Cancer Science最新文献

{"title":"Splicing Factor Mutations in Clonal Hematopoiesis and Progression to Myeloid Neoplasms","authors":"Yang Lyu,&nbsp;Yutong Zhang,&nbsp;Ayana Kon","doi":"10.1111/cas.70461","DOIUrl":"10.1111/cas.70461","url":null,"abstract":"<p>Splicing factor (SF) mutations are recurrent driver alterations in myeloid neoplasms and also represent a distinctive class of mutations in clonal hematopoiesis (CH), an age-associated expansion of hematopoietic clones carrying somatic driver mutations. SF-mutant CH is characterized by relatively late emergence and accelerated clonal expansion in older individuals. This review summarizes current knowledge of the genetic features and clonal dynamics of SF-mutant CH. We discuss disease-associated molecular consequences of SF mutations, including dysregulation of innate immune and inflammatory signaling, R-loop accumulation associated with replication stress, altered stress granule dynamics, impaired minor intron splicing, and cooperative genetic interactions. We further consider candidate mechanisms that may contribute to age-dependent selection of SF-mutant clones during CH, including attenuated interferon responsiveness and telomere-dependent changes in replicative fitness. Together, current evidence highlights the unique biology of SF-mutant CH and the unresolved mechanisms underlying its preferential expansion in older individuals. Clarifying these mechanisms may improve risk stratification, inform early-intervention strategies, and advance our understanding of age-associated clonal evolution and leukemogenesis.</p>","PeriodicalId":9580,"journal":{"name":"Cancer Science","volume":"117 10","pages":"2609-2618"},"PeriodicalIF":4.9,"publicationDate":"2026-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13394321/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148382429","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":"Clinical and Imaging Features of Tepotinib-Induced Interstitial Lung Disease in the Post-Marketing Setting in Japan","authors":"Terufumi Kato,&nbsp;Tomohisa Baba,&nbsp;Masahiro Endo,&nbsp;Shehla Endo,&nbsp;Eisuke Horii,&nbsp;Masahiko Kusumoto","doi":"10.1111/cas.70471","DOIUrl":"10.1111/cas.70471","url":null,"abstract":"<p>The objective of this study was to investigate the clinical and imaging features of tepotinib-induced interstitial lung disease (ILD) using real-world data obtained during routine clinical use of tepotinib in Japan. The study was conducted as a voluntary safety-monitoring activity and targeted cases reported during the period from 1st June 2020 (the launch date of tepotinib in Japan) to 31st December 2023. An ILD adjudication committee, composed of external respiratory and radiology experts, assessed the clinical and imaging features of the ILD. The committee expertly identified 35 patients with tepotinib-induced ILD, with an estimated reported incidence of 2.9% (35/1190 patients). The estimated reported incidence of the fatal ILD was 0.9% (11/1190 patients). More than half of the ILDs were classified as ≤grade 2 (19/35 patients), with the predominant imaging pattern of organizing pneumonia (OP) (15/19 patients), followed by hypersensitivity pneumonitis (HP) and diffuse alveolar damage (DAD) patterns (3 and 1/19 patients, respectively). In contrast, among the ≥grade 3 ILDs (15/35 patients), DAD was the most frequently observed pattern (7/15 patients), followed by OP and HP patterns (6 and 2/15 patients, respectively). The median time to onset of the 35 ILDs from the start of tepotinib administration was 50.0 days (range: 4–205 days). Fatal outcomes occurred more frequently in patients with pre-existing ILD/interstitial lung abnormality (ILA) (8/12 patients), whereas most patients without pre-existing ILD/ILA experienced better outcomes of recovered/resolving (19/23 patients). These findings highlight the importance of close monitoring for ILD occurrence during the real-world clinical use of tepotinib.