Cancer Science最新文献

{"title":"Gastric Mucosal Molecular Alterations and Multimodal Field-Based Risk Models for Gastric Cancer Development","authors":"Genki Usui,&nbsp;Atsushi Kaneda","doi":"10.1111/cas.70432","DOIUrl":"10.1111/cas.70432","url":null,"abstract":"<p>Gastric cancer risk involves <i>Helicobacter pylori</i> infection, lifestyle and environmental exposures, host susceptibility, and precancerous mucosal changes, such as atrophy and intestinal metaplasia. Although clinical, endoscopic, and histological findings underpin current risk stratification, outcome heterogeneity persists among individuals with similar phenotypes. Here, we review evidence supporting the gastric “multimodal field” as an additional risk assessment layer, emphasizing inflammation- and exposure-associated DNA methylation as a scalable biomarker of field cancerization. Prospective studies and deep profiling of high-risk intestinal metaplasia support methylation-based field cancerization. In a longitudinal health check-up cohort, our work supports an integrated approach combining methylation markers with routinely available clinical variables. We discuss near-term multimodal extensions that may improve interpretability and predictive precision and support more effective personalized surveillance strategies.</p>","PeriodicalId":9580,"journal":{"name":"Cancer Science","volume":"117 9","pages":"2323-2334"},"PeriodicalIF":4.9,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13394432/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148151813","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":"Organ-Specific Cancer-Associated Fibroblast Subtypes Across the Digestive System Linked to Cancer Hallmarks","authors":"Huaitao Wang,&nbsp;Takashi Semba,&nbsp;Atsuko Yonemura,&nbsp;Hiroshi Naito,&nbsp;Lingfeng Fu,&nbsp;Takuya Tajiri,&nbsp;Masaaki Iwatsuki,&nbsp;Takatsugu Ishimoto","doi":"10.1111/cas.70435","DOIUrl":"10.1111/cas.70435","url":null,"abstract":"<p>Cancer-associated fibroblasts (CAFs) are major stromal components of the tumor microenvironment (TME) and play diverse roles in gastrointestinal (GI) cancer progression, immunity, and therapeutic resistance. However, the heterogeneity, tissue specificity, and clinical relevance of CAFs across GI cancers remain incompletely defined. We integrated 14 independent single-cell RNA-sequencing datasets comprising 239 GI adenocarcinoma samples to define the subtypes of CAFs. Machine learning–based deconvolution was applied to 18 bulk transcriptomic cohorts (3396 patients) to estimate CAF subtype abundance and assess prognostic associations by meta-analysis. Functional states, differentiation trajectories, cell–cell communication, and spatial organization were analyzed using gene-set enrichment, transcription factor activity inference, pseudotime modeling, ligand–receptor analysis, and spatial transcriptomics. We identified eight CAF subtypes with distinct transcriptional programs and organ-specific distributions. Two myofibroblastic CAF subtypes (myCAF1 and myCAF2) were consistently associated with poor prognosis, characterized by extracellular matrix remodeling, TGF-β signaling, hypoxia adaptation, and close crosstalk with immunosuppressive macrophages, as well as tumor cells displaying epithelial-mesenchymal transition and hypoxia signatures. In contrast, inflammatory CAF (iCAF) 1 was associated with a favorable prognosis and increased infiltration of antitumor immune cells. Spatial transcriptomic analyses further revealed that distinct CAF subtypes preferentially occupied discrete spatial domains within the GI TME. Our study demonstrated that the functional state and spatial context of CAFs jointly affect tumor progression and outcomes in patients with GI cancers. myCAF-driven stromal niches promote immune suppression and poor prognosis, whereas a balanced inflammatory CAF program may support antitumor immunity.