Cancer Science最新文献

{"title":"Afatinib Versus Osimertinib for Non-Small Cell Lung Cancer With Uncommon EGFR Mutations: Real-World Outcomes","authors":"Yutaro Nagano,&nbsp;Hiroshi Yokouchi,&nbsp;Ryota Saito,&nbsp;Osamu Honjo,&nbsp;Toshiyuki Sumi,&nbsp;Takayuki Kaburagi,&nbsp;Kenichiro Ito,&nbsp;Yasuyuki Ikezawa,&nbsp;Keiki Yokoo,&nbsp;Hajime Kikuchi,&nbsp;Sayaka Kudo,&nbsp;Masami Yamazoe,&nbsp;Ryota Shigaki,&nbsp;Keita Tagami,&nbsp;Toshiyuki Tenma,&nbsp;Tatsuru Ishikawa,&nbsp;Mamoru Takahashi,&nbsp;Takaaki Sasaki,&nbsp;Hajime Asahina,&nbsp;Shiro Hinotsu,&nbsp;Hirofumi Chiba,&nbsp;Satoshi Oizumi","doi":"10.1111/cas.70400","DOIUrl":"10.1111/cas.70400","url":null,"abstract":"<p>Non–small cell lung cancers (NSCLC) harboring uncommon epidermal growth factor receptor (EGFR) mutations (UMs) are clinically heterogeneous, and the optimal first-line EGFR tyrosine kinase inhibitor (EGFR-TKI), as well as the role of subsequent immune checkpoint inhibitor (ICI)–based regimens, remains uncertain. We conducted a multicenter retrospective cohort study including patients with advanced or recurrent non-squamous NSCLC harboring UMs who received first-line afatinib or osimertinib between January 2015 and January 2024 at 29 hospitals in Japan, excluding exon 20 insertions and de novo T790M mutations. Inverse probability of treatment weighting adjusted baseline imbalances, and post–EGFR-TKI treatment patterns were evaluated. Among 162 patients (afatinib, <i>n</i> = 95; osimertinib, <i>n</i> = 67), weighted analyses demonstrated no significant differences in time to treatment failure (hazard ratio [HR], 1.04; 95% confidence interval [CI], 0.61–1.77) or overall survival (HR, 1.34; 95% CI, 0.73–2.44). Afatinib was associated with higher response rates and more frequent adverse events requiring dose reduction. Subgroup analyses suggested differential treatment effects according to mutation subtype, with osimertinib favoring L861X mutations and afatinib favoring compound mutations. Among 56 patients who received subsequent systemic therapy, clinical outcomes were comparable between ICI plus platinum doublet and platinum doublet alone. These findings indicate that afatinib and osimertinib provide comparable survival outcomes as first-line therapies for NSCLC with UMs, with treatment effects varying by molecular subtype, while subsequent ICI-based regimens may confer limited additional benefit.</p>","PeriodicalId":9580,"journal":{"name":"Cancer Science","volume":"117 8","pages":"2236-2246"},"PeriodicalIF":4.9,"publicationDate":"2026-08-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13394325/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148102109","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":"MTAP Deficiency as a Metabolic Vulnerability in Cancer: Implications for Synthetic Lethal Therapy","authors":"Hiroaki Ikushima,&nbsp;Hidenori Kage","doi":"10.1111/cas.70429","DOIUrl":"10.1111/cas.70429","url":null,"abstract":"<p>The homozygous deletion of the chromosome 9p21.3 locus, which includes cyclin-dependent kinase inhibitor 2A/B (<i>CDKN2A/B</i>) and methylthioadenosine phosphorylase (<i>MTAP</i>) genes, is one of the most common genomic alterations in cancer. <i>MTAP</i> encodes an essential enzyme in the methionine salvage pathway. Historically, deletions at this locus have been characterized primarily by cell cycle dysregulation driven by <i>CDKN2A/B</i> loss. However, recent studies have revealed that the co-deletion of <i>MTAP</i> exposes profound metabolic vulnerabilities. Loss of the MTAP function increases cellular dependency on protein arginine methyltransferase 5 (PRMT5). Consequently, targeted PRMT5 inhibition effectively induces synthetic lethality specifically in <i>MTAP</i>-deleted tumors. Based on this unique mechanism, the development of novel therapeutic agents exploiting this synthetic lethality is actively underway. In this review, we provide a comprehensive overview of the physiological roles of the MTAP-PRMT5 axis and the mechanistic principles underlying this synthetic lethality in <i>MTAP</i>-deficient cells. Furthermore, drawing upon insights from the analysis of real-world patient data, we discuss the clinical and molecular characteristics of <i>MTAP</i>-deleted tumors, review the landscape of ongoing clinical trials, and explore novel therapeutic strategies.