Cancer Science最新文献

{"title":"The Pathological Roles of Cationic Amino Acid Transporters (CATs) in Cancer","authors":"Thant Thant Myo Oo,&nbsp;Yasuhiro Saito","doi":"10.1111/cas.70468","DOIUrl":"10.1111/cas.70468","url":null,"abstract":"<p>Cationic amino acid transporters (CATs), encoded by the SLC7A family, play essential roles in the uptake of arginine and other cationic amino acids, thereby regulating cellular metabolism, signaling, and immune responses. Among SLC7A transporters, SLC7A1–4 constitute the classical CAT family and have emerged as important regulators of tumor biology. Arginine is increasingly recognized as a critical metabolic resource within the tumor microenvironment. Consequently, dysregulated CAT expression can affect both cancer cell fitness and tumor–immune interactions. In this review, we summarize current knowledge regarding the biological and pathological roles of SLC7A1–4 in cancer. SLC7A1 is broadly associated with enhanced tumor growth, metabolic adaptation, and therapeutic resistance through increased arginine uptake. In contrast, SLC7A2 exhibits context-dependent functions, displaying both tumor-promoting and tumor-suppressive activities depending on tumor type and immune context regulation. Emerging evidence also implicates SLC7A3 in metastatic progression through transcriptional programs that increase arginine availability, whereas the physiological role of SLC7A4 remains largely unresolved. Despite its structural similarity to other CAT family members, convincing evidence for its membrane localization, cationic amino acid transport activity, and cancer-associated functions is still lacking. We further discuss the mechanistic pathways linking CAT to cancer progression and tumor–immune metabolic competition. Finally, we highlight key unresolved questions, including functional redundancy among CAT family members, context-dependent biological effects, and the uncertain role of SLC7A4. A deeper understanding of CAT biology may provide new opportunities for therapeutic strategies targeting amino acid metabolism in cancer.</p>","PeriodicalId":9580,"journal":{"name":"Cancer Science","volume":"117 10","pages":"2636-2643"},"PeriodicalIF":4.9,"publicationDate":"2026-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13394352/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148431401","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 Exosomal piR-hsa-28212 Promotes Lymphatic Metastasis in Breast Cancer","authors":"Yafen Wang,&nbsp;Tianli Zhang,&nbsp;Xue Kong,&nbsp;Yao Tong,&nbsp;Yanru Li,&nbsp;Xiangjun Dong,&nbsp;Chuanxin Wang,&nbsp;Juan Li","doi":"10.1111/cas.70450","DOIUrl":"10.1111/cas.70450","url":null,"abstract":"<p>Lymph node (LN) metastasis is a critical indicator of poor prognosis in breast cancer (BC). BC-derived exosomes influence intercellular communication within the tumor microenvironment, driving metastatic progression. However, the precise mechanisms by which exosomes facilitate LN metastasis in BC remain unclear. We performed small RNA sequencing on serum exosomes to identify Piwi-interacting RNAs (piRNAs) associated with BC LN metastasis. Functional investigations of exosomal piR-hsa-28212 included in vitro assays for migration and tube formation of human lymphatic endothelial cells (HLECs), alongside an in vivo footpad-popliteal LN metastasis model. Specific interactions between piR-hsa-28212 and TBX1 (T-box transcription factor 1), as well as TBX1 and VEGF receptor 3 (VEGFR3), were validated through luciferase reporter assays. The stability of TBX1 mRNA was analyzed by actinomycin D assay. RNA pulldown, RNA immunoprecipitation (RIP), and RNA fluorescence in situ hybridization (FISH) assays were conducted to explore the interaction between piR-hsa-28212 and METTL3. PiR-hsa-28212 was significantly upregulated in serum exosomes of BC patients with LN metastasis. Exosomal piR-hsa-28212 enhanced HLECs migration and tube formation in vitro and promoted lymphangiogenesis and LN metastasis in