Pub Date : 2026-01-27DOI: 10.1186/s12943-026-02578-w
Junxin Li,Yu Huang,Jiawei Li,Min Shi,Yi Xiao,Fei Du,Gongli Hu
Hepatocellular carcinoma (HCC), the most common form of primary liver cancer, is frequently diagnosed at advanced stages, limiting curative options. Multi-kinase inhibitors (MKIs), such as sorafenib and lenvatinib, serve as first-line therapies for unresectable HCC. However, the widespread development of drug resistance significantly diminishes the clinical efficacy of MKIs, and current treatments lack effective strategies to enhance MKI sensitivity. Metabolic reprogramming, a hallmark of cancer cells that facilitates unchecked growth and metastasis, has emerged as a critical mechanism driving MKI resistance in HCC. This review comprehensively examines the roles of glycolysis, lipid metabolism, and amino acid metabolism in promoting MKI resistance, with a focus on key molecular regulators that could serve as potential targets to reverse resistance. Additionally, this review synthesizes preclinical and clinical evidence of therapeutic agents that synergize with MKIs by modulating metabolic pathways, and discusses the regulatory role of metabolic reprogramming in the tumor immune microenvironment (TIME) of HCC, offering innovative strategies to improve treatment outcomes for patients with HCC. These findings highlight metabolic reprogramming as a crucial target for developing novel interventions aimed at overcoming MKI resistance in clinical practice.
{"title":"Metabolic reprogramming-driven resistance to multi-kinase inhibitors in hepatocellular carcinoma: molecular mechanisms and therapeutic opportunities.","authors":"Junxin Li,Yu Huang,Jiawei Li,Min Shi,Yi Xiao,Fei Du,Gongli Hu","doi":"10.1186/s12943-026-02578-w","DOIUrl":"https://doi.org/10.1186/s12943-026-02578-w","url":null,"abstract":"Hepatocellular carcinoma (HCC), the most common form of primary liver cancer, is frequently diagnosed at advanced stages, limiting curative options. Multi-kinase inhibitors (MKIs), such as sorafenib and lenvatinib, serve as first-line therapies for unresectable HCC. However, the widespread development of drug resistance significantly diminishes the clinical efficacy of MKIs, and current treatments lack effective strategies to enhance MKI sensitivity. Metabolic reprogramming, a hallmark of cancer cells that facilitates unchecked growth and metastasis, has emerged as a critical mechanism driving MKI resistance in HCC. This review comprehensively examines the roles of glycolysis, lipid metabolism, and amino acid metabolism in promoting MKI resistance, with a focus on key molecular regulators that could serve as potential targets to reverse resistance. Additionally, this review synthesizes preclinical and clinical evidence of therapeutic agents that synergize with MKIs by modulating metabolic pathways, and discusses the regulatory role of metabolic reprogramming in the tumor immune microenvironment (TIME) of HCC, offering innovative strategies to improve treatment outcomes for patients with HCC. These findings highlight metabolic reprogramming as a crucial target for developing novel interventions aimed at overcoming MKI resistance in clinical practice.","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":"229 1","pages":""},"PeriodicalIF":37.3,"publicationDate":"2026-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146056384","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}
Mitochondria are central to health and disease by precisely regulating metabolism and interacting closely with other organelles. Mitochondrial dysfunction contributes to the initiation and development of numerous diseases, including cancer. In cancer cells, metabolic reprogramming, impaired mitochondrial quality control, and mitochondrial DNA damage are linked to tumor initiation, development, and metastasis. Dysregulated mitochondrial function in cells within the tumor microenvironment, such as CD8 + T cells, also promotes cancer progression. Therapeutic approaches targeting mitochondria range from dietary interventions to small-molecule drugs aimed at restoring mitochondrial dysfunction. In this review, we summarize the relationships between mitochondrial dysfunction and cancer from the perspectives of metabolism, quality control, mitochondrial DNA stability, ion homeostasis, and the tumor microenvironment. We also provide updates on mitochondria-targeted therapies, highlighting key translational gaps from bench to bedside. Finally, we discuss future directions for mitochondria-targeted cancer therapy, emphasizing mitochondrial homeostasis as a critical target for improving therapeutic outcomes.
