Cancer Science最新文献

{"title":"Trichostatin A Sensitizes Tumor Cells to Apoptosis Induced by Soluble Trimeric TRAIL-Expressing Human Mesenchymal Stromal Cells","authors":"Ryosuke Uchibori,&nbsp;Ken Ohmine,&nbsp;Keiya Ozawa","doi":"10.1111/cas.70283","DOIUrl":"10.1111/cas.70283","url":null,"abstract":"<p>Mesenchymal stromal cells (MSCs) are promising vehicles for delivering therapeutic agents to tumors, as a result of their tumor-homing ability. This study aimed to develop MSCs expressing a trimeric soluble form of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), which was enhanced by incorporating an isoleucine zipper (SCZT), to improve apoptosis-inducing efficacy. Because some cancer cells are resistant to TRAIL, we also investigated the effects of combining SCZT-expressing MSCs with trichostatin A (TSA), a histone deacetylase inhibitor that enhances the expression of TRAIL death receptors (DR4/DR5) in tumor cells. TSA increased TRAIL sensitivity in resistant tumor cells in vitro by upregulating DR5, leading to enhanced caspase-8 activation and tumor cell death. MSCs accumulated at tumor sites in vivo, and the combination of SCZT-MSCs and TSA significantly suppressed tumor growth in both TRAIL-sensitive and TRAIL-resistant mouse models. Notably, this combination led to complete tumor regression in some TRAIL-resistant tumors. These in vivo findings indicate that efficient tumor targeting by MSCs is crucial for achieving therapeutic efficacy, especially in TRAIL-resistant tumors. Overall, our results demonstrate that co-treatment with TSA enhances the antitumor effect of TRAIL-expressing MSCs, offering a potential strategy to overcome TRAIL resistance and improve MSC-based cancer therapies.</p>","PeriodicalId":9580,"journal":{"name":"Cancer Science","volume":"117 2","pages":"456-467"},"PeriodicalIF":4.3,"publicationDate":"2025-11-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12861110/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145649885","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":"Crucial Contribution of BACH1 to Bladder Cancer Progression via Upregulating Epithelial-Mesenchymal Transition Pathway","authors":"Tomoya Hatayama,&nbsp;Kenshiro Takemoto,&nbsp;Kohei Kobatake,&nbsp;Kento Miura,&nbsp;Liyanage P. Perera,&nbsp;Ryoken Yamanaka,&nbsp;Kazuma Yukihiro,&nbsp;Hiroyuki Shikuma,&nbsp;Kyosuke Iwane,&nbsp;Ryo Tasaka,&nbsp;Yuki Kohada,&nbsp;Miki Naito,&nbsp;Shunsuke Miyamoto,&nbsp;Yohei Sekino,&nbsp;Hiroyuki Kitano,&nbsp;Keisuke Goto,&nbsp;Akihiro Goriki,&nbsp;Keisuke Hieda,&nbsp;Osamu Kaminuma,&nbsp;Nobuyuki Hinata","doi":"10.1111/cas.70284","DOIUrl":"10.1111/cas.70284","url":null,"abstract":"<p>Bladder cancer (BC) is a prevalent urological malignancy, with muscle-invasive subtypes exhibiting a particularly poor prognosis despite recent therapeutic advances. Established risk factors such as smoking contribute to carcinogenesis through the generation of reactive oxygen species, which trigger oxidative stress responses (OSRs). Broad-complex-Tramtrack-Bric a brac and Cap'n' collar homology 1 (BACH1), a key transcription factor regulating OSRs, has been implicated in epithelial-mesenchymal transition (EMT) and metastasis in several malignancies. This study aimed to clarify the role of BACH1 in BC progression and metastasis. Clinical analyses revealed that BACH1-positive expression was correlated with aggressive tumor features, including advanced pathological stage, high tumor grade, and poor prognosis. In vitro experiments demonstrated that BACH1 knockdown suppressed, while overexpression enhanced, the invasive, migratory, and proliferative activities. RNA sequencing indicated significant enrichment of EMT-related and cytokine-driven immune pathways following BACH1 knockdown. Furthermore, in vivo mouse allograft experiments showed that Bach1 knockout cells exhibited reduced tumor growth and fewer lung metastases, accompanied by altered expression of EMT markers and modulation of cytokine-driven immune signaling. Collectively, these findings suggest that BACH1 plays a crucial role in BC progression and metastasis, at least in part, through two complementary mechanisms, EMT activation and immune microenvironment modulation via cytokine signaling.