Cancer letters最新文献

{"title":"Extracellular vesicle-associated LMP1 from EBV-positive nasopharyngeal carcinoma induces LIF-mediated immunosuppressive macrophage polarization and impairs anti-tumor immunity","authors":"Tzu-Tung Liu,&nbsp;Kai-Ping Chang,&nbsp;Meng-Hsin Li,&nbsp;Yun-Hua Sui,&nbsp;Fang-Yu Tsai,&nbsp;Hsuan-Chung Chen,&nbsp;Chen-Han Huang,&nbsp;Ya-Wen Chen,&nbsp;Shih Sheng Jiang,&nbsp;Shu-Chen Liu","doi":"10.1016/j.canlet.2026.218892","DOIUrl":"10.1016/j.canlet.2026.218892","url":null,"abstract":"<div><div>Epstein–Barr virus (EBV)-associated nasopharyngeal carcinoma (NPC) is characterized by a highly infiltrated yet immunosuppressive tumor microenvironment (TME), in which tumor-associated macrophages (TAMs) contribute to disease progression. Here, we identify an extracellular vesicle (EV)-mediated LMP1–NF-κB–LIF signaling axis that promotes macrophage reprogramming and immune suppression in NPC. Single-cell transcriptomic analysis revealed that EV exposure induces transcriptional remodeling across tumor and immune-cell populations, accompanied by an increased proportion of TAMs within the myeloid compartment. NPC-derived EVs were taken up by macrophages, where EV-associated LMP1 induced NF-κB activation, LIF expression, and polarization toward an immunosuppressive phenotype. Loss- and gain-of-function studies, together with structure-function analyses of the LMP1 CTAR1/CTAR2 domains, further supported the requirement of these CTAR domains for efficient NF-κB activation and LIF induction. Functionally, EV-educated macrophages exhibited impaired phagocytic activity and promoted inhibitory T-cell responses. In zebrafish, 3D spheroid, and mouse xenograft models, EV-educated macrophages promoted NPC growth and vascular dissemination, whereas blockade of LIF signaling with soluble LIFR attenuated these effects. Tumor LIF expression positively correlated with CTLA4 expression. In NPC tissues, LIF expression was preferentially associated with stromal macrophages, and elevated stromal LIF expression was associated with metastasis, advanced nodal disease, and advanced clinical stage. Stromal immune-cell LMP1 expression also correlated with LIF expression and was higher in patients who developed metastasis. Collectively, these findings support an EV-associated LMP1–NF-κB–LIF axis that links EBV-positive NPC cells to macrophage-mediated immune suppression and tumor progression and provide a basis for further investigating this pathway as a potential therapeutic target.</div></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"661 ","pages":"Article 218892"},"PeriodicalIF":11.8,"publicationDate":"2026-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149179449","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":"Multidimensional Regulation of Metal Ions in the Tumor Microenvironment and Innovative Strategies for Diagnosis and Therapy.","authors":"Yanna Bi, Yating Zhao, Yanlei Ge, Zhesheng Chen, Lianmei Zhao, Guogui Sun","doi":"10.1016/j.canlet.2026.218859","DOIUrl":"https://doi.org/10.1016/j.canlet.2026.218859","url":null,"abstract":"<p><p>Metal ions serve as key regulators of the dynamic equilibrium within the tumor microenvironment (TME). In recent years, the TME has emerged as a central regulatory hub for tumor initiation, progression, and metastasis; its complexity has become both a frontier and a major challenge in oncology research. Current therapies are often constrained by immune tolerance, metabolic heterogeneity, and microenvironment-mediated escape mechanisms, necessitating breakthroughs in novel targets and strategies. Metal ions, functioning as enzyme cofactors, signaling molecules, and redox regulators, profoundly affect tumor progression by modulating redox homeostasis, immune responses, and metabolic reprogramming. This review provides a comprehensive overview of recent advances in metal ion-mediated regulation of the TME. It focuses on elucidating the multidimensional mechanisms by which metal ions facilitate immunogenic remodeling and metabolic interactions, and prospectively explores innovative metal-ion-based diagnostic and therapeutic strategies. It further highlights the potential of personalized metal metabolomics to advance precision oncology and facilitate the clinical translation of metal ion-based theranostic strategies.</p>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":" ","pages":"218859"},"PeriodicalIF":11.8,"publicationDate":"2026-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149179439","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":"Acute MCL1 Loss via Homoharringtonine-Mediated Translational Inhibition Enables Potent Apoptotic Synergy with BCLXL Blockade.","authors":"Akira Ohtsu, Tatsuhiro Sawada, Larysa Poluben, Mai Onose, Hayumi Oyama, Ayaka Katayama, Fang Xie, Betul Ersoy-Fazlioglu, Juan M Jiménez-Vacas, Yusuke Otani, Yoshiyuki Miyazawa, Yoshitaka Sekine, Yuta Maeno, Takanori Shimizu, Tsukasa Oda, Shaoyong Chen, Olga Voznesensky, Xin Yuan, Luigi Giovanni Cecchi, Robert A Cerulli, Motohiro Izumi, Ikei S Kobayashi, Atsushi Tanaka, Nobuo Sasaki, Susumu S Kobayashi, Kazuhiro Suzuki, Steven P