{"title":"Targeting mitochondrial homeostasis as a cancer treatment strategy: current status and future prospects.","authors":"Hongling Zhong,Renjie Pan,Yuzhen Ouyang,Tengfei Xiao,Wangning Gu,Hongmin Yang,Hui Wang,Hucheng Li,Tianfang Peng,Pan Chen","doi":"10.1186/s12943-026-02571-3","DOIUrl":"https://doi.org/10.1186/s12943-026-02571-3","url":null,"abstract":"Mitochondria are central to health and disease by precisely regulating metabolism and interacting closely with other organelles. Mitochondrial dysfunction contributes to the initiation and development of numerous diseases, including cancer. In cancer cells, metabolic reprogramming, impaired mitochondrial quality control, and mitochondrial DNA damage are linked to tumor initiation, development, and metastasis. Dysregulated mitochondrial function in cells within the tumor microenvironment, such as CD8 + T cells, also promotes cancer progression. Therapeutic approaches targeting mitochondria range from dietary interventions to small-molecule drugs aimed at restoring mitochondrial dysfunction. In this review, we summarize the relationships between mitochondrial dysfunction and cancer from the perspectives of metabolism, quality control, mitochondrial DNA stability, ion homeostasis, and the tumor microenvironment. We also provide updates on mitochondria-targeted therapies, highlighting key translational gaps from bench to bedside. Finally, we discuss future directions for mitochondria-targeted cancer therapy, emphasizing mitochondrial homeostasis as a critical target for improving therapeutic outcomes.","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":"64 1","pages":""},"PeriodicalIF":37.3,"publicationDate":"2026-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146056386","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":"Spatiotemporal dynamics of tumor-associated neutrophils: bridging the gap between cancer progression and immunotherapy.","authors":"Xiangyuan Chu,Junying Ma,Shihua Li,Meng Wang,Yu Tian,Chao Lv","doi":"10.1186/s12943-026-02570-4","DOIUrl":"https://doi.org/10.1186/s12943-026-02570-4","url":null,"abstract":"","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":"68 1","pages":""},"PeriodicalIF":37.3,"publicationDate":"2026-01-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146044566","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 : 2026-01-24DOI: 10.1186/s12943-026-02574-0
Dorde Komljenovic,Tobias Bäuerle,Jessica Alves-de-Lima,Laura Trigueros,Cara Dietz,Zoltan Winter,Tommaso Araceli,Quirin Strotzer,Christina Wendl,Matthias Brendel,Martin A Proescholdt,Patrick N Harter,Katja Evert,Tobias Pukrop,Raquel Blazquez
BACKGROUNDNeurological failure contributes to 15-50% of deaths in patients with brain metastases, yet the underlying mechanisms remain poorly understood. Clinical causes range from local compression to meningeal metastasis. In this context, a link between infiltrative histopathological growth patterns (HGPs) and meningeal metastasis was recently described and prompted this reverse translation study.METHODSWe conducted a retrospective postmortem histological assessment and a prospective MRI-based proof-of-concept study to explore neurological decline mechanisms in two experimental brain metastasis models with different HGPs: (i) the non-infiltrative TUBO model, characterized by well-defined tumor borders and a multilayered astrocytic capsule; and (ii) the infiltrative E0771-LG model, exhibiting diffuse infiltration and widespread astrogliosis.RESULTSIn the TUBO model, neurological death resulted from local metastatic expansion compressing vital structures, while the E0771-LG model caused mortality mainly through widespread secondary dissemination. We provide the first direct evidence of contralateral recolonization by secondary metastasis-initiating cells (secMICs), and highlight the high efficiency of secondary spread. Additionally, we show that secMICs exploit distinct anatomical structures to reach distant brain regions, bypassing classical vascular dissemination routes. Notably, the HGP and its associated features are intrinsic to tumor cells and are established early during metastatic colonization.CONCLUSIONSThis study identifies the HGP as a potential surrogate for predicting the underlying cause of organ failure in brain metastases. Additionally, it highlights the significant role of secondary dissemination and recolonization in brain metastasis, processes that have been largely overlooked in clinical practice. These findings address a critical knowledge gap and may inform future treatment strategies.