vivo. Mechanistically, exosomal piR-hsa-28212 transferred from BC cells to HLECs stabilized TBX1 mRNA, thereby upregulating VEGFR3 expression. In BC cells, piR-hsa-28212 directly bound to and stabilized METTL3 protein, modulating N6-methyladenosine (m6A) methylation of vascular endothelial growth factor C (VEGFC) mRNA and consequently increasing VEGFC expression and secretion. Collectively, these findings reveal an exosome-mediated piRNA regulatory mechanism that synergistically amplifies VEGFC/VEGFR3 signaling to drive LN metastasis in BC, highlighting piR-hsa-28212 as a potential therapeutic target.</p><p><b>Trial Registration:</b> KYLL-2022-338</p>","PeriodicalId":9580,"journal":{"name":"Cancer Science","volume":"117 10","pages":"2733-2751"},"PeriodicalIF":4.9,"publicationDate":"2026-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13394147/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148260211","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":"KYNU in Gastric Cancer Cells Promotes Tumor Progression by Influencing Macrophage Polarization Via PF4","authors":"Xilun Cui,&nbsp;Changfeng Li,&nbsp;Yuanda Liu,&nbsp;Chang Liu,&nbsp;Wei Yang","doi":"10.1111/cas.70458","DOIUrl":"10.1111/cas.70458","url":null,"abstract":"<p>Gastric cancer (GC) progression is driven by an immunosuppressive tumor microenvironment (TME). Kynureninase (KYNU) is upregulated in GC and linked to poor prognosis, while platelet factor 4 (PF4)-induced nonclassical macrophages promote immune evasion. This study investigates whether KYNU regulates macrophage polarization via PF4 in GC. KYNU expression was modulated in GC cells to assess PF4 regulation and nonclassical macrophage polarization. Functional consequences were evaluated by proliferation, migration, invasion, and phagocytosis assays. Mechanistic studies included transcriptomics, PI3K/Akt manipulation, and rescue experiments. In vivo validation used a syngeneic mouse model, and clinical relevance was confirmed by multimarker tissue analysis. High KYNU expression in GC cells specifically promoted macrophage polarization toward a nonclassical phenotype characterized by S100A8 and MMP7 expression. These non-classical polarized macrophages subsequently enhanced GC cell proliferation, migration, and invasion while suppressing phagocytic activity. Mechanistically, KYNU upregulated PF4 expression with the involvement of the PI3K/Akt signaling pathway, which in turn drove nonclassical macrophage polarization. In vivo studies demonstrated that KYNU promoted tumor growth through this pathway, whereas PI3K/Akt inhibition suppressed both tumor progression and nonclassical macrophage infiltration. Clinical analysis further confirmed the coordinated upregulation of KYNU, p-Akt, PF4, and S100A8 in human GC tissues. KYNU acts as a signaling transducer in GC, involving PI3K/Akt to upregulate PF4, driving nonclassical macrophage polarization and tumor progression. This mechanism represents a novel pathogenic driver and a promising therapeutic target for reprogramming the immunosuppressive TME.</p>","PeriodicalId":9580,"journal":{"name":"Cancer Science","volume":"117 10","pages":"2676-2692"},"PeriodicalIF":4.9,"publicationDate":"2026-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13394043/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148354505","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":"Tissue Factor-High Ovarian Clear Cell Carcinoma Shows Immune-Cold Features and Preclinical Activity of Tisotumab Vedotin","authors":"Yutaro Mori,&nbsp;Ryo Tamura,&nbsp;Kotaro Takahashi,&nbsp;Kaoru Yamawaki,&nbsp;Tatsuya Ishiguro,&nbsp;Teiichi Motoyama,&nbsp;Koji Okamoto,&nbsp;Kosuke Yoshihara","doi":"10.1111/cas.70472","DOIUrl":"10.1111/cas.70472","url":null,"abstract":"<p>Tissue factor (TF; encoded by <i>F3</i>) is frequently overexpressed in ovarian clear cell carcinoma (OCCC), but the biological features of TF-high tumors and their therapeutic implications remain poorly defined. We analyzed <i>F3</i>-high and <i>F3</i>-low OCCC using bulk RNA sequencing (<i>n</i> = 112) and single-nucleus RNA sequencing (<i>n</i> = 6; three <i>F3</i>-high and three <i>F3</i>-low cases). Bulk transcriptomic analysis showed enrichment of <i>MYC</i> and cell-cycle pathways in <i>F3</i>-high tumors, whereas immune and inflammatory pathways were enriched in <i>F3</i>-low tumors. Single-nucleus RNA sequencing showed that <i>F3</i>-high tumors contained fewer immune cells and that malignant epithelial cells displayed attenuated interferon-related programs. Transcriptomic analysis identified <i>VTCN1</i>, which encodes B7-H4, as upregulated in <i>F3</i>-high tumors and positively associated with <i>F3</i> expression. Based on these findings, we evaluated TF and B7-H4 expression by immunohistochemistry in a subset of tumors (<i>n</i> = 56), confirming their co-expression at the protein level. In patient-derived models, higher TF expression was associated with greater sensitivity to tisotumab vedotin (TV) in vitro, and TV treatment significantly suppressed xenograft growth in vivo. These findings support TF-high OCCC as an immune-cold subgroup characterized by proliferative transcriptional programs, frequent B7-H4 co-expression, and preclinical sensitivity to TV.</p>","PeriodicalId":9580,"journal":{"name":"Cancer Science","volume":"117 10","pages":"2838-2851"},"PeriodicalIF":4.9,"publicationDate":"2026-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13395055/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148431384","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":"FDX1 Depletion Activates CD8+ T Cell Antitumor Immunity by Promoting DMBT1 Secretion in Cuproptosis of Colorectal Cancer","authors":"Jieqiong Wu,&nbsp;Zaixi Lian,&nbsp;Mingzhou Li,&nbsp;Xingtu Qin,&nbsp;Xiaoyu Lei,&nbsp;Lihua Yang,&nbsp;Lin Bing,&nbsp;Qiuyue Li,&nbsp;Lingyan Zhou,&nbsp;Zhiyang Ma,&nbsp;Xuemei Xu,&nbsp;Jinghao Huang,&nbsp;Zilong Chen,&nbsp;Lijie Chen,&nbsp;Lingjie Zhang,&nbsp;Zhiyuan Xiao,&nbsp;Xiangyu Jian,&nbsp;Xiaoqin Zhang,&nbsp;Yanqing Ding,&nbsp;Yaping Ye,&nbsp;Li Liang,&nbsp;Hongli Jiao,&nbsp;Shuyang Wang","doi":"10.1111/cas.70457","DOIUrl":"10.1111/cas.70457","url":null,"abstract":"<p>Cuproptosis, a copper-dependent form of regulated cell death, has been documented in colorectal cancer (CRC), yet its impact on the tumor immune microenvironment remains incompletely understood. Here, we demonstrate that elesclomol-induced cuproptosis potently activates innate and adaptive antitumor immunity, markedly enhancing CD8⁺ T cell cytotoxicity while attenuating exhaustion. Mechanistically, FDX1, which correlates inversely with CD8⁺ T cell infiltration and predicts poor prognosis, functions as a core regulator of CD8⁺ T cell functionality during cuproptosis. FDX1 promotes CRC proliferation and metastasis while suppressing CD8⁺ T cell cytokine production. We further show that FDX1 binds DICER1 to reduce DMBT1 mRNA stability, with FDX1 and DMBT1 expression exhibiting significant negative correlation in CRC tissues. Our findings establish the FDX1–DICER1–DMBT1 axis as a critical regulator of CRC progression and immune evasion, suggesting that therapeutic targeting of this pathway could enhance antitumor immunity and overcome resistance to existing immunotherapies.</p>","PeriodicalId":9580,"journal":{"name":"Cancer Science","volume":"117 10","pages":"2659-2675"},"PeriodicalIF":4.9,"publicationDate":"2026-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13394069/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148340749","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":"Feiwei Heji Enhances Antitumor Immunity by MLL4-Dependent Regulation of Pyroptosis in Lung Cancer","authors":"Nan Cheng,&nbsp;Ruoyu Jiang,&nbsp;Wei Li,&nbsp;Wenjie Huang,&nbsp;Qiao Peng,&nbsp;Tong Zhao,&nbsp;Chufeng Zhang","doi":"10.1111/cas.70459","DOIUrl":"10.1111/cas.70459","url":null,"abstract":"<p>Feiwei Heji (FWHJ) is a traditional Chinese medicine formula used for lung cancer with Qi-Yin deficiency. This