</p>","PeriodicalId":9580,"journal":{"name":"Cancer Science","volume":"117 10","pages":"2827-2837"},"PeriodicalIF":4.9,"publicationDate":"2026-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13394608/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148450053","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":"Genomic Evolution and Immune Contexture With Therapeutic Relevance in Pancreatic Neuroendocrine Neoplasms","authors":"Yohei Tabe,&nbsp;Eito Nakagawa,&nbsp;Daisuke Asano,&nbsp;Eriko Katsuta,&nbsp;Daisuke Ban,&nbsp;Shogo Kumagai","doi":"10.1111/cas.70466","DOIUrl":"10.1111/cas.70466","url":null,"abstract":"<p>Neuroendocrine neoplasms (NENs) are a heterogeneous family of epithelial malignancies that share neuroendocrine differentiation but differ in lineage origin, genomic architecture, immune contexture, and clinical behavior. Pancreatic neuroendocrine neoplasms (PanNENs) are particularly informative because well-differentiated pancreatic neuroendocrine tumors (PanNETs) and poorly differentiated pancreatic neuroendocrine carcinomas (PanNECs) arise in the same organ yet follow distinct evolutionary trajectories. Despite advances in surgery, targeted therapy, chemotherapy, and peptide receptor radionuclide therapy (PRRT), advanced PanNENs remain largely incurable, and immune checkpoint blockade has shown limited and inconsistent benefit. Recent genomic, epigenomic, and immune profiling studies indicate that differentiation state and lineage programs are major organizing principles of PanNEN biology. PanNETs are typically defined by chromatin regulatory alterations, relative lineage stability, and weakly inflamed immune microenvironments, although a subset shows increased tumor-associated macrophage infiltration and other immunoregulatory features linked to aggressive disease. By contrast, PanNECs are characterized by lineage instability, cell-cycle dysregulation, and a more inflamed yet functionally suppressed immune context, with greater immune-cell infiltration and more frequent checkpoint pathway engagement. However, these features do not necessarily indicate effective antitumor immunity, because inflammatory engagement may coexist with impaired antigen presentation, including human leukocyte antigen class I loss, tumor-intrinsic immune evasion, and suppressive myeloid networks. We propose that genomic alterations, epigenetic states, and immune architectures evolve as a coupled system in PanNENs. We discuss how lineage identity shapes antigen presentation defects, immune suppression, and therapeutic vulnerability, and we outline biologically rational, precision-guided strategies, including epigenetic modulation, targeting of immunosuppressive cell populations, and lineage-informed therapies.</p>","PeriodicalId":9580,"journal":{"name":"Cancer Science","volume":"117 10","pages":"2619-2635"},"PeriodicalIF":4.9,"publicationDate":"2026-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13394173/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148473656","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":"Selective Depletion of Tumor-Infiltrating CD4+CCR8+ Tregs by AZ084, a Novel CCR8 Antagonist","authors":"Yepeng Mao,&nbsp;Ziqi Tao,&nbsp;Shuna Liu,&nbsp;Zhijie Liu,&nbsp;Yuelu Zhang,&nbsp;Lingfei Zhou,&nbsp;Lina Yan,&nbsp;Ting Wang,&nbsp;Wenwen Shang,&nbsp;Jianfang Lou,&nbsp;Xi Huang,&nbsp;Xin Fu,&nbsp;Fang Wang","doi":"10.1111/cas.70465","DOIUrl":"10.1111/cas.70465","url":null,"abstract":"<p>Regulatory T cells (Tregs) are key mediators of immunosuppression in ovarian cancer, yet strategies for selectively targeting tumor-infiltrating Tregs remain limited. CD4⁺CCR8⁺ Tregs have been proposed as a highly suppressive subset, but their functional relevance and therapeutic potential require further investigation. Here, we