Cancer Science最新文献

{"title":"MAP17 Enhances Chemoresistance and Tumorigenicity of Glioblastoma-Initiating Cells via the Canonical NF-кB Pathway","authors":"Shenshen Dou,&nbsp;You Lee Son,&nbsp;Toru Kondo","doi":"10.1111/cas.70385","DOIUrl":"10.1111/cas.70385","url":null,"abstract":"<p>Glioblastoma (GBM) is the most common malignant brain tumor in adults. Despite multimodal treatments, including surgery, radiation therapy, and temozolomide (TMZ) chemotherapy, the median survival remains poor at approximately 15 months. One reason for the therapeutic resistance is the existence of GBM-initiating cells (GICs) within the tumor. Therefore, understanding the molecular insights of how GICs contribute to the therapy recurrence is crucial for developing new therapeutic strategies. Comparing expression profiles of TMZ-resistant GICs (GICRs) with those of GICs, we identified membrane-associated protein 17 (MAP17) as a new factor that is exclusively expressed in GICRs. We show that overexpression of MAP17 in GICs significantly increased their proliferation, TMZ resistance, and tumorigenicity, whereas its knockdown impaired these properties, indicating that MAP17 plays a critical role in both TMZ resistance and tumorigenicity of GICs. We also show that MAP17 increased the expression of anti-apoptotic protein BCL2 through the activation of RELA-dependent NF-κB pathway in GICs. Furthermore, we demonstrate that overexpression of BCL2 increased TMZ resistance in GICs and their tumorigenicity, while its knockdown deprived these malignant characters in GICRs. Taken together, these findings identify a novel signaling pathway, MAP17-NF-κB-BCL2, that controls TMZ resistance and tumorigenicity of GICs.</p>","PeriodicalId":9580,"journal":{"name":"Cancer Science","volume":"117 7","pages":"1841-1851"},"PeriodicalIF":4.9,"publicationDate":"2026-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cas.70385","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147786373","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":"Relationship Between PTBP1 and Pancreatic Cancer Based on microRNA and Behavior During TYMS-Mediated Carcinogenesis","authors":"Shigenori Suzuki,&nbsp;Hiroaki Hase,&nbsp;Yosuke Inomata,&nbsp;Jun Arima,&nbsp;Kentaro Jingushi,&nbsp;Atsushi Tomioka,&nbsp;Nao Kawaguchi,&nbsp;Hiroki Hamamoto,&nbsp;Ryo Tanaka,&nbsp;Yoshiro Imai,&nbsp;Mitsuhiro Asakuma,&nbsp;Tomohito Tanaka,&nbsp;Kazutake Tsujikawa,&nbsp;Kohei Taniguchi,&nbsp;Sang-Woong Lee","doi":"10.1111/cas.70402","DOIUrl":"10.1111/cas.70402","url":null,"abstract":"<p>Polypyrimidine tract-binding protein 1, an alternative splicing factor, drives cancer-associated metabolic reprogramming by modulating pyruvate kinase M splicing. Although organ-abundant microRNAs (miRs) regulate this protein, its role in tumor progression remains unclear. Therefore, we investigated the functional relationship between polypyrimidine tract-binding protein 1-associated microRNAs and this protein in pancreatic cancer to identify pancreas-enriched microRNAs and explore polypyrimidine tract-binding protein 1 function beyond metabolic regulation. The expression of miR-216b-5p, which is typically pancreas-enriched, was significantly downregulated in clinical pancreatic cancer samples, whereas polypyrimidine tract-binding protein 1 expression was markedly upregulated. Mechanistically, miR-216b-5p directly binds to the 3′ UTR of polypyrimidine tract-binding protein 1 mRNA, thereby suppressing its expression and inhibiting cancer cell proliferation. Proteomic analysis, integrated with publicly available individual-nucleotide resolution UV crosslinking and immunoprecipitation data, identified thymidylate synthase as a novel downstream target of polypyrimidine tract-binding protein 1, likely regulated via splicing-related RNA-level mechanisms. Thymidylate synthase expression was also elevated in pancreatic cancer tissues and correlated with poor prognosis. Functional assays revealed that polypyrimidine tract-binding protein 1 and thymidylate synthase silencing induced cell cycle arrest. Our findings uncover a previously unrecognized miR-216b-5p/polypyrimidine tract-binding protein 1/thymidylate synthase regulatory axis that promotes pancreatic cancer progression and establish polypyrimidine tract-binding protein 1 as a central molecular regulator of tumor biology beyond its metabolic role.