</p>","PeriodicalId":9580,"journal":{"name":"Cancer Science","volume":"117 8","pages":"2085-2097"},"PeriodicalIF":4.9,"publicationDate":"2026-08-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13394919/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148036812","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":"MiR-375 in CAFs-Derived EVs Promotes HCC Progression via Regulating RASA1 and May Potentially Serve as a Biomarker for HCC","authors":"Wei Qin,&nbsp;Li Wang,&nbsp;Beiyuan Hu,&nbsp;Cuicui Xiao,&nbsp;XiaoYing Wu,&nbsp;Huan Tian,&nbsp;Songlin Peng","doi":"10.1111/cas.70422","DOIUrl":"10.1111/cas.70422","url":null,"abstract":"<p>Cancer-associated fibroblasts (CAFs) in the tumor microenvironment play an important role in cancer initiation and progression through mediating crosstalk between CAFs and cancer cells. In our study, we unveiled that CAFs-derived extracellular vesicles (EVs) could deliver miR-375 to endothelial cells (EC) and further contribute to tumor angiogenesis by regulating Ras GTPase Activating Protein 1 (RASA1) in hepatocellular carcinoma (HCC). We also found that HCC patients with more advanced disease showed higher levels of miR-375 in plasma EVs, which were preferentially expressed in the EVs of CAFs. These data provided direct evidence supporting the pivotal role of the tumor suppressor miR-375, which is selectively sorted into CAF-derived EVs, in promoting angiogenesis during HCC progression and revealed that genetically modified CAF-derived EVs may provide a potential therapeutic strategy for HCC. Furthermore, our study indicated that miR-375 in plasma EVs could serve as a potential predictive and prognostic biomarker in HCC patients.</p>","PeriodicalId":9580,"journal":{"name":"Cancer Science","volume":"117 8","pages":"2208-2220"},"PeriodicalIF":4.9,"publicationDate":"2026-08-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13395009/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148018221","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":"RASD2 Drives Renal Clear Cell Carcinoma Progression via RAF1 (Ser338) Phosphorylation","authors":"Jingxuan Yu,&nbsp;Gang Yu,&nbsp;Yuan Liu,&nbsp;Yu Zhou,&nbsp;Wei Liu,&nbsp;Lin Wang,&nbsp;Lide Liu,&nbsp;Yan Liu,&nbsp;Tiejun Pan,&nbsp;Zhenyu Liu,&nbsp;Lei Gao","doi":"10.1111/cas.70415","DOIUrl":"10.1111/cas.70415","url":null,"abstract":"<p>Clear cell renal cell carcinoma (ccRCC) is a highly aggressive malignancy with limited treatment options. Although RASD2, which encodes a Ras-related GTP-binding protein, has been linked to melanoma progression, its role in ccRCC remains unclear. In this study, we systematically investigated the oncogenic functions and mechanisms of RASD2 in ccRCC. Clinically, RASD2 was significantly overexpressed in tumor tissues compared with adjacent normal tissues and correlated with poor patient prognosis. Functional studies demonstrated that RASD2 promotes proliferation, migration, and invasion of the ccRCC cells in vitro, findings further supported by xenograft models in nude mice. Mechanistically, RASD2 activated the P38/ERK–MAPK pathway, and inhibition experiments confirmed its necessity for RASD2-driven oncogenesis. Through co-immunoprecipitation and LC–MS/MS, we identified RAF1 as a key