</p>","PeriodicalId":9580,"journal":{"name":"Cancer Science","volume":"117 2","pages":"364-376"},"PeriodicalIF":4.3,"publicationDate":"2025-11-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12861106/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145641753","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":"Microtubule Inhibitors Induce Cross-Resistance to Osimertinib Through CaMKII Activation in EGFR-Mutated NSCLC","authors":"Kento Kono,&nbsp;Ryosuke Tanino,&nbsp;Yukari Tsubata,&nbsp;Eshat Fahmida Haque,&nbsp;Takeshi Isobe,&nbsp;Tamio Okimoto","doi":"10.1111/cas.70274","DOIUrl":"10.1111/cas.70274","url":null,"abstract":"<p>The current standard postoperative adjuvant therapy for patients with epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC) includes chemotherapy, including microtubule inhibitors prior to the administration of osimertinib, an EGFR-tyrosine kinase inhibitor (TKI). However, multidrug resistance following treatment with microtubule inhibitors has been reported, and the optimal sequence of drug administration for EGFR-mutated NSCLC remains undefined. In this study, we investigated whether prior treatment with microtubule inhibitors induces acquired cross-resistance to osimertinib in EGFR-mutated NSCLC cells in vitro. To model acquired resistance, PC-9 cells were exposed to vinorelbine or paclitaxel for 18 weeks—approximating the clinical duration of four adjuvant chemotherapy cycles—and subsequent drug sensitivity and signaling pathway alterations were assessed using cell viability assays, RNA sequencing, and immunoblotting. We found that two human NSCLC cell lines derived from PC-9 exhibited reduced sensitivity to osimertinib after 18 weeks of in vitro treatment with tubulin inhibitors: vinorelbine (PC-9/VNR) and paclitaxel (PC-9/PTX). Furthermore, PC-9/VNR and PC-9/PTX cells showed activation of FZD7 and calcium/calmodulin-dependent protein kinase II (CaMKII), along with increased sensitivity to the CaMKII inhibitor KN-93, which exerted additive or synergistic effects. These findings suggest that CaMKII plays a critical role in EGFR-TKI resistance. This study underscores the importance of optimizing the timing of EGFR-TKI administration in the therapeutic sequence for EGFR-mutated NSCLC.</p>","PeriodicalId":9580,"journal":{"name":"Cancer Science","volume":"117 2","pages":"418-428"},"PeriodicalIF":4.3,"publicationDate":"2025-11-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12861095/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145641739","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":"Importance of SUMOylation Consensus Sequence of MAFK in Regulating EMT, Tumor Growth, Stemness, and Drug Resistance","authors":"Thuy Linh Dang Cao,&nbsp;Yukari Okita,&nbsp;Reon Yahatabara,&nbsp;Manar A. Elhinnawi,&nbsp;Nuriza Ulul Azmi,&nbsp;Thanasis Poullikkas,&nbsp;Hozumi Motohashi,&nbsp;Mitsuyasu Kato","doi":"10.1111/cas.70282","DOIUrl":"10.1111/cas.70282","url":null,"abstract":"<p>Posttranslational modification is crucial for modulating protein functions. SUMOylation is a posttranslational modification where a small ubiquitin-related (like) modifier (SUMO) conjugates to a lysine residue in the substrate proteins. SUMOylation has been shown to affect the alteration of substrate proteins' functions, subcellular localization, or stability. Furthermore, it has been reported that SUMOylation is involved in regulating angiogenesis, cellular migration, and epithelial–mesenchymal transition (EMT). Moreover, a link between SUMO proteins and multidrug resistance in hepatocellular carcinoma and multiple myeloma has been