</p>","PeriodicalId":9580,"journal":{"name":"Cancer Science","volume":"117 9","pages":"2496-2508"},"PeriodicalIF":4.9,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13394947/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148139541","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":"Oncogenic BRAF and KRAS Promote Global DNA Hypomethylation Through a Directed Pathway That Upregulates TET3","authors":"Ichiro Onoyama,&nbsp;W. Rod Hardy,&nbsp;Shoichiro Takeishi,&nbsp;Lihua Julie Zhu,&nbsp;Yanglan Tan,&nbsp;Lloyd Hutchinson,&nbsp;Jianhong Ou,&nbsp;Leyuan Ma,&nbsp;Ching-Man Virbasius,&nbsp;Masafumi Yasunaga,&nbsp;Keiichi I. Nakayama,&nbsp;Scott A. Shaffer,&nbsp;Michael R. Green","doi":"10.1111/cas.70434","DOIUrl":"10.1111/cas.70434","url":null,"abstract":"<p>Aberrant epigenetic modification is one of the characteristics of the cancer genome. DNA hypermethylation of cytosine-phospho-guanine (CpG) islands, a hallmark of cancer cells, is well-studied and contributes to cancer development by silencing tumor suppressor genes. However, the mechanisms and biological significance of global DNA hypomethylation in cancer are still unclear. Here, using the v-Raf murine sarcoma viral oncogene homolog B1 (BRAF) V600E knock-in mouse models, we demonstrate that endogenous expression of oncogenic BRAFV600E in non-transformed cells promotes global DNA hypomethylation by increasing the levels of ten-eleven translocation 3 (TET3), which converts 5-methylcytosine (5-mC) into 5-hydroxymethylcytosine (5-hmC). Furthermore, TET3 is targeted for proteasomal degradation by F-box and WD repeat domain containing 7 (FBXW7). BRAFV600E increases TET3 levels by inhibiting glycogen synthase kinase 3β (GSK3β), which phosphorylates TET3 and leads to its ubiquitination and proteasomal degradation. We further found elevated levels of TET3 and 5-hmC in BRAFV600E-induced mouse lung tumors and show that TET3 enhances the ability of BRAFV600E to induce the formation of lung tumors. Notably, endogenous expression of oncogenic Kirsten rat sarcoma virus (KRAS) G12D also promotes global DNA hypomethylation and induces lung tumors through a similar TET3-mediated mechanism. Our findings elucidate one of the unknown mechanisms of global DNA hypomethylation promoted by oncogenic BRAF and KRAS and establish a role for TET3 to promote transformation in cooperation with BRAF and KRAS at an early stage of tumorigenesis.</p>","PeriodicalId":9580,"journal":{"name":"Cancer Science","volume":"117 9","pages":"2397-2412"},"PeriodicalIF":4.9,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13394151/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148057800","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":"circMAN1A2 as an Isoform-Resolved Circular RNA Hub in Cancer","authors":"Hanyu Shang,&nbsp;Hui Wang,&nbsp;Yonghang Xu,&nbsp;Lingyun Geng,&nbsp;Yanqing Wang","doi":"10.1111/cas.70445","DOIUrl":"10.1111/cas.70445","url":null,"abstract":"<p>Circular RNAs (circRNAs) are covalently closed transcripts generated by spliceosome-mediated back-splicing. Their high stability and tissue-, cell-state-, and disease-context specificity support roles as cancer regulators and biomarkers. circMAN1A2, derived from the MAN1A2 locus, is recurrently dysregulated across malignancies. This review aims to summarize current knowledge of circMAN1A2 biology and evaluates its mechanistic and translational relevance in cancer. Emerging evidence indicates that circMAN1A2 should be considered an isoform-resolved RNA hub. Alternative circularization generates multiple