Cancer Science最新文献

{"title":"Ketogenic Diet and β-Hydroxybutyrate Suppress Bladder Cancer Growth and Enhance Anti-PD-L1 Immunotherapy Efficacy","authors":"Yuan Zeng,&nbsp;Gangli Gu,&nbsp;Lin Yang,&nbsp;Bohao Fan,&nbsp;Haochen Cui,&nbsp;Lei Yan,&nbsp;Zhao Liu","doi":"10.1111/cas.70447","DOIUrl":"10.1111/cas.70447","url":null,"abstract":"<p>The limited clinical efficacy of immune checkpoint inhibitors (ICIs) remains a major challenge in the treatment of bladder cancer (BCa). Here, we report that a ketogenic diet (KD) and its principal circulating metabolite, β-hydroxybutyrate (β-HB), suppress bladder tumor growth and enhance responses to PD-L1 inhibitor. In a syngeneic MB49 model, KD reduced tumor growth compared with normal diet (ND). KD increased plasma β-HB and was associated with higher intratumoral PD-L1 expression. Exogenous β-HB supplementation under ND recapitulated the antitumor effect of KD, further enhancing anti-PD-L1 efficacy. Mechanistically, β-HB increased intracellular reactive oxygen species (ROS) and disrupted mitochondrial membrane potential in bladder cancer cells, leading to ATP depletion and enhanced apoptosis. Besides, β-HB also upregulated PD-L1 in vitro and in vivo through GPR109A-JAK2-STAT3 signaling axis. Immune profiling of treated tumors showed increased infiltration and effector function of CD8⁺ T cells and NK cells and decreased immunosuppressive populations, changes that were further amplified when combined with anti-PD-L1. Together, our results indicate that KD and β-HB exert both tumor intrinsic and immune modulatory effects that sensitize bladder tumors to PD-L1 inhibitor, supporting further evaluation of ketogenic interventions as adjuvants to immunotherapy in BCa.</p>","PeriodicalId":9580,"journal":{"name":"Cancer Science","volume":"117 9","pages":"2379-2396"},"PeriodicalIF":4.9,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13394661/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148220415","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":"Combined MEK1/2 and Autophagy Inhibition Suppresses Tumor Growth via STING-Mediated Type I Interferon Response in iCCA","authors":"Chengqiang Sun,&nbsp;Zheng Gao,&nbsp;Enfu Dong,&nbsp;Liangxia Ding,&nbsp;Shanru Feng,&nbsp;Jiafeng Chen,&nbsp;Pascal Kwangwari,&nbsp;Yinghong Shi,&nbsp;Weiren Liu,&nbsp;Xin Zhang,&nbsp;Ao Huang,&nbsp;Jian Zhou,&nbsp;Sheng Wang,&nbsp;Jia Fan,&nbsp;Xiutao Fu,&nbsp;ZhenBin Ding","doi":"10.1111/cas.70436","DOIUrl":"10.1111/cas.70436","url":null,"abstract":"<p>The RAF–MEK–ERK pathway contributes to many human cancers, including intrahepatic cholangiocarcinoma (iCCA). Although MEK is an important therapeutic target, MEK inhibitors (MEKis) have limited efficacy as monotherapy in iCCA, and the underlying adaptive mechanisms remain unclear. Here, we show that MEK inhibition induces protective autophagy in iCCA cells. Mechanistically, MEK inhibition suppressed ERK–RSK signaling, activated the LKB1–ULK1 pathway, and promoted autophagy. MEK inhibition also increased reactive oxygen species (ROS) accumulation and activated PINK1/Parkin-mediated mitophagy. This autophagic response limited activation of the cGAS–STING–TBK1 pathway. Pharmacological or genetic inhibition of autophagy during MEK inhibition enhanced STING-mediated type I interferon signaling, increased IFN-α and IFN-β expression, and sensitized iCCA cells to MEKi treatment. Consistently, combined MEK and autophagy inhibition suppressed tumor growth in xenograft-bearing nude mice. These findings identify a link between MAPK signaling, autophagy, and innate immune sensing and support targeting the MEK-autophagy-STING axis to improve MEKi efficacy in iCCA.</p>","PeriodicalId":9580,"journal":{"name":"Cancer Science","volume":"117 9","pages":"2413-2425"},"PeriodicalIF":4.9,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13394133/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148145294","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":"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}