binding partner. RASD2 enhanced RAF1 phosphorylation at Ser338, thereby activating the P38/ERK–MAPK pathway. RAF1 phosphorylation at Ser338 was critical for ccRCC cell growth, migration, and invasion. The RAF1 inhibitor BAY43-9006 reduced p-RAF1 (Ser338)/RAF1 levels, suppressed ccRCC proliferation, migration, and invasion in vitro, and significantly inhibited tumor growth in vivo. These findings identify RASD2 as a novel oncoprotein that promotes ccRCC tumorigenesis through p-RAF1 (Ser338)-mediated P38/ERK–MAPK activation, suggesting RAF1 inhibition as a promising therapeutic strategy for ccRCC patients.</p>","PeriodicalId":9580,"journal":{"name":"Cancer Science","volume":"117 8","pages":"2194-2207"},"PeriodicalIF":4.9,"publicationDate":"2026-08-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13394055/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148145256","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":"Blocking SETD2 Enhances the Therapeutic Efficiency of Menin Inhibitor in MLL-Fusion Leukemia","authors":"Anpei Li,&nbsp;Yuan Zhang,&nbsp;Ziwei Li,&nbsp;Anhao Liu,&nbsp;Li Zhang,&nbsp;Shubin Gao,&nbsp;Xiao Lin,&nbsp;Xiaoming Liu,&nbsp;Huan Li,&nbsp;Guanghui Jin,&nbsp;Bin Xu","doi":"10.1111/cas.70419","DOIUrl":"10.1111/cas.70419","url":null,"abstract":"<p>During transcriptional elongation, the histone methyltransferase SETD2 binds to RNA polymerase II and deposits trimethylation marks at histone H3 lysine 36 (H3K36me3). However, the role of SETD2 in <i>MLL-</i>fusion leukemia has remained controversial over the past decade. Here, through genotyping of loss-of-function SETD2 mutations, we define the genetic basis for SETD2 acting as a haploinsufficient tumor suppressor in this disease. Then, we demonstrate that gene amplification and high expression of <i>SETD2</i> are associated with poor prognosis, supporting the double-sided roles of <i>SETD2</i> in this kind of acute leukemia. Next, we show that inhibitors of SETD2 (EZM0414) and menin (Revumenib) have synergistic efficacy against <i>MLL</i>-fusion and <i>NPM1</i>-mut leukemia and make prominent induction of cell cycle arrest, differentiation, and apoptosis. Moreover, SETD2 inhibition sensitizes leukemia cells to menin inhibitor through decreasing H3K36me3 marks, and combination therapy dramatically inhibits transcription of the canonical targeted genes, whose function may account for these phenotypic changes. The mode of action of this combined treatment is due to the attenuated both H3K36me3 at gene body regions and H3K4me3 at gene promoter regions. Finally, we clarify that the combined-drug treatment delays <i>MLL</i>-fusion leukemia progression in vivo. Taken together, these findings establish the simultaneously blocking of transcription elongation and initiation by epigenetic inhibitors as a promising therapeutic strategy for these aggressive leukemias.</p>","PeriodicalId":9580,"journal":{"name":"Cancer Science","volume":"117 8","pages":"2221-2235"},"PeriodicalIF":4.9,"publicationDate":"2026-08-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13394958/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147989853","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":"Epithelial YPEL3 Modulates CD8+ T-Cell Infiltration and Tumor Progression Through CREB1–CXCL16 Signaling in HNSCC","authors":"Yalun Li,&nbsp;Yumei Li,&nbsp;Caiyu Sun,&nbsp;Congxian Lu,&nbsp;Gang Chen,&nbsp;Tianshu Zhou,&nbsp;Bei Zhang,&nbsp;Xicheng Song","doi":"10.1111/cas.70409","DOIUrl":"10.1111/cas.70409","url":null,"abstract":"<p>Yippee-like 3 (YPEL3) has been implicated in the regulation of apoptosis, proliferation, and invasion in various cancers, but its role in head and neck squamous cell carcinoma (HNSCC) remains unclear. Here, we integrated pan-cancer data, TCGA/GEO transcriptomes, DNA