isoforms, whereas cancer tissues often show dominance of a predominantly expressed isoform. Functionally, circMAN1A2 extends beyond microRNA sponging to protein binding, proteostasis regulation, and direct circRNA–mRNA pairing mediated by the back-splice junction. Its biological effects are highly context dependent: circMAN1A2 promotes oncogenic phenotypes in several epithelial cancers, but can suppress glioblastoma by inducing ferroptosis and remodeling the immune microenvironment. We integrate evidence on circMAN1A2 isoforms, biogenesis, interactome modules, and cancer-type-specific phenotypes; highlight experimental and quantitative limitations, particularly in competing endogenous RNA models; and propose a translational route for biomarker development and therapeutic targeting, including back-splice-junction-directed oligonucleotides and isoform restoration. Reproducible, isoform-specific standards will be essential for defining the clinical actionability of circMAN1A2.</p>","PeriodicalId":9580,"journal":{"name":"Cancer Science","volume":"117 9","pages":"2345-2356"},"PeriodicalIF":4.9,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13394755/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148320121","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":"Transporter-Associated Therapeutic Efficacy of an SMVT-Targeted Boron Carrier in Boron Neutron Capture Therapy","authors":"Kenichiro Eza,&nbsp;Kohei Tsujino,&nbsp;Rina Shidoh-Kazuki,&nbsp;Yoshiki Fujikawa,&nbsp;Hideki Kashiwagi,&nbsp;Gen Futamura,&nbsp;Ryo Hiramatsu,&nbsp;Toshihiro Takami,&nbsp;Masahiko Wanibuchi,&nbsp;Naonori Hu,&nbsp;Hiroki Tanaka,&nbsp;Minoru Suzuki,&nbsp;Kai Nishimura,&nbsp;Shota Tanaka,&nbsp;Hiroyuki Nakamura,&nbsp;Shinji Kawabata","doi":"10.1111/cas.70444","DOIUrl":"10.1111/cas.70444","url":null,"abstract":"<p>Boron neutron capture therapy (BNCT) requires selective delivery of boron compounds to tumor cells to achieve therapeutic efficacy. In this study, a BNCT strategy centered on the sodium-dependent multivitamin transporter (SMVT)-targeted biotin-conjugated boron compound, BBCIP, was evaluated, with selective incorporation of p-boronophenylalanine (BPA) according to tumor transporter characteristics. To examine transporter-dependent effects, the CRL1666 metastatic brain tumor model in rats was compared with an F98 glioma model, which exhibits distinct transporter expression profiles. The F98 model is characterized by dominant L-type amino acid transporter 1 (LAT1) expression and low SMVT levels, whereas the CRL1666 model shows relatively high SMVT expression. BBCIP demonstrated stable and quantifiable intratumoral boron pharmacokinetics in both models. In BNCT experiments, BBCIP alone showed limited therapeutic efficacy in the LAT1-dominant F98 model (median survival, 29 vs. 23 days in controls), whereas survival was further improved with the addition of BPA. In contrast, in the SMVT-high CRL1666 model, BBCIP-based BNCT significantly prolonged survival (30 vs. 15.5 days in controls), with only modest additional benefit from BPA. These findings indicate that the therapeutic contribution of BBCIP-based BNCT depends on tumor transporter expression and that BPA may be advantageous in tumors with low SMVT expression. Rather than relying on a single boron carrier, these findings support a biology-driven strategy in which boron agents are selected and combined according to tumor-specific characteristics.