</p>","PeriodicalId":9580,"journal":{"name":"Cancer Science","volume":"117 7","pages":"1828-1840"},"PeriodicalIF":4.9,"publicationDate":"2026-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cas.70402","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147786479","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":"Advancements in Inorganic Chiral Nanomaterials for Anti-Tumor Immunotherapy","authors":"Siyu Chen,&nbsp;Qian Tang,&nbsp;Xiqian Chen,&nbsp;Yinghao Liang,&nbsp;Jin Qiu,&nbsp;Yongmei Liao,&nbsp;Changqiang Li,&nbsp;Hongru Yu,&nbsp;Fang Xie,&nbsp;Zongjunlin Liu","doi":"10.1111/cas.70373","DOIUrl":"10.1111/cas.70373","url":null,"abstract":"<p>While the past decade has witnessed unprecedented technological advancements, cancer remains a major health threat, with conventional therapies often constrained by substantial limitations. Immunotherapy, which mobilizes the body's immune system, is hindered by off-target effects, allergic reactions, and cytokine storms. To enhance the precision, safety, and efficacy of cancer treatments, nanomaterials—especially those with nanoscale chiral properties—are offering a new approach for modulating immune responses. The optical anisotropy factor (g-factor) of these nanomaterials has demonstrated precise, monotonic control over immune responses in vivo and in vitro, revealing that nanoscale chiral structures can act as key switches for dendritic cell maturation and function. Inorganic nanomaterials (INMs) are gaining attention for tumor immunotherapy due to their stability, biocompatibility, and precise synthesis. Their versatile surface modification, excellent optical/electrical/magnetic properties, and reproducibility further enhance their utility. Inorganic chiral nanomaterials (ICNMs), leveraging atomically precise chiral structures, enable efficient drug loading and radiosensitization to trigger anti-tumor immunity, overcoming immunosuppressive limitations. Representative ICNMs include chiral gold nanorods, cadmium selenide quantum dots, and cerium oxide nanosheets. Current research focuses on chiral structure control, surface engineering, and multifunctional integration. ICNMs enhance antitumor immunity through targeted immunomodulator delivery, induction of immunogenic cell death, direct immune-cell regulation, and reshaping of the tumor immune microenvironment. Despite their promise, challenges remain in scalable production, long-term biosafety, and chiral stability in complex biological settings. Looking forward, ICNMs are poised to enable precise, efficient, and low-toxicity tumor immunotherapy, driving transformative advances in cancer care.</p>","PeriodicalId":9580,"journal":{"name":"Cancer Science","volume":"117 6","pages":"1543-1553"},"PeriodicalIF":4.3,"publicationDate":"2026-06-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cas.70373","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147582867","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":"Macrophage-Specific Loss of Stearoyl-CoA Desaturase 1 Promotes Colon Cancer by Enhancing M2 TAM Polarization","authors":"Qing You,&nbsp;Jiaqi Du,&nbsp;Ziran Wei,&nbsp;Yandong Liu,&nbsp;Weijun Wang,&nbsp;Wenchao Gao","doi":"10.1111/cas.70393","DOIUrl":"10.1111/cas.70393","url":null,"abstract":"<p>In colon cancer (CC), the polarization of tumor-associated macrophages (TAMs) toward the M2 phenotype plays a critical role in immune therapy resistance, yet the underlying metabolic “switch” has not been fully elucidated. While the function of stearoyl-CoA desaturase 1 (Scd1) in tumor cells has been reported, its role in TAMs remains unknown. We generated Lyz2-Cre-driven myeloid-specific Scd1 knockout (Scd1 cKO) mice