph and adipose rich environments buffer lipid peroxidation and favor survival. In contrast, blood circulation increases oxidative load, and brain and liver niches impose distinct constraints on redox balance, iron handling, and lipid repair. We then examine how ferroptosis interfaces with the immune system. Ferroptotic stress can increase tumor antigenicity and danger signaling and thereby promote antitumor responses. The same stress, however, can reprogram monocytes, macrophages, and neutrophils, drive neutrophil extracellular trap formation, and support lipid exchange that weakens effector T cell function. This dual behavior helps explain why ferroptosis can restrict dissemination in some settings yet fuel pro-metastatic inflammation in others. On this mechanistic background, we evaluate therapeutic strategies that aim to exploit ferroptosis related vulnerabilities. These include inhibition of cystine supply or lipid repair pathways, radiosensitization regimens that increase lipid peroxidation, diet drug combinations that rewire sulfur and lipid metabolism, and nanoplatforms that co-deliver ferroptosis triggers with photo or sonodynamic therapies. Clinically, ferroptosis programs are increasingly linked to metastatic organotropism, responses to radiotherapy and immunotherapy, and patient survival, and they are beginning to guide biomarker development and early translational trials. We also discuss practical barriers, such as niche specific resistance circuits, constraints imposed by drug delivery and toxicity, and the scarcity of robust patient level ferroptosis readouts. Methodological advances - including compartment resolved reporters, spatial lipidomics, and circulating signatures of lipid damage - may help address these gaps. Overall, viewing metastasis through the ferroptosis lens reveals actionable vulnerabilities and supports rational radio immunometabolic combinations aimed at durable control of metastatic disease.
{"title":"Ferroptosis and metastasis: molecular checkpoints, microenvironmental dynamics, and therapeutic opportunities.","authors":"Feng Guo,Shi Zong,Xin Zhang,Zhaozhou Ren,Hua Shao,Jingwu Li,Xiaobo Wang,Yu Li,Xiaofeng Wang,Kuanbing Chen","doi":"10.1186/s12943-025-02544-y","DOIUrl":"https://doi.org/10.1186/s12943-025-02544-y","url":null,"abstract":"Ferroptosis is a non-apoptotic form of regulated cell death driven by iron dependent lipid peroxidation. It sits at the intersection of several hallmarks of metastatic cancer, including metabolic rewiring, membrane remodeling, epithelial mesenchymal plasticity, immune editing, and adaptation to distant niches. In this review, we integrate biochemical mechanisms with single cell, spatial, and in vivo data to map how ferroptotic pressure changes as tumor cells invade, travel through vessels, extravasate, enter dormancy, and re-awaken to form overt metastases. We highlight that these dynamics are strongly shaped by organ context. Lymph and adipose rich environments buffer lipid peroxidation and favor survival. In contrast, blood circulation increases oxidative load, and brain and liver niches impose distinct constraints on redox balance, iron handling, and lipid repair. We then examine how ferroptosis interfaces with the immune system. Ferroptotic stress can increase tumor antigenicity and danger signaling and thereby promote antitumor responses. The same stress, however, can reprogram monocytes, macrophages, and neutrophils, drive neutrophil extracellular trap formation, and support lipid exchange that weakens effector T cell function. This dual behavior helps explain why ferroptosis can restrict dissemination in some settings yet fuel pro-metastatic inflammation in others. On this mechanistic background, we evaluate therapeutic strategies that aim to exploit ferroptosis related vulnerabilities. These include inhibition of cystine supply or lipid repair pathways, radiosensitization regimens that increase lipid peroxidation, diet drug combinations that rewire sulfur and lipid metabolism, and nanoplatforms that co-deliver ferroptosis triggers with photo or sonodynamic therapies. Clinically, ferroptosis programs are increasingly linked to metastatic organotropism, responses to radiotherapy and immunotherapy, and patient survival, and they are beginning to guide biomarker development and early translational trials. We also discuss practical barriers, such as niche specific resistance circuits, constraints imposed by drug delivery and toxicity, and the scarcity of robust patient level ferroptosis readouts. Methodological advances - including compartment resolved reporters, spatial lipidomics, and circulating signatures of lipid damage - may help address these gaps. Overall, viewing metastasis through the ferroptosis lens reveals actionable vulnerabilities and supports rational radio immunometabolic combinations aimed at durable control of metastatic disease.","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":"8 1","pages":""},"PeriodicalIF":37.3,"publicationDate":"2026-01-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145968348","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}