</p>","PeriodicalId":9580,"journal":{"name":"Cancer Science","volume":"117 9","pages":"2555-2566"},"PeriodicalIF":4.9,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13395001/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148220371","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":"Final Analysis of Neoadjuvant Sintilimab Plus Chemotherapy in IB–IIIA Non-Small-Cell Lung Cancer: Phase 2 neoSCORE Trial","authors":"Miner Shao,&nbsp;Jie Yao,&nbsp;Lufeng Zhao,&nbsp;Ling Zhu,&nbsp;Baizhou Li,&nbsp;Lili Li,&nbsp;Bangyi Zhou,&nbsp;Yixin Zhang,&nbsp;Huiying Liu,&nbsp;Xiaoke Chen,&nbsp;Zuqun Wu,&nbsp;Zexin Chen,&nbsp;Junqiang Fan,&nbsp;Fuming Qiu","doi":"10.1111/cas.70442","DOIUrl":"10.1111/cas.70442","url":null,"abstract":"<p>The optimal number of neoadjuvant chemoimmunotherapy cycles for resectable non-small cell lung cancer (NSCLC) remains uncertain. The randomized phase 2 neoSCORE trial (NCT04459611) conducted a comprehensive final analysis, comparing the outcomes of two versus three cycles of neoadjuvant sintilimab combined with platinum-doublet chemotherapy in 60 stage IB–IIIA NSCLC patients, among whom 55 underwent surgery. After a median follow-up period of 56.9 months, no statistically significant differences in disease-free survival (DFS) or overall survival (OS) were observed between the two-cycle and three-cycle groups. Specifically, the 4-year DFS rates stood at 53.8% and 55.2% while the 4-year OS rates were 76.9% and 75.9%, respectively. Major pathological response (MPR) was strongly associated with improved DFS (HR = 0.26, 95% CI: 0.08–0.85, <i>p</i> = 0.026) and OS (HR = 0.15, 95% CI: 0.03–0.81, <i>p</i> = 0.028) on multivariable Cox analysis. Exploratory analysis revealed that maintenance immunotherapy was associated with longer DFS among patients who achieved MPR, whereas no clear DFS or OS advantage was observed among patients without MPR. In summary, no superiority of three cycles over two cycles was demonstrated in this study. MPR stands out as an independent prognostic indicator, and maintenance immunotherapy seems to be associated with long-term prognosis in patients who achieved MPR, necessitating further prospective validation.</p><p><b>Trial Registration:</b> ClinicalTrials.gov identifier: NCT04459611</p>","PeriodicalId":9580,"journal":{"name":"Cancer Science","volume":"117 9","pages":"2509-2520"},"PeriodicalIF":4.9,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13394034/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148200719","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":"Afatinib Overcomes Osimertinib Resistance via Egfr V804F Mutation in a Syngeneic Egfr-Mutant Lung Cancer Mouse Model","authors":"Takaaki Tanaka,&nbsp;Masato Fujitani,&nbsp;Masataka Taoka,&nbsp;Iwao Shimomura,&nbsp;Sachi Okawa,&nbsp;Shunta Mori,&nbsp;Tadahiro Kuribayashi,&nbsp;Jun Nishimura,&nbsp;Tomoka Nishimura,&nbsp;Ayako Morita,&nbsp;Naofumi Hara,&nbsp;Kiichiro Ninomiya,&nbsp;Go Makimoto,&nbsp;Hisao Higo,&nbsp;Kammei Rai,&nbsp;Eiki Ichihara,&nbsp;Shuta Tomida,&nbsp;Katsuyuki Hotta,&nbsp;Yosuke Togashi,&nbsp;Yoshinobu Maeda,&nbsp;Katsuyuki Kiura,&nbsp;Ryohei Katayama,&nbsp;Kadoaki Ohashi","doi":"10.1111/cas.70431","DOIUrl":"10.1111/cas.70431","url":null,"abstract":"<p>Osimertinib is the standard first-line treatment for advanced <i>EGFR</i>-mutant non-small cell lung cancer. However, acquired resistance invariably develops, and identifying novel resistance pathways is clinically important as a substantial portion remains undefined. We used an immunocompetent syngeneic lung cancer mouse model harboring an <i>Egfr</i> exon 19 deletion (mDEL tumors) to establish acquired resistance. Osimertinib-resistant tumors were generated in vivo using a drug-holiday/re-challenge protocol. The resistance mechanism was identified using Sanger sequencing, receptor tyrosine kinase arrays, and western blotting. <i>Egfr</i> V804F knock-in cells were generated using CRISPR/Cas9, and their sensitivity to osimertinib and afatinib was assessed in vitro and in