and wild-type (Scd1 WT) control mice. Both groups were subcutaneously injected with MC38 cells to establish a colon cancer model. Flow cytometry was utilized to assess the polarization status of TAMs and the infiltration of CD8+ T cells in tumor tissues. RNA sequencing (RNA-seq) combined with Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis was performed to identify differentially expressed genes and key signaling pathways. RT-qPCR and Western blot analysis were used to examine the expression of core molecules within these pathways. Scd1 cKO mice exhibited faster tumor growth and increased tumor weight compared to Scd1 WT mice. Scd1 deletion enhanced TAM polarization toward the M2 phenotype and suppressed the Hippo-YAP pathway, leading to CD8+ T cell exhaustion. Furthermore, TT-10 treatment reversed M2 polarization, restored CD8+ T cell infiltration and effector function, and slowed tumor progression. In conclusion, Scd1 knockout in macrophages accelerates colon cancer by promoting M2 polarization via inhibition of the Hippo-YAP pathway, impairing CD8+ T cell function. Targeting the Scd1-Hippo-YAP signaling axis may offer a promising new approach for immunotherapy in colon cancer.</p>","PeriodicalId":9580,"journal":{"name":"Cancer Science","volume":"117 6","pages":"1566-1579"},"PeriodicalIF":4.3,"publicationDate":"2026-06-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cas.70393","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147724337","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":"Utility of Urinary Extracellular Vesicles for Colorectal Cancer: Comparison of DNA Quality and MRD Detection","authors":"Shintaro Kanaka,&nbsp;Takeshi Yamada,&nbsp;Fumi Asai,&nbsp;Yuta Shimizu,&nbsp;Kay Uehara,&nbsp;Akihisa Matsuda,&nbsp;Seiichi Shinji,&nbsp;Yasuyuki Yokoyama,&nbsp;Goro Takahashi,&nbsp;Takuma Iwai,&nbsp;Kohki Takeda,&nbsp;Sho Kuriyama,&nbsp;Toshimitsu Miyasaka,&nbsp;Koki Hayashi,&nbsp;Hiroshi Yoshida","doi":"10.1111/cas.70368","DOIUrl":"10.1111/cas.70368","url":null,"abstract":"<p>This study evaluated the feasibility of urinary extracellular vesicles (EVs) as a liquid biopsy source for colorectal cancer (CRC) using two predefined cohorts: 97 patients for analytical validation and 63 patients for postoperative survival analysis. We compared urinary EVs, urinary cell-free tumor DNA (ctDNA), plasma EVs, and plasma ctDNA across multiple molecular dimensions, and assessed the utility of urinary EV-DNA for minimal residual disease (MRD) detection. Urinary EVs exhibited larger particle size (median 175.6 nm) and markedly higher purity, demonstrated by a substantially broader proteomic profile (4674 vs. 476 proteins) and significantly higher expression of EV-specific markers (CD63, CD81, CD9). DNA extracted from urinary EVs showed the highest concentration and best preservation of nucleic acid integrity, with the greatest Long/Short fragment ratio, outperforming all plasma-derived samples. Mutation detection sensitivity was comparable across sample types but was highest in plasma ctDNA (39.2%) and urinary EV-DNA (34.0%), exceeding urinary ctDNA (21.6%). In the survival cohort, MRD positivity—defined as detectable <i>RAS/BRAF</i> mutations in urinary EV-DNA 1 month after curative surgery—was strongly associated with inferior outcomes (HR for recurrence 5.25, 95% CI 1.74–15.80), and overall survival was significantly worse in MRD-positive patients. These findings indicate that urinary EVs provide highly pure vesicles with superior DNA quality, making them a robust and completely non-invasive source for molecular profiling. Urinary EV-DNA–based MRD assessment shows significant prognostic value and may serve as a practical tool for postoperative monitoring and risk stratification in colorectal cancer.