methylation profiles, and single-cell RNA sequencing to explore YPEL3's expression, prognosis, and immune relevance in HNSCC. YPEL3 was downregulated in tumor tissues and correlated with better overall survival, particularly in advanced-stage patients. Functional assays confirmed that YPEL3 suppressed proliferation, migration, and invasion while promoting apoptosis in vitro; its knockdown accelerated tumor growth in vivo. Bulk transcriptomics and TIMER analysis revealed that high YPEL3 expression was associated with increased stromal and immune infiltration, including CD8⁺ T cells. Single-cell analysis identified an epithelial subcluster (Epi.C3) enriched for YPEL3, expanded in tumors, and linked to poor prognosis. Mechanistically, YPEL3-high epithelial cells secreted CXCL16, interacting with CXCR6 on CD8⁺ T cells to promote immune engagement. YPEL3 regulated CXCL16 via CREB1 but not TFAP2C. Co-culture assays showed that epithelial YPEL3 modulated the CXCL16–CXCR6 axis in T cells. In vivo, YPEL3 loss was associated with reduced CD8⁺ T-cell infiltration and impaired CD8⁺ T-cell effector function, as indicated by decreased Granzyme B, Perforin, IFN-γ, and TNF-α. Together, these findings identify YPEL3 as a tumor suppressor and an important mediator of epithelial–immune crosstalk in HNSCC, linking epithelial differentiation-associated states to antitumor immunity through the CREB1/CXCL16/CXCR6 axis.</p>","PeriodicalId":9580,"journal":{"name":"Cancer Science","volume":"117 8","pages":"2132-2151"},"PeriodicalIF":4.9,"publicationDate":"2026-08-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13394896/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148018438","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":"Neutrophil-Macrophage Interactions Shape Inflammatory Macrophage Remodeling in Gastric Cancer During Chemo-Immunotherapy","authors":"Keita H. Nagaoka,&nbsp;Hiroki Yamashita,&nbsp;Chiaki Mashima,&nbsp;Guoqiang Zhang,&nbsp;Hitoshi Saito,&nbsp;Tatsunori Minamide,&nbsp;Takuya Nakatsuru,&nbsp;Ryo Kamata,&nbsp;Shunsuke A. Sakai,&nbsp;Gaku Yamamoto,&nbsp;Tomoko Y. Morita,&nbsp;Kazuki Nakai,&nbsp;Yumi Hakozaki,&nbsp;Kumi Kinoshita,&nbsp;Yui Takahashi,&nbsp;Izuma Nakayama,&nbsp;Akihito Kawazoe,&nbsp;Sai M. Pulukuri,&nbsp;Yuko Ishii,&nbsp;Hiroshi Haeno,&nbsp;Yukie Kashima,&nbsp;Kohei Shitara,&nbsp;Tomonori Yano,&nbsp;Takeshi Saito,&nbsp;Akihiro Ohashi","doi":"10.1111/cas.70384","DOIUrl":"10.1111/cas.70384","url":null,"abstract":"<p>The tumor microenvironment (TME) in gastric cancer (GC) is a dynamic ecosystem where immune, stromal, and malignant cells influence therapeutic outcomes. Although macrophages and neutrophils are key regulators of the TME, their coordinated responses to distinct treatments remain unclear. In this study, we performed single-cell RNA sequencing on GC biopsy specimens from treatment-naïve (TN) patients, as well as patients treated with chemotherapy (C), chemotherapy plus nivolumab (CN), or chemotherapy plus trastuzumab (CT). Comparative analyses revealed marked remodeling of the myeloid compartment, particularly involving the CN group. Neutrophils in the CN group exhibited transcriptional reprogramming, characterized by major histocompatibility complex (MHC) class II expression, inflammatory activation, and enrichment of maturation-related signatures. Pseudotime and ligand–receptor analyses identified neutrophils as a prominent sender of signals communicating with macrophages via chemokine and cytokine signaling. These neutrophil-derived signals promoted macrophage polarization toward a CXCL10⁺ M1-like phenotype and activated inflammatory signaling pathways. In vivo validation using a syngeneic CT26 mouse model confirmed that neutrophil depletion abolished the antitumor efficacy of combined oxaliplatin and PD-1 blockade, underscoring the functional importance of this crosstalk. Collectively, our findings demonstrate that PD-1 blockade combined with chemotherapy reprograms the GC TME by enhancing neutrophil–macrophage interactions, which amplify inflammatory signaling and strengthen antitumor immunity. These results highlight the myeloid-centered axis as a potential determinant of immunotherapy responses in GC.