study investigated the antitumor effect of FWHJ on lung cancer and explored the underlying mechanisms. The major chemical components of FWHJ were identified by HPLC. Lewis lung carcinoma (LLC) tumor-bearing mice received oral FWHJ at different doses. Tumor histopathology was assessed by H&amp;E and TUNEL staining. Expression of MLL4, pyroptosis-related proteins (NLRP3, caspase-1, and GSDMD), and inflammatory cytokines (IL-1β and IFN-β) was detected by Western blot, immunohistochemistry, and ELISA. Tumor-infiltrating immune cells were evaluated by flow cytometry. An MLL4 overexpression model was established to validate the role of MLL4 in the antitumor effects of FWHJ. HPLC analysis showed that FWHJ primarily contains naringin, chlorogenic acid, amygdalin, and harpagoside. Oral FWHJ significantly inhibited tumor growth, upregulated NLRP3, caspase-1, and GSDMD, as well as their cleaved forms, and increased the release of IL-1β and IFN-β, indicating the activation of pyroptosis. FWJH also enhanced antitumor immunity, characterized by an increased CD8⁺/CD4⁺ T cells ratio and elevated proportion of CD28⁺ and IFN-γ⁺ CD8⁺ T cells in the tumor microenvironment. Mechanistically, FWHJ significantly downregulated MLL4 expression, and MLL4 overexpression largely attenuated its antitumor and immune-enhancing effects. These findings suggest that FWHJ suppresses lung cancer progression by downregulating MLL4, activating pyroptosis, and promoting immune cell infiltration, highlighting that MLL4 may serve as a key regulator mediating the antitumor effects of FWHJ.</p>","PeriodicalId":9580,"journal":{"name":"Cancer Science","volume":"117 10","pages":"2693-2704"},"PeriodicalIF":4.9,"publicationDate":"2026-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13427049/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148649680","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":"Phase II Trial of Nivolumab in Advanced Solid Tumors Based on Genomic Profiling: BELIEVE Trial (NCCH1901) Subcohort","authors":"Masashi Kanai,&nbsp;Kuniko Sunami,&nbsp;Tatsunori Shimoi,&nbsp;Satoshi Nishiwaki,&nbsp;Ichiro Kinoshita,&nbsp;Tetsuhiro Yoshinami,&nbsp;Chigusa Morizane,&nbsp;Yusuke Sato,&nbsp;Toshio Kubo,&nbsp;Mamoru Ito,&nbsp;Hiroshi Nishihara,&nbsp;Toru Mukohara,&nbsp;Hidekazu Shirota,&nbsp;Ryo Ko,&nbsp;Taro Shibata,&nbsp;Manabu Muto,&nbsp;Noboru Yamamoto","doi":"10.1111/cas.70463","DOIUrl":"10.1111/cas.70463","url":null,"abstract":"<p>Comprehensive genomic profiling (CGP) tests can identify putative biomarkers for immune checkpoint inhibitors (ICIs), including tumor mutational burden (TMB); however, their clinical utility remains uncertain. In this study, the efficacy and safety of nivolumab treatment based on the CGP results were investigated using a subcohort from the BELIEVE trial (NCCH1901; jRCTs031190104). This trial aims to improve drug accessibility for patients with advanced solid tumors harboring actionable genetic variants through off-label drug administration. Patients for whom off-label nivolumab treatment was proposed based on CGP results were eligible. Nivolumab was administered until disease progression or unacceptable toxicity. The primary endpoint was the best objective response rate (ORR) in patients with measurable disease. Secondary endpoints included progression-free survival (PFS), overall survival (OS), disease control rate (DCR), and safety. Among 60 enrolled patients, 56 patients who received study treatment were included in the analysis. TMB-High was the most frequent biomarker prompting nivolumab treatment (47/56, 83.9%), followed by <i>CD274</i> (PD-L1) amplification (6/56, 10.7%) and <i>CDK12</i> inactivating variants (3/56, 5.4%). Among 50 patients with measurable disease, the ORR was 16.0% (95% confidence interval [CI], 7.2–29.1) and the DCR was 40.0% (95% CI, 26.4–54.8). Median PFS and OS were 2.7 months (95% CI, 2.2–4.3) and 7.2 months (95% CI, 4.4–9.0), respectively. Although a subset of patients achieved durable responses, nivolumab treatment guided by CGP results demonstrated limited efficacy. The predictive value of TMB-High may differ across tumor types, and integration with other clinicogenomic factors is warranted to improve its predictive accuracy.