demonstrate that CCR8 is preferentially expressed on tumor-infiltrating CD4⁺ Tregs in syngeneic ID8 and B16 tumor models, accounting for a significantly higher proportion compared with CD4⁺ conventional T cells and CD8⁺ T cells (<i>p</i> &lt; 0.001). Functionally, CD4⁺CCR8⁺ Tregs exhibited enhanced suppressive activity, markedly inhibiting IFN-γ production by CD8⁺ T cells (<i>p</i> &lt; 0.01). The antagonist AZ084 significantly impaired Treg differentiation and alleviated Treg-mediated suppression in vitro (<i>p</i> &lt; 0.01). In vivo, AZ084 treatment effectively suppressed tumor growth in both ovarian cancer and melanoma models (<i>p</i> &lt; 0.01), accompanied by a reduction in tumor-infiltrating CD4⁺CCR8⁺ Tregs and an increase in CD8⁺ T cell infiltration and effector function (<i>p</i> &lt; 0.05). Importantly, AZ084 had minimal impact on splenic immune cell composition (<i>p</i> &gt; 0.05), suggesting limited systemic immunotoxicity. Collectively, our findings identify CCR8 as a selective marker and functional regulator of tumor-infiltrating Tregs. Targeting CCR8 with AZ084 represents a promising strategy to enhance antitumor immunity while preserving peripheral immune homeostasis, providing a potential therapeutic approach for ovarian cancer.</p>","PeriodicalId":9580,"journal":{"name":"Cancer Science","volume":"117 10","pages":"2719-2732"},"PeriodicalIF":4.9,"publicationDate":"2026-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13394841/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148431061","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":"Downregulation of KRTAP2-3 Suppresses Proliferation and Tumor Formation of Oral Cancer Cells via Inactivation of KRAS Signals","authors":"Qianqian Miao,&nbsp;Zhijun Huang,&nbsp;Kazuki Takahashi,&nbsp;Haruka Ibi,&nbsp;Kohei Miyazono,&nbsp;Katarzyna A. Podyma-Inoue,&nbsp;Tetsuro Watabe","doi":"10.1111/cas.70355","DOIUrl":"10.1111/cas.70355","url":null,"abstract":"<p>The progression and metastasis of oral squamous cell carcinoma (OSCC), the most common type of head and neck squamous cell carcinoma (HNSCC), are driven by complex molecular mechanisms, including proliferative signaling pathways such as KRAS signaling and epithelial-mesenchymal transition (EMT). Despite advances in cancer research, the dual challenge of suppressing both proliferation and metastasis of OSCC cells remains unresolved. As a poor prognostic factor in HNSCC, we recently identified the keratin-associated protein 2–3 (KRTAP2-3), which induces EMT and metastasis of OSCC cells. However, its involvement in OSCC progression has not yet been fully elucidated. In the present study, we aimed to examine the roles of endogenous KRTAP2-3 in the proliferation and tumor formation of OSCC cells. Using multiple OSCC cell lines, we demonstrated that downregulation of KRTAP2-3 not only induced mesenchymal-epithelial transition (MET) but also reduced cell proliferation. Furthermore, RNA sequencing analyses of OSCC cells and HNSCC tumor tissues revealed that KRTAP2-3 downregulation suppressed KRAS signaling accompanied by decreased expressions of fibroblast growth factor-5 (FGF-5) and Fos-like antigen 1 (FOSL1), poor prognostic factors in HNSCC. Knockdown of either FGF-5 or FOSL1 significantly reduced OSCC cell proliferation, highlighting their critical roles in KRTAP2-3-mediated tumor progression. Furthermore, downregulation of KRTAP2-3 significantly suppressed tumor formation of OSCC cells. These findings suggest that KRTAP2-3 promotes OSCC progression by maintaining mesenchymal and proliferative traits via pathways related to FGF-5, FOSL1, and KRAS signaling. Targeting the KRTAP2-3 may represent a promising therapeutic strategy for OSCC, addressing the dual challenge of suppressing both proliferation and metastasis.