Balk, Seiji Arai","doi":"10.1016/j.canlet.2026.218895","DOIUrl":"https://doi.org/10.1016/j.canlet.2026.218895","url":null,"abstract":"<p><p>Antiapoptotic buffering in solid tumors is generally mediated by both BCLXL and MCL1, so that BH3 mimetic drugs targeting only one have limited efficacy. To identify agents that may sensitize tumors to BH3 mimetics targeting BCLXL, we screened prostate cancer cells against a panel of mitochondria-targeted drugs in combination with navitoclax, a BH3 mimetic targeting BCL2 and BCLXL. Homoharringtonine (HHT) in combination with navitoclax and as a single agent emerged as a potent inducer of apoptosis. HHT has been identified as an inhibitor of protein translation, and proteomic analysis showed broad suppression of translation-related pathways, while immunoblotting demonstrated rapid decreases in short-lived proteins, including MCL1. HHT dose response and time course studies showed marked declines in MCL1 within 2 hours that were associated with apoptosis in response to BCLXL inhibition with navitoclax or A1331852. Further cell viability assays showed synergy between HHT and BCLXL inhibitors in multiple prostate, lung, and colorectal cancer cell lines. HHT monotherapy in vivo caused tumor regression in two prostate cancer xenograft models. Analysis of tumor tissue taken at 4 hours after dosing showed decreases in MCL1 and MYC, indicating that HHT levels obtainable in vivo are adequate to deplete short-lived proteins and potentially sensitize to BH3 mimetics targeting BCLXL. These findings support further exploration of HHT as a single agent in solid tumors and establish a rationale for investigating safer, tumor-selective approaches to combine HHT-mediated translational inhibition with BCLXL targeting.</p>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":" ","pages":"218895"},"PeriodicalIF":11.8,"publicationDate":"2026-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149179463","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":"Therapy-associated myeloid niches as spatial drivers of cancer treatment resistance and targets for mechanism-matched intervention.","authors":"Ting Li, Yanxia Lin, Qingwei Gang, Xudong Zhu, Tao Hong, Lin Su, Yuehan Hao","doi":"10.1016/j.canlet.2026.218861","DOIUrl":"10.1016/j.canlet.2026.218861","url":null,"abstract":"<p><p>Tumor drug resistance is still the core obstacle limiting the long-term benefit of modern anticancer therapy, especially in the context of treatment tolerance, persistence of minimal residual disease (MRD) and recurrence after treatment. Increasing evidence has shown that therapy-associated myeloid niches can involve cell recruitment, enrichment of pre-existing populations, or state reprogramming, together with local relationships among myeloid cells, tumor cells, stroma, vessels, and other immune cells. These niches can support residual tumor-cell survival, immune escape, local regrowth, and distant dissemination through overlapping mechanisms linking fibrotic exclusion and perivascular organization with hypoxic metabolic suppression and myeloid replenishment. The formation of neutrophil extracellular traps, failure of antigen uptake and presentation, impaired T-cell priming, and phagocytic escape can further sustain treatment tolerance. Focusing on the myeloid cell state and common molecular circuits, this article presents an evidence assessment framework that interprets spatial and clinical associations alongside functional and pharmacologic findings without assigning hierarchical ranks. It summarizes lessons from clinical failure, considering potentially limited target contributions, compensatory pathways, inadequate exposure, and toxicity, while distinguishing drug exposure and local pharmacodynamic changes from clinical benefit. Candidate biomarkers, intervention windows, and selective delivery approaches require validation to guide mechanism-matched combinations. In the future, longitudinal tissue analyses, functional validation, and prospective studies should test whether these combinations provide durable benefit with acceptable safety in defined patient populations and treatment settings.</p>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":" ","pages":"218861"},"PeriodicalIF":11.8,"publicationDate":"2026-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149179490","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":"Reactive oxygen species define leukemia stem cell identity in pediatric acute myeloid leukemia.","authors":"Maddalena Benetton, Ambra Da Ros, Alberto Peloso, Giorgia Longo, Sara Perpinello, Chiara Frasson, Tiago Branco Fonseca, Elena Varotto, Silvia Bresolin, Claudia Tregnago, Luca Scorrano, Benjamin J Huang, Soheil Meshinchi, Franco Locatelli, Martina Pigazzi","doi":"10.1016/j.canlet.2026.218866","DOIUrl":"10.1016/j.canlet.2026.218866","url":null,"abstract":"<p><p>Standard chemotherapy effectively induces complete remission in most children with acute myeloid leukemia (AML), however relapse remains the main cause of treatment failure. Leukemia stem cells (LSCs) are proposed to constitute a therapy-resistant reservoir driving disease