</p>","PeriodicalId":9580,"journal":{"name":"Cancer Science","volume":"117 8","pages":"2115-2131"},"PeriodicalIF":4.9,"publicationDate":"2026-08-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13394609/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147989864","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":"Tumor-Derived Extracellular Vesicles in Plasma for Predicting Anti-PD-1 Antibody Efficacy in Non-Small Cell Lung Cancer","authors":"Tomonari Kinoshita,&nbsp;Shigeki Ohta,&nbsp;Seiki Wakui,&nbsp;Chihaya Maeda,&nbsp;Yuichiro Hayashi,&nbsp;Aya Misawa,&nbsp;Ryosuke Satomi,&nbsp;Shinnosuke Ikemura,&nbsp;Kenzo Soejima,&nbsp;Tomonori Yaguchi,&nbsp;Shotaro Maruyama,&nbsp;Hiroshi Kagamu,&nbsp;Yutaka Kawakami","doi":"10.1111/cas.70412","DOIUrl":"10.1111/cas.70412","url":null,"abstract":"<p>Liquid biopsy is a promising biomarker for cancer detection and prediction of therapy responses. In this study, we developed new antibody-based sandwich assays to measure three extracellular vesicle (EV) subsets that express cell surface vimentin (CSV) and co-express epithelial cell adhesion molecule (EpCAM) or PD-L1 in plasma. Fifty-seven non-small cell lung cancer (NSCLC) patients who underwent complete resection and 89 stage IV NSCLC patients who received anti-PD-1 antibody were enrolled. Correlations between the plasma EV subsets at baseline and various clinicopathological factors were evaluated. Plasma EpCAM/CSV-EV levels were significantly higher in stage I NSCLC patients compared to healthy donors, suggesting this may be a valuable biomarker for detecting early-stage NSCLC. High plasma CSV/CSV-EV levels at baseline were significantly correlated with a poor prognosis after treatment, both in the surgery cohort and the anti-PD-1 antibody cohort, which suggests that this may be useful for predicting the post-treatment prognosis in NSCLC patients. High plasma CSV/PD-L1-EV levels at baseline were significantly correlated with poor postoperative prognosis. However, high plasma CSV/PD-L1-EV levels at baseline were significantly correlated with a favorable clinical response and prognosis following anti-PD-1 antibody treatment in stage IV NSCLC. Therefore, plasma CSV-related EV subsets at baseline may be attractive biomarkers for early cancer detection (EpCAM/CSV), prediction of postoperative prognosis (CSV/CSV), and prediction of clinical responses and prognosis after anti-PD-1 antibody therapy (CSV/PD-L1). These EV subsets can be easily measured repetitively at appropriate timing. These novel liquid biopsies may be additional and complementary diagnostic biomarkers for NSCLC patients.</p>","PeriodicalId":9580,"journal":{"name":"Cancer Science","volume":"117 8","pages":"2152-2165"},"PeriodicalIF":4.9,"publicationDate":"2026-08-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13394557/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148007207","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":"MAFF Suppresses Necroptosis in Pancreatic Cancer via the GATA4-MLKL Axis","authors":"Xinwei Zhou,&nbsp;Zheng Zhao,&nbsp;Ning Sun,&nbsp;Daoyong Zhang","doi":"10.1111/cas.70414","DOIUrl":"10.1111/cas.70414","url":null,"abstract":"<p>Pancreatic adenocarcinoma (PAAD) is a highly aggressive malignancy characterized by rapid progression. In this study, we identify the small MAF protein, MAFF, as a critical driver of PAAD tumorigenesis and a negative