Cancer Science最新文献

{"title":"FXR1-Directed Alternative Splicing of MK5 Drives Hepatocellular Carcinoma Progression by Activating GSK3β Signaling","authors":"Yutong Li,&nbsp;Jin Xiang,&nbsp;Bin Cheng,&nbsp;Chenhao Li,&nbsp;Kai Wang,&nbsp;Ni Tang,&nbsp;Luyi Huang","doi":"10.1111/cas.70371","DOIUrl":"10.1111/cas.70371","url":null,"abstract":"<p>Alternative splicing plays a crucial role in the development and progression of hepatocellular carcinoma (HCC), yet the underlying regulatory mechanisms and therapeutic potential remain largely unexplored. Here, we identified the RNA-binding protein FMR1 autosomal homolog 1 (FXR1) as a key driver of HCC pathogenesis through the regulation of alternative splicing. FXR1 was highly expressed in HCC tissues, and its elevated expression was associated with a poor prognosis. Mechanistically, high FXR1 induced the retention of exon 6 in <i>mitogen-activated protein kinase-activated protein kinase 5</i> (<i>MK5</i>), generating a long, kinase-competent isoform (termed <i>MK5-L</i>). This isoform acted as an important oncogenic factor for HCC progression by phosphorylating GSK3β and subsequently activating the Wnt/β-catenin pathway. Functional studies showed that the FXR1/MK5-L axis is critical for HCC cell proliferation and metastasis, both in vivo and in vitro. Importantly, therapeutic intervention using an FXR1-targeting antisense oligonucleotide (ASO) effectively suppresses tumor progression and metastasis in preclinical models by shifting splicing toward the inactive <i>MK5-S</i> isoform. Overall, our study unveils a novel splicing-mediated oncogenic pathway and establishes FXR1 and its downstream target MK5-L as promising prognostic biomarkers and therapeutic targets for HCC.</p>","PeriodicalId":9580,"journal":{"name":"Cancer Science","volume":"117 6","pages":"1580-1593"},"PeriodicalIF":4.3,"publicationDate":"2026-06-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cas.70371","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147640293","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"JI-CJ002 and Dabrafenib Combination Enhances Antitumor Activity in Melanoma Associated With the Downregulation of B7-H3","authors":"Sang-Eun Lee,&nbsp;Young Ha Kim,&nbsp;Bo Shin Heo,&nbsp;Chunhoo Cheon,&nbsp;Seong-Gyu Ko","doi":"10.1111/cas.70387","DOIUrl":"10.1111/cas.70387","url":null,"abstract":"<p>Melanoma is the most lethal form of skin cancer, with a significantly poor prognosis after metastasis. The BRAF inhibitor dabrafenib increases response rates and overall survival (OS) in advanced-stage melanoma; however, most patients develop resistance rapidly, highlighting the need for improved combination regimens. This study investigated the therapeutic efficacy of JI-CJ002, an herbal extract consisting of <i>Angelica gigas</i>, <i>Aconitum carmichaeli,</i> and <i>Zingiber officinale</i> blended in a 2:1:3 (w/w) ratio, and assessed the combined antineoplastic effects of JI-CJ002 with dabrafenib in melanoma. JI-CJ002 suppressed epithelial–mesenchymal transition (EMT), invasion, and melanin synthesis, and these effects were maintained in combination with dabrafenib. The combination treatment was associated with reduced B7-H3 expression, along with inhibition of signaling pathways implicated in melanoma progression, including JAK2/STAT3, PI3K/AKT/mTOR, and NF-κB. Efficacy of the combination regimen was further evaluated in an A375 xenograft murine model. In vivo studies demonstrated that combination therapy reduced tumor volume without causing systemic toxicity, accompanied by decreased proliferation markers (PCNA and Ki-67), increased apoptotic marker (cleaved caspase-3), and decreased B7-H3 expression in tumor tissues. These results suggest that JI-CJ002 may enhance the antitumor activity of dabrafenib, accompanied by modulation of oncogenic pathways.