vivo. We established two distinct osimertinib-resistant tumor lines in a syngeneic lung cancer mouse model (mDEL OsiR #1/#3). The analysis revealed an on-target secondary <i>Egfr</i> V804F mutation (corresponding to human <i>EGFR</i> V802F) in both tumor lines. Importantly, <i>Egfr</i> V804F knock-in cells demonstrated significant osimertinib resistance, with a 5.7–10.5-fold increase in in vitro IC₅₀ (mean, 8.2-fold), but remained highly sensitive to afatinib. Furthermore, afatinib effectively overcame osimertinib resistance in the V804F knock-in cell-derived mouse model. Consistently, afatinib treatment resulted in marked tumor shrinkage and suppression of EGFR signaling in the established mDEL OsiR #1/#3 in vivo. These findings establish secondary <i>Egfr</i> V804F/<i>EGFR</i> V802F as an on-target osimertinib resistance mechanism, providing a preclinical rationale for evaluating afatinib in biomarker-selected patients harboring this alteration.</p>","PeriodicalId":9580,"journal":{"name":"Cancer Science","volume":"117 9","pages":"2426-2442"},"PeriodicalIF":4.9,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13394164/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148145307","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":"Microbiome–Driven Carcinogenesis and Circulating Microbial Signals in Genitourinary Cancers","authors":"Atsunari Kawashima,&nbsp;Kentaro Jingushi,&nbsp;Takuro Saito,&nbsp;Toshihiro Uemura,&nbsp;Akinaru Yamamoto,&nbsp;Nesrine Sassi,&nbsp;Hiromu Horitani,&nbsp;Shunsuke Inoguchi,&nbsp;Yuki Horibe,&nbsp;Yu Ishizuya,&nbsp;Takuji Hayashi,&nbsp;Yoshiyuki Yamamoto,&nbsp;Norio Nonomura","doi":"10.1111/cas.70448","DOIUrl":"10.1111/cas.70448","url":null,"abstract":"<p>The microbiome is increasingly recognized as a regulator of carcinogenesis, tumor immunity, and response to immune checkpoint inhibitors (ICIs), but its role in genitourinary cancers remains less clearly defined than in melanoma or colorectal cancer. In this review, we summarize evidence that microbiome-related pathways influence urothelial carcinoma (UC) and renal cell carcinoma (RCC) across the continuum from tumor initiation to immunotherapy outcome. We highlight recent preclinical studies showing that gut microbial environments can causally modify urothelial carcinogenesis through carcinogen metabolism, inflammatory priming, and diet-microbiome interactions in N-butyl-N-(4-hydroxybutyl) nitrosamine-based mouse models, including a newly established upper tract urothelial carcinoma mouse model, as well as emerging clinical data indicating that circulating extracellular vesicle (EV)-associated bacterial DNA is associated with tumor immune phenotypes and ICI outcomes in UC and RCC. Because blood is a low-biomass matrix, we use the term “circulating microbial signals” rather than “blood microbiome” and emphasize the need for contamination-aware analysis, careful EV characterization, and external validation. Current evidence supports a framework in which microbiome-related signals connect intestinal ecology, systemic immune tone, tumor immune contexture, and treatment response, while indicating that circulating EV-associated bacterial DNA remains an exploratory biomarker platform.