Pancreatic cancer exhibits a heightened level of autophagy, which supports the survival of cancer cells within the malignant microenvironment. The THUMP domain-containing protein 3 (THUMPD3)/ tRNA Methyltransferase Activator Subunit 11-2 (TRMT112) complex has been identified as a tRNA m2G methyltransferase in mammalian cells, and its functional role remains largely unexplored in pancreatic cancer. In this study, we demonstrate that both THUMPD3 and TRMT112 are upregulated in pancreatic cancer and significantly correlate with poor prognosis for patients. Knockdown of THUMPD3/TRMT112 inhibited pancreatic cancer cell growth in vitro and in vivo. Additionally, THUMPD3/TRMT112 knockdown significantly reduced autophagic flux, suggesting a role for THUMPD3/TRMT112-mediated tRNA m2G modification in promoting pancreatic cancer cell proliferation and maintaining autophagy. Mechanistically, THUMPD3/TRMT112 deficiency suppressed TFEB translation via impaired m2G modification of tRNALeu(CAG), thereby inhibiting pancreatic cancer cell growth and autophagy. In summary, this study has unveiled the crucial role of the THUMPD3/TRMT112 m2G tRNA methyltransferase complex in maintaining pancreatic cancer cell growth and autophagy, presenting a promising target for future precision medicine interventions.
{"title":"tRNA m2G methyltransferase complex THUMPD3-TRMT112 promotes pancreatic cancer progression and autophagy via modulating TFEB translation.","authors":"Wenbin Yuan,Shi Li,Yue Xi,Rui Tian,Yuan Liu,Xingyu Chen,Rui Zhang,Hao Lyu,Shuai Xiao,Dong Guo,Qi Zhang,Wenying Qin,Chaojun Yan,Xing-Zhen Chen,Cefan Zhou,Jingfeng Tang","doi":"10.1186/s12943-025-02540-2","DOIUrl":"https://doi.org/10.1186/s12943-025-02540-2","url":null,"abstract":"Pancreatic cancer exhibits a heightened level of autophagy, which supports the survival of cancer cells within the malignant microenvironment. The THUMP domain-containing protein 3 (THUMPD3)/ tRNA Methyltransferase Activator Subunit 11-2 (TRMT112) complex has been identified as a tRNA m2G methyltransferase in mammalian cells, and its functional role remains largely unexplored in pancreatic cancer. In this study, we demonstrate that both THUMPD3 and TRMT112 are upregulated in pancreatic cancer and significantly correlate with poor prognosis for patients. Knockdown of THUMPD3/TRMT112 inhibited pancreatic cancer cell growth in vitro and in vivo. Additionally, THUMPD3/TRMT112 knockdown significantly reduced autophagic flux, suggesting a role for THUMPD3/TRMT112-mediated tRNA m2G modification in promoting pancreatic cancer cell proliferation and maintaining autophagy. Mechanistically, THUMPD3/TRMT112 deficiency suppressed TFEB translation via impaired m2G modification of tRNALeu(CAG), thereby inhibiting pancreatic cancer cell growth and autophagy. In summary, this study has unveiled the crucial role of the THUMPD3/TRMT112 m2G tRNA methyltransferase complex in maintaining pancreatic cancer cell growth and autophagy, presenting a promising target for future precision medicine interventions.","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":"30 1","pages":""},"PeriodicalIF":37.3,"publicationDate":"2026-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145961325","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 : 2026-01-13DOI: 10.1186/s12943-025-02566-6
Di Yan,Ying Yu,Chengtong Liang,Zixing Cui,Lei Shi,Guiling Li,Chuanli Ren
Emerging evidence reveals that intratumoral microbial (ITM) communities within the tumor immune microenvironment (TIME) critically influence tumor progression and immunotherapy response. Studies have shown that resident bacteria within tumors, such as Sphingobacterium multivorum, regulate the secretion of chemokines like CCL20 and CXCL8, promoting the infiltration of regulatory T cells (Tregs) and inhibiting the function of cytotoxic T cells (CD8+ T cells)-thereby weakening the efficacy of immune checkpoint inhibitors. Additionally, microbial metabolites may serve as potential biomarkers for predicting sensitivity to immunotherapy. Concurrently, engineered bacteria (e.g., oncolytic mineralizing bacteria) demonstrate significant antitumor effects by activating innate immunity and enhancing antitumor-specific immune responses, providing new strategies to overcome immunotherapy resistance. These findings highlight the dual role of ITM in tumor immune evasion and immunotherapy sensitivity, laying an important theoretical foundation for developing novel immunotherapy strategies targeting tumoral microbiota metabolism.