recurrence, but their reliable identification remains unresolved. We explored intracellular reactive oxygen species (ROS) levels in pediatric AML at diagnosis and sorted ROS-low (RL) and ROS-high (RH) cell fractions. We found that RL cells exhibited increased quiescence, sustained serial colony-forming capacity and engraftment in mice when compared to the RH fraction. Moreover, in a 3D niche model, RL cells preferentially localized to hypoxic regions and were resistant to cytarabine, altogether indicating enrichment for functional LSCs. Transcriptomic analyses revealed enrichment of stemness, adhesion and niche-interaction programs in RL cells, alongside downregulation of mitochondrial and oxidative phosphorylation pathways. Consistently, RL cells displayed reduced oxygen consumption and ATP production, together with remodeled cristae structure despite preserved mitochondrial mass. Paradoxically, complex I inhibition selectively impaired RL cell viability, indicating a dependency on oxidative phosphorylation. Using RL transcriptome, we derived a gene signature that, when applied to single-cell RNA-sequencing data of pediatric AML cases, identified LSCs within the bulk regardless of differentiation status, and showed significant prognostic value. Finally, transcriptional program trajectory indicated that RL fraction contributed to generate the whole AML bulk, whereas gene mutations were maintained in RL and RH cells. Overall, this ROS-based strategy represents a new tool to isolate stem cells transcending traditional markers, and identifies novel clinically relevant vulnerabilities to target LSCs.</p>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":" ","pages":"218866"},"PeriodicalIF":11.8,"publicationDate":"2026-10-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149104493","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":"Visualizing and Targeting Tumor-Associated Neutrophils: Advanced Imaging, Therapeutic Reprogramming, and Cell-Based Delivery for Precision Oncology.","authors":"Aoyu Liu, Dian Chen, Yuelin Huang, Chunting Wang, Cuiying Zhu, Jingjing Hu, Ling Zhan, Youqun Lai, Defan Yao, Dengbin Wang","doi":"10.1016/j.canlet.2026.218805","DOIUrl":"https://doi.org/10.1016/j.canlet.2026.218805","url":null,"abstract":"<p><p>Tumor-associated neutrophils (TANs) are increasingly recognized as heterogeneous and context-dependent regulators of cancer progression and treatment response. Through cytokine secretion, protease release, oxidative activity, and formation of neutrophil extracellular traps (NETs), TANs remodel the tumor microenvironment (TME) and influence immune regulation, angiogenesis, invasion, and metastasis. Recent advances in molecular imaging enable selected neutrophil-associated molecular processes to be monitored in vivo using optical, photoacoustic, chemiluminescent, and magnetic resonance approaches. These approaches include neutrophil elastase (NE) activity-responsive imaging, NETosis-related imaging, and myeloperoxidase (MPO) activity-responsive imaging. These readouts provide spatially and temporally resolved information on neutrophil-associated molecular activity and, when combined with complementary cellular, histological, and functional analyses, support more robust characterization of the underlying cellular sources and biological functions. In parallel, neutrophil-directed treatments seek to limit recruitment, suppress or reprogram protumor functions, and inhibit NET formation or promote NET clearance. Neutrophils and neutrophil-derived materials are also being developed as drug-delivery platforms, including live or engineered neutrophils, neutrophil membrane-coated nanocarriers, and extracellular vesicles. This review summarizes advances across these areas and discusses how imaging readouts relate to biological interpretation, candidate interventions, confirmatory assessments, therapeutic outcomes, and safety. Although current evidence remains predominantly preclinical and context dependent, integrating molecular imaging with cellular phenotyping, functional validation, and longitudinal outcome assessment may support more selective and adaptive neutrophil-centered strategies for precision oncology.</p>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":" ","pages":"218805"},"PeriodicalIF":11.8,"publicationDate":"2026-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148943843","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":"Myeloid-derived suppressor cells in the tumor microenvironment: cellular crosstalk, immunosuppressive effects, and therapeutic targets.","authors":"Lisichen Zhu, Hui Liu, Sihan Zhang, Daiming Fan, Xiaojie Yuan, Xiaoliang Gao, Yongzhan Nie","doi":"10.1016/j.canlet.2026.218803","DOIUrl":"https://doi.org/10.1016/j.canlet.2026.218803","url":null,"abstract":"<p><p>Tumor microenvironment (TME)-induced immunosuppression is a major driver of cancer treatment failure and resistance to immunotherapy. Myeloid-derived suppressor cells (MDSCs) are not only pivotal suppressors of effector immune responses but also central organizers of tumor-supportive metabolic, stromal, and cellular crosstalk. This