</p>","PeriodicalId":9580,"journal":{"name":"Cancer Science","volume":"117 9","pages":"2357-2365"},"PeriodicalIF":4.9,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13394628/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148303620","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":"Elucidating the Pro-Tumor Role of LncRNA CROCCP2 in Glioma via the miR-5584-5p/HOXD11/Autophagy Pathway","authors":"Feng Wang,&nbsp;Ganni Lei,&nbsp;Yuan Peng,&nbsp;Maoqiao Liu,&nbsp;Tianqi Jiang,&nbsp;Minghui Wang,&nbsp;Zhe Wang,&nbsp;Jun Pu,&nbsp;Jia Liu","doi":"10.1111/cas.70433","DOIUrl":"10.1111/cas.70433","url":null,"abstract":"<p>Glioma is the most common primary malignant tumor of the central nervous system, characterized by high invasiveness and a high recurrence rate. The clinical therapeutic efficacy remains limited, necessitating the exploration of novel molecular mechanisms and therapeutic targets. Long non-coding RNAs (lncRNAs), as key epigenetic regulators in tumor progression, can influence tumorigenesis and development through lncRNA–miRNA–mRNA regulatory axes. Here, we reveal the critical role of the lncRNA CROCCP2/miR-5584-5p/HOXD11 axis in glioma. LncRNA CROCCP2 was significantly upregulated in glioma tissues and cell lines, in vitro, markedly promoting the proliferation, migration, and invasion of glioma cells. Mechanistically, LncRNACROCCP2 acts as a competing endogenous RNA to sponge miR-5584-5p, thereby relieving its suppression of the target gene HOXD11, leading to HOXD11 upregulation. HOXD11 negatively regulated autophagy, as reflected by reduced LC3B-II and Beclin1 levels and increased p62 expression. Conversely, CROCCP2 or HOXD11 knockdown activated autophagy and provided supportive evidence for ongoing autophagic flux based on the addition of LC3B-II and p62 after bafilomycin A1 treatment. Knockdown of either lncRNA CROCCP2 or HOXD11 suppressed glioma cell proliferation, migration, and invasion in vitro. In addition, HOXD11 silencing markedly inhibited subcutaneous and intracranial tumor growth in nude mice; furthermore, HOXD11 knockout can even halt the growth of subcutaneous tumors. Collectively, our findings suggest that the lncRNA CROCCP2/miR-5584-5p/HOXD11 axis contributes to glioma cell malignant phenotypes in vitro and tumor growth in vivo, at least partly through negative regulation of autophagy, providing a potential molecular target for glioma therapy.</p>","PeriodicalId":9580,"journal":{"name":"Cancer Science","volume":"117 9","pages":"2443-2460"},"PeriodicalIF":4.9,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13394559/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148165217","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":"UBE2C-Mediated CD147-CTLA-4 Axis Promotes T Cell Exhaustion and Immunosuppressive Microenvironment in Bladder Cancer","authors":"Xuwei Hong,&nbsp;Ting Hong,&nbsp;Xinyu Liu,&nbsp;Peixiu Yao,&nbsp;Weiqiang Lin,&nbsp;Guoyuan Liu,&nbsp;Huihong Guan,&nbsp;Yonghai Zhang","doi":"10.1111/cas.70430","DOIUrl":"10.1111/cas.70430","url":null,"abstract":"<p>Despite immune checkpoint inhibitors (ICIs) having benefited bladder cancer (BCa) patients, their limited response rates urge elucidation of intrinsic resistance mechanisms. In this study, we demonstrated that ubiquitin conjugating enzyme E2C (UBE2C) promotes the proliferation, invasion, and migration of BCa and inhibits DNA damage, accompanied by a decrease in T cell abundance. In syngeneic C57BL/6 BCa models and BCa–CD8⁺ T-cell cocultures, UBE2C silencing reduced CD147 and CTLA-4 abundance, restored IFN-γ, TNF-α, and TGF-β secretion, expanded CD3⁺CD8⁺ subsets, and attenuated tumor growth, invasion, and migration. Conversely, UBE2C or CD147/CTLA-4 overexpression reinstated T-cell exhaustion and malignant progression. Targeting the UBE2C–CD147–CTLA-4 axis resensitizes BCa to immune attack, offering a rational strategy to extend the efficacy of current immunotherapies.</p>","PeriodicalId":9580,"journal":{"name":"Cancer Science","volume":"117 9","pages":"2366-2378"},"PeriodicalIF":4.9,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13394930/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148044288","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}