</p>","PeriodicalId":9580,"journal":{"name":"Cancer Science","volume":"117 6","pages":"1651-1666"},"PeriodicalIF":4.3,"publicationDate":"2026-06-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cas.70387","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147700641","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"SOD2-Superoxide Metabolic Axis Regulates Mitophagy and Modulates TKIs Sensitivity in Head and Neck Squamous Cell Carcinoma","authors":"Wan-Hang Zhou,&nbsp;Shuo-Jin Huang,&nbsp;An-Xun Wang","doi":"10.1111/cas.70374","DOIUrl":"10.1111/cas.70374","url":null,"abstract":"<p>Superoxide dismutase 2 (SOD2) has been implicated in head and neck squamous cell carcinoma (HNSCC), yet its mechanistic contribution in regulating tumor responses to tyrosine kinase inhibitors (TKIs) remains unclear. Here, we investigated whether SOD2 shapes TKI sensitivity in HNSCC through a mitochondrial superoxide-mitophagy axis. Bioinformatic analyses revealed that elevated SOD2 expression was negatively correlated with mitophagy signatures in HNSCC. Functional experiments showed that SOD2 silencing led to mitochondrial superoxide accumulation, impaired mitochondrial function, and significant mitophagy activation in HNSCC cells. Pharmacological modulation further supported a superoxide-dependent mechanism, as Mito-TEMPO suppressed mitochondrial superoxide and mitophagy induction, whereas rotenone enhanced mitochondrial superoxide and mitophagy activity. Importantly, SOD2 knockdown increased apoptotic susceptibility and sensitized HNSCC cells to TKI treatment, which was partially reversed by superoxide scavenging but reinforced by superoxide elevation. Consistently, SOD2 knockout xenograft models exhibited enhanced antitumor responsiveness to TKIs in vivo. Collectively, these findings identified SOD2 as a key regulator of mitochondrial redox homeostasis and mitophagy, thereby modulating therapeutic sensitivity in HNSCC, and suggest that targeting the SOD2-superoxide metabolic axis may represent a promising strategy to improve TKIs efficacy in HNSCC.</p>","PeriodicalId":9580,"journal":{"name":"Cancer Science","volume":"117 6","pages":"1594-1607"},"PeriodicalIF":4.3,"publicationDate":"2026-06-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cas.70374","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147582007","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"ROWVA: A Structure-Based Metric for Predicting the Pathogenicity of Protein Variants Using Alphafold2","authors":"Taiki Furutani,&nbsp;Yuka Okusha,&nbsp;Hiroki Nagami,&nbsp;Hiroko Hanafusa,&nbsp;Shuta Tomida,&nbsp;Ryusuke Sawada,&nbsp;Yasuyuki Hosono,&nbsp;Masahiro Nakatochi","doi":"10.1111/cas.70380","DOIUrl":"10.1111/cas.70380","url":null,"abstract":"<p>p53, an important tumor suppressor protein, functions as a tetramer. Therefore, malignant variants in the tetramer-forming domain increase the likelihood of p53 dysfunction. Recent developments in genome analysis technology have expanded our understanding of malignant variants. However, variants of uncertain significance are also being increasingly identified. Hence, methods to assess the pathogenicity of these variants are required. In this study, we aimed to examine whether AlphaFold2 can be used to evaluate the functional impacts of p53 variants based on predicted three-dimensional (3D) structural information. For each variant present in datasets of p53 functional score, we performed 3D structural prediction using AlphaFold2. We analyzed the correlations among multiple AlphaFold2-derived scores to predict functional scores, such as protein stability and pathogenicity labels, for each dataset. The root-mean-square deviation obtained by comparing the 3D structures predicted by AlphaFold2 for the wild-type and variant structures showed a high correlation with each functional score. Overall, these findings indicate that AlphaFold2 can be used to evaluate variants.</p>","PeriodicalId":9580,"journal":{"name":"Cancer Science","volume":"117 6","pages":"1736-1747"},"PeriodicalIF":4.3,"publicationDate":"2026-06-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cas.70380","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147628949","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Multifunctional Role of Mitochondrial Fatty Acid Oxidation in Cancer Immunotherapy and Aging","authors":"Koji Kitaoka,&nbsp;Shuhei Hirose,&nbsp;Yu Wang,&nbsp;Tomonori Yaguchi,&nbsp;Kenji Chamoto","doi":"10.1111/cas.70388","DOIUrl":"10.1111/cas.70388","url":null,"abstract":"<p>Recent studies have demonstrated the intricate relationship between tumor immunity, aging, and inflammation. Mitochondrial activity is one of the major connection hubs of this physiological interplay. Fatty acid