</p>","PeriodicalId":9580,"journal":{"name":"Cancer Science","volume":"117 10","pages":"2752-2768"},"PeriodicalIF":4.9,"publicationDate":"2026-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13393517/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148551283","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":"Ezh2 Inhibits the Differentiation of Short-Lived Effector CD8+ T Cells and Promotes T Cell-Dependent Antitumor Immunity","authors":"Kenji Takagi,&nbsp;Junpei Suzuki,&nbsp;Yuko Matsuoka,&nbsp;Makoto Kuwahara,&nbsp;Taro Oshikiri,&nbsp;Masakatsu Yamashita","doi":"10.1111/cas.70439","DOIUrl":"10.1111/cas.70439","url":null,"abstract":"<p>Appropriate regulation of the differentiation balance between effector CD8⁺ T cells and memory CD8⁺ T cells is crucial for an appropriate immune response. We previously reported that the tumor suppressor menin suppresses the differentiation of CD8⁺ T cells into short-lived effector T cells (SLECs) and positively regulates memory CD8⁺ T cell differentiation. In this study, we identified Ezh2, a histone H3K27 methyltransferase, as a factor responsible for regulating SLECs differentiation, located downstream of menin. In antigen-stimulated CD8⁺ T cells, the Ezh2 expression gradually decreased with proliferation, reaching the lowest levels in terminally differentiated CD8⁺ T cells. The decrease in the expression of Ezh2 was accelerated by menin deficiency. Reduced histone H3K27 acetylation at the <i>Ezh2</i> locus was observed in <i>Menin</i>-deficient CD8⁺ T cells, indicating that menin is required for maintaining the expression of Ezh2. In vitro studies have demonstrated that <i>Ezh2</i>-deficient activated CD8⁺ T cells exhibit enhanced differentiation into SLECs, along with increased effector functions. In contrast, Ezh2-deficient effector CD8⁺ T cells showed a marked increase in apoptosis upon IL-2 removal. In studies using mouse tumor models, T cell-specific Ezh2 knockout mice exhibited increased tumor growth and reduced survival relative to wild-type mice, with a significant decrease in the number of tumor-infiltrating CD8⁺ T cells. RNA sequencing revealed that <i>Ezh2</i>-deficient effector CD8⁺ T cells exhibit the increased expression of terminal differentiation-related molecules and apoptosis-related genes. These results demonstrate that Ezh2 functions downstream of menin and is essential for the proper regulation of T cell-dependent antitumor immunity.</p>","PeriodicalId":9580,"journal":{"name":"Cancer Science","volume":"117 10","pages":"2644-2658"},"PeriodicalIF":4.9,"publicationDate":"2026-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13394198/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148145266","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":"A Three-Dimensional Culture–Drug Sensitivity Test Predicts MDM2 Inhibitor–Sensitivity in SMARCB1/INI1-Deficient Tumors","authors":"Hiroaki Goto,&nbsp;Chiyoko Nishime,&nbsp;Takashi Ohtsu,&nbsp;Mieko Ito,&nbsp;Maiko Sagisaka,&nbsp;Takuya Naruto,&nbsp;Norihiko Kitagawa,&nbsp;Mio Tanaka,&nbsp;Masakatsu Yanagimachi,&nbsp;Yukihiko Hiroshima,&nbsp;Junko Takita,&nbsp;Yasuhide Hayashi,&nbsp;Yohei Miyagi","doi":"10.1111/cas.70451","DOIUrl":"10.1111/cas.70451","url":null,"abstract":"<p>Loss of SMARCB1/INI1 expression is a common feature of various types of tumors including malignant rhabdoid tumor, an aggressive cancer of children. Because SMARCB1/INI1 deficiency leads to genome-wide transcriptional dysregulation, identifying a specific therapeutic target that acts on a wide range of SMARCB1/INI1-deficient tumors has been challenging. This study aimed to establish if the personalized selection of effective drugs against SMARCB1/INI-deficient tumors is possible by in vitro drug sensitivity profiling. The in vitro drug sensitivity profiles of tumors from SMARCB1/INI1-deficient tumor cell line–derived mouse xenograft (CDX) models were evaluated by a short-term collagen gel–embedded three-dimensional