reported. Classified as a set of transcription factors belonging to the basic region leucine zipper (bZIP) family, musculoaponeurotic fibrosarcoma (MAF) proteins are divided into two groups: large MAF (c-MAF, MAFA, and MAFB) and small MAF (MAFF, MAFG, and MAFK). We previously demonstrated that MAFK confers tumorigenic ability to nontumorigenic mammary gland epithelial cells, NMuMG cells, through induction of EMT. Furthermore, the knockdown of MAFK significantly suppressed the tumorigenic and metastatic growth of breast cancer cells. Among MAF family proteins, the SUMOylation consensus sequence, ψKxE, is highly conserved, and SUMOylation has been shown in MAF family proteins, MAFB and MAFG, respectively. In this study, we focused on SUMOylation and investigated the importance of the SUMOylation consensus sequence in MAFK for MAFK-induced EMT, cellular migration and invasion, tumor and sphere formation, acquisition of stem-like properties, and drug resistance against doxorubicin by using the non-SUMOylation mimic mutant. Additionally, our results suggest that these findings depend on the expression of ATP-binding cassette (ABC) transporter 2 (ABCG2).</p>","PeriodicalId":9580,"journal":{"name":"Cancer Science","volume":"117 2","pages":"445-455"},"PeriodicalIF":4.3,"publicationDate":"2025-11-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12861103/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145641717","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 YAP/TAZ–CDC6 Axis Initiates and Maintains Malignant Transformation","authors":"David Nduru,&nbsp;Yudai Ohta,&nbsp;Akihiro Nita,&nbsp;Mayumi Niimura,&nbsp;Samson Ngurari,&nbsp;Toshiro Moroishi","doi":"10.1111/cas.70279","DOIUrl":"10.1111/cas.70279","url":null,"abstract":"<p>Malignant transformation involves the acquisition of proliferative advantages by cells, often through the dysregulation of key signaling pathways. The Hippo pathway effectors YAP and TAZ are well-established regulators of cell proliferation, and their aberrant activation is linked to tumorigenesis in various cancers. However, the molecular mechanisms by which YAP and TAZ sustain malignant transformation remain unclear. In this study, we employed an in vitro transformation model using immortalized mouse embryonic fibroblasts (iMEFs) constitutively expressing active YAP or TAZ. We demonstrated that YAP or TAZ hyperactivation is sufficient to induce malignant transformation, and that the removal of these proteins reverses the transformed phenotype, indicating their necessity for both tumor initiation and maintenance. Transcriptomic profiling identified a 17-gene signature specifically upregulated by YAP, which was enriched in cell cycle–related genes. Among these, CDC6, a DNA replication licensing factor, emerged as a critical target of YAP and TAZ. Functional assays revealed that CDC6 depletion impaired YAP/TAZ-induced anchorage-independent growth. Moreover, analysis of The Cancer Genome Atlas (TCGA) datasets showed elevated <i>CDC6</i> expression across multiple human tumors with high YAP and TAZ activity, and a strong positive correlation between <i>CDC6</i> and <i>YAP/TAZ</i> expression. These findings highlight that the conserved YAP/TAZ–CDC6 axes are key drivers of malignant transformation and underscore their potential as therapeutic targets across diverse cancer types.