{"title":"Local metastatic expansion versus secondary intra-organ dissemination: two causes of neurological death explained by fundamentally different metastatic colonization patterns.","authors":"Dorde Komljenovic,Tobias Bäuerle,Jessica Alves-de-Lima,Laura Trigueros,Cara Dietz,Zoltan Winter,Tommaso Araceli,Quirin Strotzer,Christina Wendl,Matthias Brendel,Martin A Proescholdt,Patrick N Harter,Katja Evert,Tobias Pukrop,Raquel Blazquez","doi":"10.1186/s12943-026-02574-0","DOIUrl":"https://doi.org/10.1186/s12943-026-02574-0","url":null,"abstract":"BACKGROUNDNeurological failure contributes to 15-50% of deaths in patients with brain metastases, yet the underlying mechanisms remain poorly understood. Clinical causes range from local compression to meningeal metastasis. In this context, a link between infiltrative histopathological growth patterns (HGPs) and meningeal metastasis was recently described and prompted this reverse translation study.METHODSWe conducted a retrospective postmortem histological assessment and a prospective MRI-based proof-of-concept study to explore neurological decline mechanisms in two experimental brain metastasis models with different HGPs: (i) the non-infiltrative TUBO model, characterized by well-defined tumor borders and a multilayered astrocytic capsule; and (ii) the infiltrative E0771-LG model, exhibiting diffuse infiltration and widespread astrogliosis.RESULTSIn the TUBO model, neurological death resulted from local metastatic expansion compressing vital structures, while the E0771-LG model caused mortality mainly through widespread secondary dissemination. We provide the first direct evidence of contralateral recolonization by secondary metastasis-initiating cells (secMICs), and highlight the high efficiency of secondary spread. Additionally, we show that secMICs exploit distinct anatomical structures to reach distant brain regions, bypassing classical vascular dissemination routes. Notably, the HGP and its associated features are intrinsic to tumor cells and are established early during metastatic colonization.CONCLUSIONSThis study identifies the HGP as a potential surrogate for predicting the underlying cause of organ failure in brain metastases. Additionally, it highlights the significant role of secondary dissemination and recolonization in brain metastasis, processes that have been largely overlooked in clinical practice. These findings address a critical knowledge gap and may inform future treatment strategies.","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":"214 1","pages":""},"PeriodicalIF":37.3,"publicationDate":"2026-01-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146042466","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}
Colorectal cancer (CRC) remains a major global health burden, with therapeutic resistance accounting for the majority of treatment failures and cancer-related deaths. Cancer stem cells (CSCs), which possess intrinsic drug tolerance and self-renewal capacity, drive both primary and acquired resistance. CSCs maintain drug tolerance through the activation of core signaling cascades, including Wnt/β-catenin, Notch, Hedgehog, PI3K/Akt, and MAPK/ERK pathways, as well as through epithelial-mesenchymal transition (EMT), enhanced DNA repair, and PD-1/PD-L1-mediated immune evasion. These molecular alterations transform the tumor microenvironment (TME) into a stemness-supportive, immunosuppressive niche, thereby promoting tumor recurrence and metastasis. Recent advances in CSCs-directed therapy include monoclonal antibodies targeting stem cell surface antigens, small-molecule inhibitors that disrupt self-renewal pathways, epigenetic agents that reprogram stemness, and immunotherapies aimed at reactivating anti-tumor immune surveillance. Emerging multi-drug regimens that combine CSCs-targeted agents with chemotherapy, pathway inhibitors, or immune checkpoint blockade exhibit synergistic efficacy by simultaneously disrupting multiple resistance mechanisms. Additionally, nanotechnology-based delivery systems further improve drug bioavailability and tumor specificity while reducing systemic toxicity. Despite notable progress, substantial challenges remain, including the pronounced heterogeneity of CSCs, activation of compensatory signaling pathways, and the lack of robust biomarkers for CSCs identification and therapeutic monitoring. Future research should prioritize integrative multi-omics approaches to delineate CSCs-specific vulnerabilities, the rational development of synergistic combination therapies, and the efficient clinical translation of CSCs-directed strategies. This review aims to describe the molecular mechanisms of CSCs-driven drug resistance in CRC, highlighting the current and emerging therapeutic strategies to guide the development of more effective, personalized interventions.