</p>","PeriodicalId":9580,"journal":{"name":"Cancer Science","volume":"117 6","pages":"1667-1677"},"PeriodicalIF":4.3,"publicationDate":"2026-06-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cas.70368","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147576116","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":"MYC Addiction as a Targetable Vulnerability in Nelarabine-Resistant T-Cell Acute Lymphoblastic Leukemia","authors":"Jingjing Gao,&nbsp;Chunxu Lin,&nbsp;Suchang Chen,&nbsp;Qi Mo,&nbsp;Chu Bao,&nbsp;Huali Deng,&nbsp;Ziyin Chen,&nbsp;Weichao Hao,&nbsp;Luyong Zhang,&nbsp;Min Wei","doi":"10.1111/cas.70382","DOIUrl":"10.1111/cas.70382","url":null,"abstract":"<p>Acquired resistance represents a fundamental obstacle limiting the long-term efficacy of cancer chemotherapy. In T-cell acute lymphoblastic leukemia (T-ALL), the nucleoside analog prodrug nelarabine is a critical salvage therapy for relapsed/refractory (R/R) patients; however, resistance is common and rapid, worsening prognosis. The molecular mechanisms underlying this process remain largely to be elucidated. Here, we identify the oncogene MYC as a key functional mediator driving nelarabine resistance. Through unbiased transcriptomic profiling and functional validation, we demonstrate that nelarabine-resistant T-ALL cells develop a profound addiction to a hyperactive MYC transcriptional program. Critically, MYC knockdown restores nelarabine sensitivity, causally linking MYC to the resistant phenotype. While this discovery reveals a therapeutic vulnerability, MYC itself is considered an ‘undruggable’ protein, making direct inhibition a formidable challenge. We therefore pursued an indirect strategy, employing BET family protein degraders to dismantle the upstream epigenetic machinery essential for MYC transcription. Consistent with a MYC-driven mechanism, treatment with ARV-771 and ARV-825 induced potent degradation of BET proteins, suppressed MYC transcription, and profoundly impaired the viability and proliferation of nelarabine-resistant cells. Importantly, this strategy showed strong therapeutic efficacy in an in vivo model of nelarabine-resistant T-ALL, significantly reducing leukemia burden and extending survival. Our work establishes the first mechanistic link between nelarabine resistance and MYC dependency, providing a compelling preclinical rationale and therapeutic strategy to overcome this challenge. Collectively, this study offers a paradigm for reversing chemotherapy resistance by exploiting acquired transcriptional addictions.</p><p><b>Trial Registration:</b> Registry and the Registration No. of the study/trial. Yes, approved number: IRB Approval No.: Med-Ethics [2026] IIT No. (19)</p>","PeriodicalId":9580,"journal":{"name":"Cancer Science","volume":"117 6","pages":"1608-1622"},"PeriodicalIF":4.3,"publicationDate":"2026-06-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cas.70382","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147634856","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":"CD90 Promotes Gastric Cancer Progression by Regulating SLC1A5-Mediated Glutamine Metabolism Through YY1","authors":"Zihua Zhou,&nbsp;Siyi Liu,&nbsp;Chenyu Zhang,&nbsp;Jun Deng,&nbsp;Lin Liang,&nbsp;Yanhong Zhou","doi":"10.1111/cas.70377","DOIUrl":"10.1111/cas.70377","url":null,"abstract":"<p>CD90 (THY1) is a cell surface glycoprotein that plays a crucial role in the occurrence and development of various malignant tumors. It affects tumor cell proliferation, metastasis, angiogenesis, stem cell characteristics, and energy metabolism. CD90 is an important biomarker for many malignant tumors and is closely related to tumor prognosis. However, the role and specific mechanisms of CD90 in glutamine metabolism in gastric cancer (GC) cells remain incompletely understood. In this study, we report that CD90 affects glutamine metabolism in GC cells through SLC1A5, ultimately promoting GC progression. Mechanistically, CD90 promotes the binding of YY1 to the SLC1A5 promoter, enhances the transcriptional activity of the SLC1A5 promoter, and increases its transcriptional level. This, in turn, affects SLC1A5-mediated glutamine metabolism and ferroptosis in GC cells, ultimately facilitating GC progression. Our results suggest that CD90 plays an important role in regulating glutamine metabolism in GC cells, providing important experimental evidence for elucidating the pathogenesis of GC.