regulator of the necroptotic pathway. MAFF silencing significantly suppressed malignant phenotypes in PAAD cells in vitro and attenuated overall tumor growth in vivo, while ectopic expression promoted tumor progression. Mechanistically, RNA-sequencing and Gene Set Enrichment Analysis (GSEA) identified necroptosis as a key pathway suppressed by MAFF. We established that MAFF acts as a direct transcriptional repressor of <i>GATA4</i>, which in turn serves as a transcriptional activator of the necroptotic executioner <i>MLKL</i>. Consequently, MAFF depletion leads to the reactivation of the GATA4-MLKL axis, triggering necroptotic cell death. The growth-inhibitory effects of MAFF silencing were effectively reversed by pharmacological inhibition of necroptosis or genetic knockdown of <i>GATA4</i> or <i>MLKL</i>. Analysis of clinical data from TCGA and GTEx databases revealed that MAFF is significantly overexpressed in human PAAD tissues compared to normal controls, with elevated levels correlating with advanced histological grade and poor patient prognosis. Collectively, our findings demonstrate that MAFF facilitates PAAD progression by suppressing GATA4-mediated necroptosis, highlighting the MAFF-GATA4-MLKL axis as a promising therapeutic target and prognostic biomarker in pancreatic cancer.</p>","PeriodicalId":9580,"journal":{"name":"Cancer Science","volume":"117 8","pages":"2181-2193"},"PeriodicalIF":4.9,"publicationDate":"2026-08-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13394936/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147976688","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":"MAPK Inhibitor-Tolerant Persister Cells in Melanoma: Mechanisms and Therapeutic Vulnerabilities","authors":"Bhoomi Shah,&nbsp;Mackenzie M. Mayhew,&nbsp;Jacob Sellers,&nbsp;Russell G. Witt","doi":"10.1111/cas.70418","DOIUrl":"10.1111/cas.70418","url":null,"abstract":"<p>Though major advancements have been made within the realm of targeted and immune-based therapies, metastatic melanoma still remains one of the most notoriously incurable malignancies due to early drug tolerance and eventual resistance. Increasing evidence has started to show drug-tolerant persister cells as a critical nongenetic mechanism that allows survival under MAPK pathway inhibition. While genetically resistant clones support stable mutations, persister cells enter reversible, slow-cycling states which are triggered by stressful conditions. This review synthesizes current research on the various molecular and cellular mechanisms which support melanoma persister cell formation, focusing specifically on phenotype plasticity, selective translational control, metabolic rewiring, redox buffering, and compensatory signaling pathways. We highlight how dynamic transitions among MITF-low, SOX10-low, and KDM5B-high states enable persistence under therapeutic pressure, and how epitranscriptomic regulation and metabolic shifts toward oxidative/lipid-dependent processes help decouple and focus on survival rather than proliferation. Furthermore, we examine microenvironment-driven activation of RhoA-FAK-AKT signaling and redox-adaptive sulfur metabolism as unique adaptive resistance mechanisms. Finally, our paper emphasizes persister states serving as evolutionary intermediates from which stable resistance can eventually emerge, and outline therapeutic strategies which exploit the transient persister vulnerability and help prevent melanoma drug-resistance.</p>","PeriodicalId":9580,"journal":{"name":"Cancer Science","volume":"117 8","pages":"2050-2063"},"PeriodicalIF":4.9,"publicationDate":"2026-08-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13394650/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147976609","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}