oxidation (FAO) is a center of the mitochondrial metabolic pathway and plays a pivotal role in maintaining cellular homeostasis. Dysfunction in mitochondrial FAO leads to an accumulation of reactive oxygen species (ROS), contributing to oxidative stress and chronic inflammation. This persistent inflammatory stress not only accelerates aging but also impairs immune surveillance, facilitating tumor progression. Modulation of mitochondrial FAO reprograms the metabolism of tumor-infiltrating lymphocytes and macrophages, thereby impacting anti-tumor immunity. Understanding these interconnected pathways offers potential therapeutic avenues to enhance cancer immunotherapy and mitigate inflammation.</p>","PeriodicalId":9580,"journal":{"name":"Cancer Science","volume":"117 6","pages":"1554-1565"},"PeriodicalIF":4.3,"publicationDate":"2026-06-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cas.70388","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147724270","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Bispecific Ligand-Based EphB4 CAR-T Cells Generated Using Ephrin-B2 Show Potent Antitumor Activity Against Lung Adenocarcinoma","authors":"Hirotaka Kumeda,&nbsp;Koichi Hirabayashi,&nbsp;Shuji Mishima,&nbsp;Kotaro Morita,&nbsp;Yu Furui,&nbsp;Marina Fujioka,&nbsp;Tomoyuki Nakajima,&nbsp;Miyuki Tanaka,&nbsp;Yoshinori Sato,&nbsp;Takeshi Uehara,&nbsp;Shigeki Yagyu,&nbsp;Kimihiro Shimizu,&nbsp;Yozo Nakazawa","doi":"10.1111/cas.70397","DOIUrl":"10.1111/cas.70397","url":null,"abstract":"<p>Chimeric antigen receptor (CAR)-T cells generated using ephrin-B2, the natural ligand for ephrin type-B receptor 4 (EphB4), have demonstrated antitumor activity; however, their efficacy remains unvalidated. Therefore, we evaluated the dual-targeting antitumor ability of these cells and confirmed their efficacy against lung adenocarcinoma. First, we evaluated EphB4 and EphA2 expression in samples from 74 patients with lung adenocarcinoma using immunohistochemistry. Next, EphB4 CAR-T cells were generated via <i>piggyBac</i>-mediated gene transfer, and their phenotype was evaluated. Subsequently, we conducted an antigen stimulation assay to assess the bispecificity of the EphB4 CAR-T cells. Finally, the antitumor effects of EphB4 CAR-T cells on lung adenocarcinoma cell lines were assessed. EphB4 and EphA2 positivity in lung adenocarcinoma samples was 93% and 100%, respectively. EphB4 CAR-T cells were successfully generated with high CAR positivity and a high proportion of naïve/stem cell memory-like T cells. In the antigen stimulation assay, the cells responded in an antigen-specific manner after stimulation with both EphB4 and EphA2 proteins. In the co-culture experiment, EphB4 CAR-T cells significantly suppressed the growth of all four lung adenocarcinoma cell lines compared to mock-T cells. In vivo, mice treated with EphB4 CAR-T cells displayed a significantly lower tumor burden than those treated with either CD19 CAR-T cells or phosphate-buffered saline. Additionally, mice treated with EphB4 CAR-T cells survived significantly longer than those in the other groups. In conclusion, ligand-based EphB4 CAR-T cells are bispecific, targeting both EphB4 and EphA2. Furthermore, these cells exert significant antitumor effects against lung adenocarcinoma.</p>","PeriodicalId":9580,"journal":{"name":"Cancer Science","volume":"117 6","pages":"1724-1735"},"PeriodicalIF":4.3,"publicationDate":"2026-06-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cas.70397","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147730415","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Docetaxel-Induced Immune Activation Shows Antitumor Synergy With the Tumor-Targeted CD40 Agonist KK2269","authors":"Yuta Tezuka,&nbsp;Kyoko Kawasaki,&nbsp;Yoshiki Sumitomo,&nbsp;Masato Saito,&nbsp;Akari Yao,&nbsp;Munetoshi Ando","doi":"10.1111/cas.70376","DOIUrl":"10.1111/cas.70376","url":null,"abstract":"<p>Tumor-targeted CD40 agonists have emerged as one of the novel strategies to activate intratumoral antigen-presenting cells (APCs), subsequently inducing T-cell-specific antitumor responses. However, their clinical efficacy as monotherapy has been limited, highlighting the need for effective combination therapies. We developed KK2269, a bispecific antibody targeting epithelial cell