</p>","PeriodicalId":9580,"journal":{"name":"Cancer Science","volume":"117 10","pages":"2819-2826"},"PeriodicalIF":4.9,"publicationDate":"2026-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13394981/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148398562","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 Melanoma Transplanted in Nude Mice Has Both Host- and Tumor-Derived Blood Vessel- and Nerve-Like Structures","authors":"Koya Obara,&nbsp;Azusa Sasaki,&nbsp;Yuko Hamada,&nbsp;Yutaro Kubota,&nbsp;Yusuke Aoki,&nbsp;Noriyuki Masaki,&nbsp;Michael Bouvet,&nbsp;Yasuyuki Amoh,&nbsp;Robert M. Hoffman","doi":"10.1111/cas.70441","DOIUrl":"10.1111/cas.70441","url":null,"abstract":"<p>Nestin-expressing stem cells located in the bulge area of the hair follicle can give rise to multiple cell types. In the present study, we subcutaneously transplanted red fluorescent protein (RFP)-labeled SK-MEL-5 human melanoma cells into nestin-driven green fluorescent protein (ND-GFP)-nude mice. Nestin-GFP-positive cells differentiated into CD31-positive endothelial cells and αSMA-positive pericytes, and βIII-tubulin-positive neurons, forming blood vessel-like and nerve-like structures within the transplanted melanoma. Bevacizumab, a vascular endothelial growth factor (VEGF)-targeting monoclonal antibody, suppressed nestin-positive blood-vessel structures and nerve structures from forming within the tumor but did not significantly inhibit tumor growth. Due to bevacizumab treatment, blood-vessel-like and nerve-like structures expressing CD31, αSMA, and βIII tubulin formed without the expression of nestin in the transplanted melanoma but remained RFP-positive, suggesting that they trans-differentiated from melanoma cells. Relative mRNA expression of VEGFA also significantly decreased in the melanoma after bevacizumab treatment of the mice. In contrast, VEGFR2 and FGF6, markers that are related to blood vessels, significantly increased compared with the non-treated mice. In the bevacizumab-treated mice, mRNA expression of Tuj1, BDNF, and IGF1 markers related to nerves significantly increased within the melanoma. In the bevacizumab-treated mice, nestin expression was not detected, but RFP was maintained in the blood-vessel-like and nerve-like structures in the melanoma. Since nestin was not detected and RFP was maintained, it suggests these structures trans-differentiated from the melanoma cells. The present study suggests that both the host and cancer cells can differentiate into blood-vessel-like and nerve-like structures in the melanoma.</p>","PeriodicalId":9580,"journal":{"name":"Cancer Science","volume":"117 10","pages":"2790-2802"},"PeriodicalIF":4.9,"publicationDate":"2026-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13430620/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148664814","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":"Indole-3-Propionic Acid Drives Dendritic H3K27 Acetylation to Enhance CD8+ T Cell Immunity in Hepatocellular Carcinoma","authors":"Rui Zhao,&nbsp;Siqi Liu,&nbsp;Qian Zhang,&nbsp;Wenrui Wang,&nbsp;Lanlan Yang,&nbsp;Xue Shao,&nbsp;Shengnan Jia,&nbsp;Zhenjing Jin","doi":"10.1111/cas.70462","DOIUrl":"10.1111/cas.70462","url":null,"abstract":"<p>Indole-3-propionic acid (IPA) is documented to improve the effectiveness of tumor immunotherapy via regulating anti-tumor immunity. However, the impacts of IPA in hepatocellular carcinoma (HCC) patients undergoing sintilimab combined with bevacizumab (SCB) treatment remain unknown. This study investigated the effects and underlying mechanisms of IPA in SCB-treated HCC. Serum, tumor tissue, fecal and lymph node tissue samples were collected from HCC patients with or without a response to SCB therapy. Humanized orthotopic and subcutaneous