culture–drug sensitivity test (3D-DST). With the 3D-DST, molecular targeting drugs, including inhibitors of aurora B kinase, mammalian target of rapamycin, mitogen-activated protein kinase, WNT/β-catenin, or mouse double minute 2 homolog (MDM2), were selected as therapeutic drug candidates in SMARCB1/INI1-deficient tumors. A CDX tumor, which was resistant to MDM2 inhibitors in the 3D-DST, expressed lower <i>TP53</i> compared to an MDM2 inhibitor–sensitive tumor. In cultured cell lines, exposure to MI-773, a MDM2 inhibitor, disturbed the expression of a significant number of genes and induced p21 protein expression in MDM2 inhibitor–sensitive cells. However, such changes were not observed in resistant cells. These results suggest that 3D-DST can predict biologically relevant drug sensitivity profiles in SMARCB1/INI1-deficient tumors.</p>","PeriodicalId":9580,"journal":{"name":"Cancer Science","volume":"117 10","pages":"2852-2862"},"PeriodicalIF":4.9,"publicationDate":"2026-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13394486/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148340735","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":"NTAQ1 Promotes Hepatocellular Carcinoma Growth by Facilitating the Protein Degradation of the Tumor Suppressor PRDM2","authors":"Tomohiko Ikehara,&nbsp;Hajime Otsu,&nbsp;Taro Tobo,&nbsp;Kiyotaka Hosoda,&nbsp;Tadashi Abe,&nbsp;Masahiro Hashimoto,&nbsp;Yusuke Nakano,&nbsp;Katsushi Dairaku,&nbsp;Yuya Ono,&nbsp;Yuki Miyata,&nbsp;Chihiro Matsumoto,&nbsp;Takanari Tatsumi,&nbsp;Satoshi Higuchi,&nbsp;Takashi Ofuchi,&nbsp;Akinori Tsujimoto,&nbsp;Yuki Ando,&nbsp;Qingjiang Hu,&nbsp;Yusuke Yonemura,&nbsp;Akira Shimizu,&nbsp;Takaaki Masuda,&nbsp;Yuji Soejima,&nbsp;Koshi Mimori","doi":"10.1111/cas.70456","DOIUrl":"10.1111/cas.70456","url":null,"abstract":"<p>Recent studies have demonstrated the crucial role of the arginine/N-degron pathway, which mediates protein degradation, in cancer initiation and progression. N-terminal glutamine amidohydrolase 1 (NTAQ1), an upstream enzyme in this pathway that catalyzes the deamidation of N-terminal glutamine residues, remains poorly understood in tumor biology. This study aimed to investigate the clinical significance and molecular functions of NTAQ1 in hepatocellular carcinoma (HCC). Copy number variation analysis using The Cancer Genome Atlas identified NTAQ1 as a potential driver of HCC progression. The biological role of NTAQ1 in HCC was investigated using in vitro experiments involving NTAQ1 overexpression (OE) in HCC cell lines. NTAQ1, located on the amplified chromosome 8q, exhibited elevated expression in the HCC tissues. NTAQ1 was also identified as an independent poor prognostic factor in patients with HCC, and immunohistochemical staining revealed that it primarily localized in the cytoplasm and membranes of HCC cells. NTAQ1 OE promoted HCC colony formation. Through in silico analysis, the tumor suppressor gene PR/SET Domain 2 (<i>PRDM2</i>) was identified to have a strong inverse correlation with NTAQ1 at the protein level. In vitro assays revealed that NTAQ1 OE enhanced PRDM2 degradation. Furthermore, NTAQ1 OE reduced DNA repair and apoptosis through decreased PRDM2 expression. In conclusion, NTAQ1 was identified as a novel driver gene in HCC that accelerates tumor growth by promoting degradation of the PRDM2 protein, thereby impairing DNA repair and suppressing apoptosis. These findings indicate that NTAQ1 could be a valuable target for treating HCC.</p>","PeriodicalId":9580,"journal":{"name":"Cancer Science","volume":"117 10","pages":"2803-2818"},"PeriodicalIF":4.9,"publicationDate":"2026-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13394586/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148354543","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":"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}