</p>","PeriodicalId":9580,"journal":{"name":"Cancer Science","volume":"117 2","pages":"353-363"},"PeriodicalIF":4.3,"publicationDate":"2025-11-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12861111/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145641715","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":"Third-Generation EGFR-TKIs Combined With Chemotherapy in Advanced Non-Small Cell Lung Cancer: A Real-World Study","authors":"YuQin Jiang,&nbsp;Qi Liang,&nbsp;Yuting Zhu,&nbsp;Xiao Liang,&nbsp;Ruohan Huang,&nbsp;Wenxin Zhou,&nbsp;Chen Zhang,&nbsp;Jun Li,&nbsp;Jiali Xu,&nbsp;Renhua Guo","doi":"10.1111/cas.70269","DOIUrl":"10.1111/cas.70269","url":null,"abstract":"<p>FLAURA2 has demonstrated that third-generation epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) plus chemotherapy brought a significant survival benefit over EGFR-TKI monotherapy. This suggests that EGFR-TKIs combined with chemotherapy may be a viable therapeutic strategy. Our study aimed to evaluate the efficacy, safety, and progression pattern of third-generation EGFR-TKIs combined with chemotherapy in advanced <i>EGFR</i>-mutant (<i>EGFR</i>m) non-small cell lung cancer (NSCLC) in the real world. This study designed as an observational, retrospective, single-center, real-world project enrolled 382 NSCLC individuals receiving third-generation EGFR-TKIs combined with platinum-based chemotherapy as first-line therapy. The primary end point was progression-free survival (PFS), and secondary end points included overall survival (OS), objective response rate (ORR), disease control rate (DCR), and adverse events (AEs). From July 2016 to May 2024, 382 patients were retrospectively included for the analysis. Of these patients, 120, 165, and 97 patients received osimertinib, aumolertinib, and furmonertinib plus chemotherapy as first-line therapy, respectively. Overall, the median follow-up duration was 34.6 months (95% CI: 32.2–35.6), the median PFS was 30.9 months (95% CI: 27.5–39.3), and the median OS was 53.9 months (95% CI: 46.2–NR). Overall, the ORR was 76.4% and the DCR was 98.2%. One hundred thirty-seven (35.9%) individuals experienced Grade 3 or higher AEs. Different third-generation EGFR-TKI groups show no statistically significant difference in PFS (HR = 0.75; 95% CI: 0.51–1.10; <i>p</i> = 0.25) after inverse probability of treatment weighting (IPTW), nor in AEs or severe AEs (<i>p</i> = 0.852; <i>p</i> = 0.502). First-line third-generation EGFR-TKI combined with pemetrexed-based chemotherapy demonstrated a favorable ORR and PFS benefit in advanced <i>EGFR</i>m NSCLC.</p>","PeriodicalId":9580,"journal":{"name":"Cancer Science","volume":"117 2","pages":"476-490"},"PeriodicalIF":4.3,"publicationDate":"2025-11-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12861108/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145641730","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":"TGM2 Regulates Radiosensitivity via POGZ-Mediated Repair of DNA Double-Strand Breaks in Cervical Cancer","authors":"Yunbo Chi,&nbsp;Peng Dong,&nbsp;Ning Zhang,&nbsp;Baocai Liu,&nbsp;Qian Wang,&nbsp;Guanghui Cheng","doi":"10.1111/cas.70277","DOIUrl":"10.1111/cas.70277","url":null,"abstract":"<p>The high capacity of cancer cells for DNA damage repair constitutes a critical factor contributing to their radioresistance. Previous studies have demonstrated that aberrant expression of transglutaminase 2 (TGM2) is linked to treatment resistance. However, the role of TGM2 in cervical cancer radiosensitivity and its underlying mechanisms remain unclear. In this study, we found that TGM2 was significantly upregulated in radioresistant cervical cancer cells and tissues. TGM2 knockdown significantly enhanced the radiosensitivity of cervical cancer cells, while TGM2 overexpression conferred radioresistance. TGM2 depletion exacerbated ionizing radiation (IR)-induced DNA double-strand breaks (DSBs). Mechanistically, IR triggered the nuclear translocation of TGM2, where it physically interacted with POGO transposable element derived with ZNF domain protein (POGZ) and upregulated POGZ protein levels. TGM2 knockdown impaired BRCA1 recruitment to DSB sites, phenocopying POGZ depletion effects. Rescue experiments demonstrated that POGZ knockdown reversed the radioresistance and reduction in DNA DSBs caused by TGM2 overexpression. Subcutaneous xenograft mouse models further verified these findings and the regulatory role of TGM2 in cervical cancer radiosensitivity in vivo. Together, our results demonstrated that TGM2 regulates radiosensitivity by POGZ-mediated DNA DSBs repair, providing a novel strategy for increasing cervical cancer radiosensitivity.