HCC NOG mouse models were established. IPA-treated mouse dendritic cells (DCs) were co-cultured with mouse CD8⁺ T-cells, which were subsequently co-cultured with Hepa1-6 cells. IPA levels were elevated in the serum, tumor tissues, and feces of responders, and serum IPA levels were positively correlated with the proportion of IFN-γ⁺CD8⁺ T cells in tumor tissues as well asac-H3K27 and IL-12A levels in lymph node DCs. IPA amplified the suppressive impact of SCB on tumor growth in HCC mice. Moreover, IPA increased ac-H3K27 and IL-12A levels in DCs and upregulated effector CD8⁺ T-cell immunity in HCC mice. Administration of a CD8-neutralizing antibody and injection of shIL-12A-transfected DCs weakened IPA-mediated inhibition of HCC in vivo. Furthermore, the ac-H3K27 inhibitor A-485 suppressed IL-12A expression and effector CD8⁺ T-cell immunity induced by IPA, thereby promoting the proliferation, invasion, and migration of Hepa1-6 cells in vitro. These findings demonstrate that IPA enhances the effect of SCB-treated HCC by upregulating H3K27 acetylation to promote IL-12A expression in DCs, thereby potentiating CD8⁺ T-cell immunity, which provides a basis for its potential use as a clinical adjuvant therapy.</p>","PeriodicalId":9580,"journal":{"name":"Cancer Science","volume":"117 10","pages":"2705-2718"},"PeriodicalIF":4.9,"publicationDate":"2026-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13394779/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148473643","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":"NRF2/xCT-Mediated Antioxidant Adaptation Attenuates Apoptosis Induced by ASCT2 Inhibition in Prostate Cancer","authors":"Jiaxing Wei,&nbsp;Yasutaka Yamada,&nbsp;Takaaki Tamura,&nbsp;Masahiro Sugiura,&nbsp;Xue Zhao,&nbsp;Meng Ni,&nbsp;Adilan Aierken,&nbsp;Tomokazu Sazuka,&nbsp;Yusuke Imamura,&nbsp;Shinichi Sakamoto","doi":"10.1111/cas.70437","DOIUrl":"10.1111/cas.70437","url":null,"abstract":"<p>Glutamine supports biosynthesis and redox homeostasis in cancer cells. The glutamine transporter ASCT2 is highly expressed in prostate cancer and is associated with higher Gleason grade. Although ASCT2 inhibition induces reactive oxygen species (ROS) accumulation and apoptosis, cancer cells may activate antioxidant adaptive mechanisms that limit therapeutic efficacy. Here, we identified an NRF2/xCT-dependent redox-adaptive response following ASCT2 inhibition in prostate cancer. Mechanistically, ASCT2 inhibition induced ROS accumulation, promoted nuclear translocation of NRF2, and upregulated xCT together with other NRF2-associated antioxidant genes. Functional redox analysis showed that ASCT2 inhibition reduced glutathione-dependent redox capacity, whereas combined ASCT2 and xCT inhibition further increased GSSG accumulation and markedly decreased GSH levels and the GSH/GSSG ratio. These findings were further validated in C4-2 cells as an additional prostate cancer model. Cell death discrimination assays showed that combined ASCT2 and xCT inhibition induced lipid peroxidation that was partially rescued by ferrostatin-1, whereas z-VAD produced a stronger rescue effect and Annexin V/PI staining confirmed prominent apoptotic cell death. In castrated 22Rv1 xenograft models, combined treatment with V-9302 and erastin produced the strongest inhibition of tumor growth without significant body weight loss during treatment. Collectively, these findings demonstrate that NRF2/xCT-mediated residual glutathione redox buffering functions as an adaptive survival mechanism following ASCT2 inhibition and provide a mechanistic rationale for combined targeting of ASCT2 and xCT to overcome redox-adaptive resistance in prostate cancer.</p>","PeriodicalId":9580,"journal":{"name":"Cancer Science","volume":"117 10","pages":"2769-2789"},"PeriodicalIF":4.9,"publicationDate":"2026-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13394672/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148473689","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}