adhesion molecule (EpCAM) on tumor cells and CD40 on APCs, designed to selectively activate APCs in the presence of EpCAM-positive tumors. Our studies demonstrated that KK2269 activates APCs only in the presence of EpCAM-expressing cells. Using the immunologically cold B16F10-mouse EpCAM subcutaneously transplanted model, the antitumor effects of KK2269 in combination with clinically approved drugs, including anti-programmed cell death 1 (PD-1) antibody, docetaxel, doxorubicin, oxaliplatin, and gemcitabine were evaluated. KK2269 showed significant antitumor activity in combination with an anti-PD-1 antibody, docetaxel, doxorubicin, or oxaliplatin, but not gemcitabine, with docetaxel showing the most significant antitumor effect(s). Intratumoral immune analysis showed that KK2269 was associated with increased expression of APC activation markers, whereas docetaxel was associated with increased expression of dendritic cell (DC)-related genes. Moreover, expression of APC and T-cell activation markers was higher with docetaxel+KK2269 than with either monotherapy. The antitumor and immune activation effects of docetaxel+KK2269 were also observed in the immunosuppressive intrahepatic transplantation model. This study provides a rationale for combining a tumor-targeting CD40 agonist, KK2269, with docetaxel for the treatment of PD-1 blockade resistant tumors, including intrahepatic tumors, and supports exploration of this combination strategy in the clinic.</p>","PeriodicalId":9580,"journal":{"name":"Cancer Science","volume":"117 6","pages":"1701-1712"},"PeriodicalIF":4.3,"publicationDate":"2026-06-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cas.70376","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147700570","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"PEGylated Chitosan Nanoparticles: Engineering Multifunctional Platforms for Targeted Cervical and Lung Cancer Treatment","authors":"Prashant Kesharwani,&nbsp;Nazim Nasir,&nbsp;Shadma Wahab,&nbsp;Garima Gupta,&nbsp;Khang Wen Goh,&nbsp;Amirhossein Sahebkar","doi":"10.1111/cas.70361","DOIUrl":"10.1111/cas.70361","url":null,"abstract":"<p>Polymer-based nanocarriers have emerged as transformative platforms in cancer nanomedicine, enabling controlled and site-specific delivery of therapeutic agents. Among polysaccharide-derived materials, chitosan stands out for its biodegradability, biocompatibility, and intrinsic mucoadhesive properties that promote efficient drug encapsulation and enhanced cellular internalization. Surface PEGylation the conjugation of polyethylene glycol (PEG) chains further augments the physicochemical and biological performance of chitosan nanoparticles by enhancing colloidal stability, extending systemic circulation, and reducing opsonization by the reticuloendothelial system. In addition, ligand-mediated functionalization facilitates active tumor targeting and selective intracellular delivery, thereby improving therapeutic efficacy while minimizing off-target toxicity. This review critically summarizes recent advances in the design, synthesis, and functional modification of PEGylated chitosan nanoparticles, with emphasis on their pharmacokinetic behavior, drug release mechanisms, and anticancer performance. Comparative insights into other polymeric and lipid-based nanocarrier systems are also provided. Finally, current challenges, safety considerations, and translational perspectives are discussed, underscoring the promise of PEGylated chitosan nanoplatforms as next-generation biomaterials for precision oncology.</p>","PeriodicalId":9580,"journal":{"name":"Cancer Science","volume":"117 6","pages":"1531-1542"},"PeriodicalIF":4.3,"publicationDate":"2026-06-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cas.70361","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147595618","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Discovery of a Novel γ-Glutamylcyclotransferase Inhibitor Plumbagin by Luminescence-Based High-Throughput Screening","authors":"Keiko Taniguchi,&nbsp;Yukie Nohara,&nbsp;Mano Horinaka,&nbsp;Kozue Nose,&nbsp;Masaya Mori,&nbsp;Hiromi Ii,&nbsp;Hiroko Kawakami,&nbsp;Kazuto Yano,&nbsp;Susumu Nakata,&nbsp;Taku Yoshiya,&nbsp;Toshiyuki Sakai","doi":"10.1111/cas.70390","DOIUrl":"10.1111/cas.70390","url":null,"abstract":"<p>γ-Glutamylcyclotransferase (GGCT) is a highly expressed protein in various cancers, and its knockdown and inhibitors suppress the growth of cancer cells in vitro and in vivo. Although GGCT is a promising target for anti-cancer strategies, no drugs have progressed to clinical availability yet. We established a novel target-based and cell-based screening method for GGCT inhibitors, enabling the efficient discovery of compounds that inhibit intracellular GGCT activity. Using the chemiluminogenic probe LISA-103 in response to GGCT enzymatic activity, high-throughput screening for GGCT inhibitors was performed in lung cancer SW1573 cells. The hit compound plumbagin was identified as a novel GGCT inhibitor that suppressed its activity intracellularly. Plumbagin directly bound to a GGCT-recombinant protein and inhibited its activity. Moreover, plumbagin up-regulated p21, a cyclin-dependent kinase inhibitor, and activated the tumor suppressor RB protein, inhibiting cell growth and cell cycle progression in breast MCF7 and colon HCT116 cancer cell lines. These phenomena induced by plumbagin mimicked the effect of GGCT depletion. The treatment with plumbagin suppressed tumor growth of HCT116 xenograft mice. These results suggest the potential of plumbagin in cancer therapy as a GGCT inhibitor.</p>","PeriodicalId":9580,"journal":{"name":"Cancer Science","volume":"117 6","pages":"1713-1723"},"PeriodicalIF":4.3,"publicationDate":"2026-06-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cas.70390","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147678048","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Daunorubicin-45 Vs. Daunorubicin-60 for Induction in Intermediate-Age Patients of AML: Results From a Randomized Trial","authors":"Chunlin Zhou,&nbsp;Le Li,&nbsp;Yan Li,&nbsp;Kaiqi Liu,&nbsp;Yuntao Liu,&nbsp;Dong Lin,&nbsp;Benfa Gong,&nbsp;Guangji Zhang,&nbsp;Xiaoyuan Gong,&nbsp;Qiuyun Fang,&nbsp;Bingcheng Liu,&nbsp;Shaowei Qiu,&nbsp;Ying Wang,&nbsp;Hui Wei,&nbsp;Yingchang Mi,&nbsp;Jianxiang Wang","doi":"10.1111/cas.70383","DOIUrl":"10.1111/cas.70383","url":null,"abstract":"<p>Daunorubicin dose optimization remains crucial for AML treatment. While 90 mg/m² benefits younger adults and 45 mg/m² remains standard for older patients, the optimal dose for patients aged 55–65 years is unclear. We evaluated whether intermediate dose escalation to 60 mg/m² would improve outcomes compared to that of standard 45 mg/m² in this population. In this prospective, randomized, open-label, single-center trial, newly diagnosed AML patients aged 55–65 years were randomly assigned 1:1 to receive daunorubicin 45 mg/m² (Group S) or 60 mg/m² (Group M) on days 1–3, combined with cytarabine for the induction. At median follow-up of 35.9 months, no significant difference in OS was observed between the two groups (HR 1.24, 95% CI 0.80–1.91; <i>p</i> = 0.333). Median OS was 48.7 months (95% CI 28.2–NR) in Group S vs. 33.0 months (95% CI 22.2–71.6) in Group M. Five-year survival rates were comparable (45.2% vs. 39.8%). CR rates after first induction were equivalent (47.1% vs. 44.4%; RD +2.7%, 95% CI –17.4 to 12.0; <i>p</i> = 0.720). MRD-negative CR rates showed no difference (35.6% vs. 32.2%; <i>p</i> = 0.632). RFS (HR 1.38, 95% CI 0.84–2.26; <i>p</i> = 0.201) and EFS (HR 1.18, 95% CI 0.81–1.74; <i>p</i> = 0.389) were similar in both arms. Regarding safety, while overall infection rates were similar, Group M showed a significantly higher incidence of documented intestinal infections compared to Group S (22.5% vs. 8.0%; <i>p</i> = 0.011). Exploratory subgroup analyses revealed no consistent patterns favoring either strategy across clinical or molecular subgroups. Daunorubicin dose escalation from 45 to 60 mg/m² provides no clinical benefit but significantly increases mucosal toxicity. Therefore, 45 mg/m² should remain the preferred regimen for this population.</p><p><b>Trial Registration:</b> ClinicalTrials.gov identifier: NCT02432872</p>","PeriodicalId":9580,"journal":{"name":"Cancer Science","volume":"117 6","pages":"1690-1700"},"PeriodicalIF":4.3,"publicationDate":"2026-06-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cas.70383","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147693121","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}