</p>","PeriodicalId":9580,"journal":{"name":"Cancer Science","volume":"117 6","pages":"1748-1765"},"PeriodicalIF":4.3,"publicationDate":"2026-06-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cas.70377","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147595663","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":"Molecular and Cell Biological Characterization of Patient-Derived Head and Neck Squamous Carcinoma Cell Lines","authors":"Kazue Ito,&nbsp;Noriko Ishida,&nbsp;Shin Ito,&nbsp;Norihisa Shindo,&nbsp;Satoshi Souma,&nbsp;Mai Mochizuki,&nbsp;Haruna Fujimori,&nbsp;Keiichi Tamai,&nbsp;Takayuki Imai,&nbsp;Tomoko Yamazaki,&nbsp;Kazunori Yamaguchi,&nbsp;Kento Sasaki,&nbsp;Yuya Miyakura,&nbsp;Shigekazu Murakami,&nbsp;Yuka Unno,&nbsp;Naoki Asano,&nbsp;Yukinori Asada,&nbsp;Jun Yasuda","doi":"10.1111/cas.70365","DOIUrl":"10.1111/cas.70365","url":null,"abstract":"<p>Head and neck squamous cell carcinoma (HNSCC) is a major cancer among head and neck malignancies with a limited availability of effective molecularly targeted therapies. The underlying oncogenic mechanisms, however, remain poorly understood. To investigate patient-specific molecular targets, we established patient-derived cell (PDC) lines from surgically resected HNSCC tissue samples. We performed comprehensive analyses, including driver gene mutation profiling using a multigene panel, transcriptomic profiling, and karyotyping. Various cancer-associated genomic alterations, primarily copy number gains, were identified, and these findings were consistent with those of previous studies. Notably, the amplification of <i>EGFR, FGFR2,</i> and <i>CCND1</i> was associated with their overexpression, suggesting potential tumor driver roles. A PDC with a <i>PIK3CA</i> activating mutation was sensitive to the PI3K inhibitor Alpelisib. We also demonstrated that PDCs harboring chromosome segregation errors were vulnerable to <i>KIF18A</i> deletion and pharmacological inhibition. These results support the value of HNSCC-derived PDCs as a platform for advances in precision medicine in oncology research.</p>","PeriodicalId":9580,"journal":{"name":"Cancer Science","volume":"117 6","pages":"1623-1634"},"PeriodicalIF":4.3,"publicationDate":"2026-06-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cas.70365","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147634737","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":"Orthotopic Esophageal Cancer Xenograft Model in Immunosuppressed Microminipigs for Near-Infrared Fluorescence Endoscopy","authors":"Takanori Miyake,&nbsp;Yutaka Kawano,&nbsp;Takanori Kashihara,&nbsp;Masaki Takasu,&nbsp;Kentaroh Takagaki,&nbsp;Shota Fujimoto,&nbsp;Tomoyuki Kawaguchi,&nbsp;Kaizo Kagemoto,&nbsp;Yoshifumi Kida,&nbsp;Koichi Okamoto,&nbsp;Masahiro Sogabe,&nbsp;Naoki Muguruma,&nbsp;Koichi Tsuneyama,&nbsp;Yasushi Sato,&nbsp;Tetsuji Takayama","doi":"10.1111/cas.70378","DOIUrl":"10.1111/cas.70378","url":null,"abstract":"<p>Esophageal squamous cell carcinoma (ESCC) often presents as flat lesions difficult to detect with conventional endoscopy, leading to poor prognosis. To overcome this, we developed a near-infrared (NIR) molecular imaging strategy using an epidermal growth factor receptor (EGFR)-targeted antibody and established a novel orthotopic microminipig (MMP) model for translational evaluation. First, cetuximab was labeled with Alexa Fluor 680 (AF680) and validated in vitro for specific binding. Among five ESCC cell lines profiled for proliferation and antigen density, KYSE410 was selected for in vivo studies due to its optimal balance of these factors. In mouse xenografts, AF680-cetuximab tumor fluorescence peaked at 96 h, achieving high signal-to-noise ratios. Subsequently, to establish a clinically relevant large-animal platform, we optimized an immunosuppression protocol for MMPs. Through iterative testing, we determined that