</p>","PeriodicalId":9580,"journal":{"name":"Cancer Science","volume":"117 2","pages":"429-444"},"PeriodicalIF":4.3,"publicationDate":"2025-11-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12861107/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145641732","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":"Extraneural Metastasis in Oligodendroglioma: A Comprehensive Review and Outcome Analysis of 90 Cases","authors":"Ahmad Daher,&nbsp;Muhammad Yaman Jaber,&nbsp;Stefania Maraka,&nbsp;Hiranmayi Vemaganti,&nbsp;Tibor Valyi-Nagy","doi":"10.1111/cas.70275","DOIUrl":"10.1111/cas.70275","url":null,"abstract":"<p>Extraneural metastasis in oligodendroglioma is a rare and poorly characterized event. We report a case whereby liver and bone metastasis occurred 19 years after diagnosis. Next generation sequencing on brain and liver oligodendroglioma showed several common mutations and a few unique ones to each organ. We identified a total of 90 similar cases and analyzed them through univariate and multivariate regression analysis to assess the impact of relevant clinical variables on overall survival, post-metastasis survival, and extraneural metastasis latency. These analyses highlighted the role of 1p19q codeletion in prolonging overall survival and delaying extraneural metastasis onset but interestingly without impacting post-metastasis survival. Aggressive treatment before metastasis was associated with shorter post-metastasis survival. Other clinical factors showed limited impact. To our knowledge, this is the only reported case with next-generation sequencing data on the primary, recurrent, and metastatic oligodendroglioma tumors, providing rare molecular insights into disease evolution. Our study also represents the largest collection of oligodendroglioma extraneural metastasis cases to date, and the only one to include detailed analysis of clinical variables and their impact on survival and metastasis.</p>","PeriodicalId":9580,"journal":{"name":"Cancer Science","volume":"117 2","pages":"316-324"},"PeriodicalIF":4.3,"publicationDate":"2025-11-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12861102/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145641697","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":"Targeting Overexpressed IDO in Stromal Cells as a Potential Therapeutic Strategy in Multiple Myeloma","authors":"Toru Ebina,&nbsp;Masaki Ri,&nbsp;Yoshiaki Marumo,&nbsp;Tomoyuki Nakamura,&nbsp;Hirokazu Sasaki,&nbsp;Yoshiko Oshima,&nbsp;Takahiro Nakashima,&nbsp;Shinya Hagiwara,&nbsp;Arisa Asano,&nbsp;Shiori Kinoshita,&nbsp;Tomotaka Suzuki,&nbsp;Tomoko Narita,&nbsp;Ayako Masaki,&nbsp;Takaomi Sanda,&nbsp;Kazufumi Yamagata,&nbsp;Kohmei Kubo,&nbsp;Hirokazu Komatsu,&nbsp;Hirotake Sakuraba,&nbsp;Shinsuke Iida","doi":"10.1111/cas.70255","DOIUrl":"10.1111/cas.70255","url":null,"abstract":"<p>Stromal cells are an essential component of the tumor microenvironment (TME) in multiple myeloma (MM). Indoleamine 2,3-dioxygenase 1 (IDO), an enzyme that metabolizes tryptophan (Trp) to kynurenine (Kyn), plays an immunosuppressive role in the TME. We previously reported that a high Kyn/Trp ratio was associated with poor prognosis in lenalidomide-treated refractory/relapsed MM patients and that IDO expression in stromal cells was upregulated by co-culture with MM cells. Here, we analyzed the mechanism through which MM cells upregulate IDO in stromal cells and aimed to identify compounds that inhibit IDO upregulation. Two MM cell lines, XG-7 and IM-9, upregulated IDO in stromal cells both directly and indirectly. These two MM cell lines also upregulated programmed cell death ligand 1 (PD-L1) in stromal cells, which was closely related to IDO upregulation. RNA sequencing analysis