{"title":"Cancer stem cell-driven drug resistance in colorectal carcinoma: molecular aspects and therapeutic potentials.","authors":"Minfeng Zhou,Huifang Niu,Dandan Cui,Menghao Xu,Jinxiao Li,Guichen Huang,Minquan Zhou,Chutong Xiong,Yunya Liu,Xiaojuan Xu,Hongxing Zhang,Fengxia Liang,Rui Chen","doi":"10.1186/s12943-025-02557-7","DOIUrl":"https://doi.org/10.1186/s12943-025-02557-7","url":null,"abstract":"Colorectal cancer (CRC) remains a major global health burden, with therapeutic resistance accounting for the majority of treatment failures and cancer-related deaths. Cancer stem cells (CSCs), which possess intrinsic drug tolerance and self-renewal capacity, drive both primary and acquired resistance. CSCs maintain drug tolerance through the activation of core signaling cascades, including Wnt/β-catenin, Notch, Hedgehog, PI3K/Akt, and MAPK/ERK pathways, as well as through epithelial-mesenchymal transition (EMT), enhanced DNA repair, and PD-1/PD-L1-mediated immune evasion. These molecular alterations transform the tumor microenvironment (TME) into a stemness-supportive, immunosuppressive niche, thereby promoting tumor recurrence and metastasis. Recent advances in CSCs-directed therapy include monoclonal antibodies targeting stem cell surface antigens, small-molecule inhibitors that disrupt self-renewal pathways, epigenetic agents that reprogram stemness, and immunotherapies aimed at reactivating anti-tumor immune surveillance. Emerging multi-drug regimens that combine CSCs-targeted agents with chemotherapy, pathway inhibitors, or immune checkpoint blockade exhibit synergistic efficacy by simultaneously disrupting multiple resistance mechanisms. Additionally, nanotechnology-based delivery systems further improve drug bioavailability and tumor specificity while reducing systemic toxicity. Despite notable progress, substantial challenges remain, including the pronounced heterogeneity of CSCs, activation of compensatory signaling pathways, and the lack of robust biomarkers for CSCs identification and therapeutic monitoring. Future research should prioritize integrative multi-omics approaches to delineate CSCs-specific vulnerabilities, the rational development of synergistic combination therapies, and the efficient clinical translation of CSCs-directed strategies. This review aims to describe the molecular mechanisms of CSCs-driven drug resistance in CRC, highlighting the current and emerging therapeutic strategies to guide the development of more effective, personalized interventions.","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":"2 1","pages":""},"PeriodicalIF":37.3,"publicationDate":"2026-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146015350","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 : 2026-01-21DOI: 10.1186/s12943-026-02576-y
Chen Li,Francisco Alejandro Lagunas-Rangel,Lutao Du,Chengxi Sun,Helgi B Schiöth
{"title":"LncRNA PVT1 in human cancers: genomic complexity, isoforms, functional elements, mechanism of action, subcellular localization and possible role as a therapeutic target.","authors":"Chen Li,Francisco Alejandro Lagunas-Rangel,Lutao Du,Chengxi Sun,Helgi B Schiöth","doi":"10.1186/s12943-026-02576-y","DOIUrl":"https://doi.org/10.1186/s12943-026-02576-y","url":null,"abstract":"","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":"31 1","pages":""},"PeriodicalIF":37.3,"publicationDate":"2026-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146015359","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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