{"title":"Intratumoral microbiome: the double-edged sword in remodeling cancer immunotherapy.","authors":"Di Yan,Ying Yu,Chengtong Liang,Zixing Cui,Lei Shi,Guiling Li,Chuanli Ren","doi":"10.1186/s12943-025-02566-6","DOIUrl":"https://doi.org/10.1186/s12943-025-02566-6","url":null,"abstract":"Emerging evidence reveals that intratumoral microbial (ITM) communities within the tumor immune microenvironment (TIME) critically influence tumor progression and immunotherapy response. Studies have shown that resident bacteria within tumors, such as Sphingobacterium multivorum, regulate the secretion of chemokines like CCL20 and CXCL8, promoting the infiltration of regulatory T cells (Tregs) and inhibiting the function of cytotoxic T cells (CD8+ T cells)-thereby weakening the efficacy of immune checkpoint inhibitors. Additionally, microbial metabolites may serve as potential biomarkers for predicting sensitivity to immunotherapy. Concurrently, engineered bacteria (e.g., oncolytic mineralizing bacteria) demonstrate significant antitumor effects by activating innate immunity and enhancing antitumor-specific immune responses, providing new strategies to overcome immunotherapy resistance. These findings highlight the dual role of ITM in tumor immune evasion and immunotherapy sensitivity, laying an important theoretical foundation for developing novel immunotherapy strategies targeting tumoral microbiota metabolism.","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":"4 1","pages":""},"PeriodicalIF":37.3,"publicationDate":"2026-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145961327","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}
BACKGROUNDTaxane-based chemotherapy is a main treatment modality for ovarian cancer and other solid tumors, but chemoresistance limits the clinical efficacy. Studies have shown tumor interaction with macrophages in the tumor microenvironment (TME) plays a significant role in taxane resistance, yet the underlying molecular mechanisms are poorly understood.METHODSIn this study, we employed translatome profiling of paclitaxel-treated cancer cells, live-cell imaging analysis, gene knockdown/knockout, and in vitro cancer-macrophage coculture assays to unravel a novel chemoresistance mechanism mediated by tumor-macrophage interaction via the NOTCH2-JAG1 axis. The in vitro data were further validated by multiple xenograft, syngeneic and patient-derived xenograft mouse tumor models of ovarian cancer as well as ovarian cancer patient samples.RESULTSWe found paclitaxel selectively induced translational upregulation of NOTCH2 via cytoplasmic polyadenylation, and this NOTCH2 upregulation persisted after mitotic exit. Subsequent NOTCH2 activation by JAG1 expressed mainly on the neighboring macrophages promoted tumor cell survival and simulated cytokine release, such as CSF1 and IL-1β, that recruited JAG1-expressing macrophages, thus forming a positive feedback loop that further enhanced the pro-tumor NOTCH2 activity. Genetic depletion or pharmacological inhibition of NOTCH2 with the γ-secretase inhibitor attenuated macrophage infiltration and sensitized tumor response to paclitaxel in multiple preclinical models of ovarian cancer. Moreover, single-cell RNA sequencing analysis identified a JAG1-high macrophage subset that was enriched by paclitaxel treatment and attenuated by NOTCH inhibition. Clinically, high NOTCH2 expression in ovarian tumors was associated with recurrence and shorter progression-free survival of ovarian cancer patients.CONCLUSIONSPaclitaxel-induced translational upregulation of NOTCH2 enables immediate juxtacrine activation by JAG1-positive macrophages, coupling tumor cell survival with immune remodeling in the tumor microenvironment to drive chemoresistance. Our results suggest NOTCH2 is a viable biomarker for paclitaxel resistance and that combining NOTCH2 inhibitor with taxane is an effective therapeutic strategy to selectively disrupt tumor-macrophage interaction and overcome macrophage-mediated taxane resistance in NOTCH2-positive tumors.