a combination of neonatal thymectomy and pharmacologic immunosuppression (tacrolimus, mycophenolate mofetil, and prednisolone), supplemented with antibiotics and proton-pump inhibitors, was essential to prevent rejection, sepsis, and gastric ulcers. This optimized regimen enabled stable orthotopic engraftment of human ESCC via endoscopic submucosal injection in the MMP esophagus. Using a custom-developed NIR fluorescence endoscope mimicking a clinical setting, we successfully visualized orthotopic tumors with clear margins at 96 h post-injection, subsequently confirmed by immunohistochemistry. In conclusion, AF680-cetuximab enables specific, high-contrast detection of ESCC. Furthermore, we report the first successful orthotopic engraftment of human cancer cells in immunosuppressed MMPs. This model provides a powerful platform for developing fluorescence-guided endoscopic diagnostics and theranostics for early-stage esophageal cancer, bridging the gap to future clinical application.</p>","PeriodicalId":9580,"journal":{"name":"Cancer Science","volume":"117 6","pages":"1678-1689"},"PeriodicalIF":4.3,"publicationDate":"2026-06-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cas.70378","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147617150","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":"SLPI/FBW7/c-Myc Axis Reduces Gemcitabine Sensitivity in PDAC by Enhancing Glycolysis and Impairing NK Cell Immunity","authors":"Haofei Chen,&nbsp;Xin Li,&nbsp;Weixiong Zhu,&nbsp;Yanxi Mu,&nbsp;Guoqing Zhang,&nbsp;Youheng Zhang,&nbsp;Yusheng Cheng,&nbsp;Wence Zhou","doi":"10.1111/cas.70369","DOIUrl":"10.1111/cas.70369","url":null,"abstract":"<p>Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive malignancy with dismal prognosis. Although gemcitabine works by directly inducing tumor cell death, as well as activating NK cell-mediated antitumor immunity, its efficacy remains rather unsatisfying. Currently, biomarkers precisely ascertaining gemcitabine resistance in PDAC are unavailable; thus, it is of much urgency to identify biomarkers accurately predicting gemcitabine sensitivity and explore innovative targets for developing sensitization strategy. Secretory leukocyte protease inhibitor (SLPI) is overexpressed in several solid tumors, but its role in PDAC remains unclear. This study aims to elucidate the function and mechanism of SLPI in modulating gemcitabine sensitivity in PDAC. In this study, we found that SLPI was markedly upregulated in PDAC cell lines and tissues, inversely correlating with gemcitabine efficacy and survival outcome of patients. In vitro, SLPI overexpression significantly reduced PDAC cell sensitivity to gemcitabine-induced direct cytotoxicity and NK cell-mediated lysis through enhancing c-Myc-driven glycolysis, whereas SLPI knockdown generated the opposite effects. Mechanistically, SLPI could directly interact with c-Myc protein, which disturbed the binding of E3 ubiquitin ligase FBW7 to c-Myc and thereby prevented ubiquitination-mediated c-Myc degradation, resultantly increasing c-Myc stability and expression. In vivo, SLPI knockdown substantially sensitized gemcitabine treatment to suppress PDAC growth, and this effect was at least partly dependent on NK cell-mediated antitumor immunity. Totally, our findings support that SLPI may serve as a promising biomarker for predicting gemcitabine therapy response, and targeting SLPI may be an effective strategy to improve gemcitabine efficacy in PDAC patients.</p><p>All procedures involving animals were conducted in compliance with institutional ethics regulations and approved by the Ethics Committee of the Second Hospital of Lanzhou University (Approval No. D2025-434).</p>","PeriodicalId":9580,"journal":{"name":"Cancer Science","volume":"117 6","pages":"1635-1650"},"PeriodicalIF":4.3,"publicationDate":"2026-06-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cas.70369","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147595631","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}