review systematically summarizes the origin and phenotypic characteristics of MDSCs and the mechanisms governing their recruitment, expansion, and activation within the TME. This review integrates current knowledge of MDSC biology through two complementary frameworks. One framework highlights the bidirectional interactions between MDSCs and immune, tumor, stromal, endothelial, and adipocyte compartments. The other classifies therapeutic approaches according to their mechanisms and translational relevance, including combinations with immunotherapy. We further evaluate clinical translation, including lessons from unsuccessful or inconclusive trials, biomarker gaps, and rational combination strategies. Together, current evidence indicates that MDSCs represent context-dependent therapeutic nodes, while functional reprogramming, spatially resolved profiling, and patient stratification may improve immunotherapy outcomes.</p>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":" ","pages":"218803"},"PeriodicalIF":11.8,"publicationDate":"2026-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148825355","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":"LINC00941 Drives Chemoresistance via Modulating PKM2 Activity and Aerobic Glycolysis in Oral Squamous Cell Carcinoma.","authors":"Shule Xie, Lianxi Mai, Yu Peng, Wenhao Sun, Yupeng Wu, Yingnan Ma, Renquan Liu, Liang Qiao, Yangu Tao, Guoxin Huang, Zhaoyu Lin","doi":"10.1016/j.canlet.2026.218775","DOIUrl":"https://doi.org/10.1016/j.canlet.2026.218775","url":null,"abstract":"<p><p>Cisplatin (CDDP) resistance represents a major determinant of poor prognosis in patients with oral squamous cell carcinoma (OSCC). While long non-coding RNAs (lncRNAs) are implicated in chemoresistance pathways, their mechanistic roles in OSCC treatment failure remain incompletely defined. This study identifies LINC00941 as a CDDP resistance-associated lncRNA, with elevated expression correlating significantly with adverse OSCC prognosis. Gain- and loss-of-function assays reveal that LINC00941 overexpression promotes both aerobic glycolysis and CDDP resistance in OSCC cells. Furthermore, elevated LINC00941 expression enhances pyruvate kinase activity, thereby fostering chemoresistance in vitro and in vivo. Mechanistic investigations reveal that LINC00941 physically interacts with pyruvate kinase M2 (PKM2), enhancing its protein stability by suppressing ubiquitin-mediated proteolysis. This stabilization amplifies glycolytic flux, ultimately inducing CDDP resistance in OSCC cells. Our findings elucidate a novel lncRNA-dependent pathway governing chemoresistance and propose targeting the LINC00941/PKM2/glycolysis axis as a translatable therapeutic strategy for overcoming CDDP resistance in OSCC.</p>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":" ","pages":"218775"},"PeriodicalIF":11.8,"publicationDate":"2026-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148788647","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":"Polyploid giant cancer cells: A hidden cost of Aurora Kinase inhibitors and antimitotic therapies revealed through the PGCC Explorer.","authors":"Kok-Siong Poon","doi":"10.1016/j.canlet.2026.218742","DOIUrl":"https://doi.org/10.1016/j.canlet.2026.218742","url":null,"abstract":"","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":" ","pages":"218742"},"PeriodicalIF":11.8,"publicationDate":"2026-07-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148535352","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":"Epithelial FOXP3: The Silent Spark That Lights the Fire of Pancreatic Cancer.","authors":"Charles J David","doi":"10.1016/j.canlet.2026.218738","DOIUrl":"https://doi.org/10.1016/j.canlet.2026.218738","url":null,"abstract":"<p><p>For decades, we have viewed pancreatic fibrosis as a passive scar-the end-stage wreckage of chronic inflammation or a late accomplice of growing tumors. A recent study by He Ren and colleagues sheds critical light on the origins of the phenomenon tracing it to an unexpected cellular culprit: a rare subset of pancreatic epithelial cells that express FOXP3-a transcription factor predominantly associated with regulatory T cells. These epithelial FOXP3 (E-FOXP3) positive cells do not need oncogenic Kras or overt inflammation to ignite fibrosis. On their own, they orchestrate a glycosylation-dependent IL-6 switch that turns quiescent pancreatic stellate cells into a self-amplifying fibrotic machine. In discovering a proto-fibrogenic \"trigger cell\" that acts silently, long before any symptom or radiological sign, the work redefines the cellular hierarchy of pancreatic fibrocarcinogenesis. Further, the paper identifies a post-translational \"sugar code\" as a therapeutic foothold, and opens a long-sought preemptive window for intercepting pancreatic cancer at its most curable stage-before the desmoplastic fortress is ever built.</p>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":" ","pages":"218738"},"PeriodicalIF":11.8,"publicationDate":"2026-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148469218","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}