{"title":"Tumor-associated macrophages promote chemoresistance to Paclitaxel via activating NOTCH2-JAG1 juxtacrine signaling.","authors":"Fazhi Yu,Qin Zhou,Weiqiang Yu,Tong Zhou,Cheng Cao,Yijia Xie,Peng Zhang,Hanyuan Liu,Wei He,Aoxing Cheng,Xiaopeng Ma,Qingfa Wu,Qi Zhao,Jing Guo,Kaiguang Zhang,Ying Zhou,Jue Shi,Zhenye Yang","doi":"10.1186/s12943-025-02546-w","DOIUrl":"https://doi.org/10.1186/s12943-025-02546-w","url":null,"abstract":"BACKGROUNDTaxane-based chemotherapy is a main treatment modality for ovarian cancer and other solid tumors, but chemoresistance limits the clinical efficacy. Studies have shown tumor interaction with macrophages in the tumor microenvironment (TME) plays a significant role in taxane resistance, yet the underlying molecular mechanisms are poorly understood.METHODSIn this study, we employed translatome profiling of paclitaxel-treated cancer cells, live-cell imaging analysis, gene knockdown/knockout, and in vitro cancer-macrophage coculture assays to unravel a novel chemoresistance mechanism mediated by tumor-macrophage interaction via the NOTCH2-JAG1 axis. The in vitro data were further validated by multiple xenograft, syngeneic and patient-derived xenograft mouse tumor models of ovarian cancer as well as ovarian cancer patient samples.RESULTSWe found paclitaxel selectively induced translational upregulation of NOTCH2 via cytoplasmic polyadenylation, and this NOTCH2 upregulation persisted after mitotic exit. Subsequent NOTCH2 activation by JAG1 expressed mainly on the neighboring macrophages promoted tumor cell survival and simulated cytokine release, such as CSF1 and IL-1β, that recruited JAG1-expressing macrophages, thus forming a positive feedback loop that further enhanced the pro-tumor NOTCH2 activity. Genetic depletion or pharmacological inhibition of NOTCH2 with the γ-secretase inhibitor attenuated macrophage infiltration and sensitized tumor response to paclitaxel in multiple preclinical models of ovarian cancer. Moreover, single-cell RNA sequencing analysis identified a JAG1-high macrophage subset that was enriched by paclitaxel treatment and attenuated by NOTCH inhibition. Clinically, high NOTCH2 expression in ovarian tumors was associated with recurrence and shorter progression-free survival of ovarian cancer patients.CONCLUSIONSPaclitaxel-induced translational upregulation of NOTCH2 enables immediate juxtacrine activation by JAG1-positive macrophages, coupling tumor cell survival with immune remodeling in the tumor microenvironment to drive chemoresistance. Our results suggest NOTCH2 is a viable biomarker for paclitaxel resistance and that combining NOTCH2 inhibitor with taxane is an effective therapeutic strategy to selectively disrupt tumor-macrophage interaction and overcome macrophage-mediated taxane resistance in NOTCH2-positive tumors.","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":"46 1","pages":""},"PeriodicalIF":37.3,"publicationDate":"2026-01-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145947418","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 : 2026-01-10DOI: 10.1186/s12943-025-02547-9
Olivier Castellanet,Jean Monatte,Nathan Corvaisier,Abdessamad El Kaoutari,Muge Kaya,Lorène Ferreira,Stephane Audebert,Luc Camoin,Alexandre de Nonneville,Anthony Gonçalves,Jean-Paul Borg,Paula Michea,Flavio Maina,Fabienne Lamballe