revealed that cytokine signaling pathways were commonly upregulated in stromal cells co-cultured with these two MM cell lines. In stromal cells co-cultured with MM cells, signal transducer and activator of transcription 1 (STAT1) and nuclear factor-κB (NF-κB) p65 was phosphorylated, and interferon regulatory factor 1 (IRF1), which binds to the IDO promoter region, was strongly upregulated. This IDO and IRF1 upregulation were abolished by Janus kinase (JAK) inhibitor. In addition, stromal cells with knockout of <i>IRF1</i> showed little upregulation of IDO when co-cultured with MM cells. These results suggest that the JAK–STAT1–NF-κB–IRF1 signaling pathway may be involved in IDO upregulation. JAK inhibitors may improve the TME in MM and positively influence immunotherapy outcomes.</p>","PeriodicalId":9580,"journal":{"name":"Cancer Science","volume":"117 2","pages":"325-334"},"PeriodicalIF":4.3,"publicationDate":"2025-11-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12861097/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145641773","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 Microenvironments in Malignant Ovarian Germ Cell Tumors: MHC Class I Loss and T-Cell Exhaustion in Dysgerminoma","authors":"Miya Nakashima,&nbsp;Takeshi Iwasaki,&nbsp;Yoshihiro Katayama,&nbsp;Masatoshi Shimo,&nbsp;Ken Takigawa,&nbsp;Naomi Shimada,&nbsp;Michiko Matsushita,&nbsp;Satoshi Kuwamoto,&nbsp;Shinya Sato,&nbsp;Masato Toya,&nbsp;Kohta Miyawaki,&nbsp;Koichi Akashi,&nbsp;Kiyoko Kato,&nbsp;Yoshinao Oda","doi":"10.1111/cas.70281","DOIUrl":"10.1111/cas.70281","url":null,"abstract":"<p>Malignant ovarian germ cell tumors are rare neoplasms primarily affecting young women. Although generally responsive to chemotherapy, long-term adverse effects remain a concern. Improved understanding of the tumor microenvironment may reveal alternative therapeutic strategies; however, comprehensive analyses in malignant ovarian germ cell tumors remain limited. We analyzed 56 malignant ovarian germ cell tumor samples: 23 dysgerminomas, 14 yolk sac tumors, and 19 immature teratomas. Immune cell infiltration and immune checkpoint molecule expression were evaluated via immunohistochemistry, while immune-related gene expression was assessed using transcriptomic profiling. In dysgerminoma, T-cell exhaustion was characterized through multiplex immunofluorescence. Major histocompatibility complex class I expression was assessed across all subtypes. Dysgerminomas showed abundant CD4⁺ and CD8⁺ T-cell, B-cell, and M1 macrophage infiltration, with the presence of tertiary lymphoid structures, indicating an immunologically active “hot tumor” phenotype. Immune checkpoint molecules were upregulated, and transcriptomic analysis revealed enrichment of immunostimulatory and immunosuppressive pathways. Conversely, yolk sac tumors were dominated by M2 macrophages, while immature teratomas exhibited minimal immune cell infiltration, a “cold tumor” feature. In dysgerminomas with high programmed cell death protein 1 levels, most CD8⁺ T cells exhibited a nonexhausted phenotype. All tumor subtypes showed loss of major histocompatibility complex class I expression. These findings indicate that malignant ovarian germ cell tumor subtypes harbor distinct tumor microenvironments, with dysgerminoma characterized by abundant but potentially ineffective T-cell responses owing to absent major histocompatibility complex class I–mediated antigen presentation. Therapeutic strategies restoring major histocompatibility complex class I expression may enhance T cell–based immunotherapy efficacy in dysgerminomas.</p>","PeriodicalId":9580,"journal":{"name":"Cancer Science","volume":"117 2","pages":"566-575"},"PeriodicalIF":4.3,"publicationDate":"2025-11-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12861093/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145606964","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}