BACKGROUNDTriple-negative breast cancer (TNBC) is a highly aggressive and heterogeneous breast cancer subtype with limited treatment options. Predicting patient response to chemo-immunotherapy remains challenging, highlighting the need for robust stratification strategies.METHODSWe performed a multi-parametric analysis combining histological, genomic, transcriptomic, proteomic, and immune profiling in the immunocompetent MMTV-R26Met TNBC mouse model and compared outcomes with patient data from human TNBC cohorts and TNBC tumor microarray. To enable therapeutic testing and functional validation, we established syngeneic grafts from primary tumors and used them to evaluate combined chemotherapy (epirubicin) and anti-PD-1 immunotherapy.RESULTSMulti-parametric analysis of TNBC heterogeneity modeled by the MMTV-R26Met mice identified four distinct TNBC clusters, defined by unique intrinsic (molecular/genomic) and extrinsic (immune) features, which closely parallel patient subtypes, including rare metaplastic forms, and correlate with clinical outcomes. Both intrinsic and immune hallmarks of primary tumors were conserved across serial syngeneic transplantations, confirming the translational value of this preclinical platform. Treatment assessments indicated cluster-specific therapeutic vulnerabilities associated with molecular and immune traits. Specifically, whereas chemo-immunotherapy is beneficial to neutrophil-enriched tumors, immunotherapy alone appears to be more effective in macrophage-enriched tumors. Our findings indicate that TNBC treatment response is shaped by the interplay between tumor-intrinsic and immune features.CONCLUSIONOur study provides a robust preclinical platform for precision immuno-oncology, enabling stratification of TNBC patients for tailored onco-immunotherapies.
{"title":"Multi-omics profiling uncovers immune-molecular clusters with distinct chemo-immunotherapeutic vulnerabilities in a mouse model of triple-negative breast cancer.","authors":"Olivier Castellanet,Jean Monatte,Nathan Corvaisier,Abdessamad El Kaoutari,Muge Kaya,Lorène Ferreira,Stephane Audebert,Luc Camoin,Alexandre de Nonneville,Anthony Gonçalves,Jean-Paul Borg,Paula Michea,Flavio Maina,Fabienne Lamballe","doi":"10.1186/s12943-025-02547-9","DOIUrl":"https://doi.org/10.1186/s12943-025-02547-9","url":null,"abstract":"BACKGROUNDTriple-negative breast cancer (TNBC) is a highly aggressive and heterogeneous breast cancer subtype with limited treatment options. Predicting patient response to chemo-immunotherapy remains challenging, highlighting the need for robust stratification strategies.METHODSWe performed a multi-parametric analysis combining histological, genomic, transcriptomic, proteomic, and immune profiling in the immunocompetent MMTV-R26Met TNBC mouse model and compared outcomes with patient data from human TNBC cohorts and TNBC tumor microarray. To enable therapeutic testing and functional validation, we established syngeneic grafts from primary tumors and used them to evaluate combined chemotherapy (epirubicin) and anti-PD-1 immunotherapy.RESULTSMulti-parametric analysis of TNBC heterogeneity modeled by the MMTV-R26Met mice identified four distinct TNBC clusters, defined by unique intrinsic (molecular/genomic) and extrinsic (immune) features, which closely parallel patient subtypes, including rare metaplastic forms, and correlate with clinical outcomes. Both intrinsic and immune hallmarks of primary tumors were conserved across serial syngeneic transplantations, confirming the translational value of this preclinical platform. Treatment assessments indicated cluster-specific therapeutic vulnerabilities associated with molecular and immune traits. Specifically, whereas chemo-immunotherapy is beneficial to neutrophil-enriched tumors, immunotherapy alone appears to be more effective in macrophage-enriched tumors. Our findings indicate that TNBC treatment response is shaped by the interplay between tumor-intrinsic and immune features.CONCLUSIONOur study provides a robust preclinical platform for precision immuno-oncology, enabling stratification of TNBC patients for tailored onco-immunotherapies.","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":"81 1","pages":""},"PeriodicalIF":37.3,"publicationDate":"2026-01-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145947423","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}
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