Cancer Science最新文献

{"title":"Advances in the Role of Chemokines in Microwave Ablation-Based Combinatorial Immunotherapy.","authors":"Ruijie An, Ningning He, Wendong Gu","doi":"10.1111/cas.70565","DOIUrl":"https://doi.org/10.1111/cas.70565","url":null,"abstract":"<p><p>Immunotherapy enhances antitumor immunity to eliminate malignant cells and has great potential to prevent tumor recurrence and distant metastasis. In addition to direct tumor destruction, microwave ablation (MWA) remodels the tumor immune microenvironment (TIME) and induces antitumor immune responses, providing a strong rationale for combination with immunotherapy. As key regulators of immune-cell trafficking and function, chemokines critically mediate the synergy between MWA and immunotherapy. In this review, we summarize the effects of MWA on the TIME, the central role of chemokine networks in this process, and recent advances in MWA-based combinatorial immunotherapy, including clinical progress. We also discuss current challenges and future directions to support the optimization of multimodal cancer therapy and improve clinical outcomes.</p>","PeriodicalId":48943,"journal":{"name":"Cancer Science","volume":" ","pages":""},"PeriodicalIF":4.3,"publicationDate":"2026-10-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149225336","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Distinct Clinicogenomic Contexts of BRAF-Altered Gliomas and Glioneuronal Tumors: A Nationwide Real-World Study.","authors":"Seiji Yamada, Tetsuya Takimoto, Sayaka Ueno, Sachiko Minamiguchi, Shigeo Ohba, Yuichi Hirose, Hideyuki Saya, Tamotsu Sudo","doi":"10.1111/cas.70568","DOIUrl":"10.1111/cas.70568","url":null,"abstract":"<p><p>BRAF alterations occur across diverse gliomas and glioneuronal tumors, but their alteration-specific clinicogenomic contexts in real-world cancer genomic profiling cohorts remain incompletely characterized. We analyzed BRAF-altered brain tumors registered in the Japanese Center for Cancer Genomics and Advanced Therapeutics database from June 2019 to March 2026. Operational diagnostic harmonization was performed using available clinicopathological and genomic information. Grade-stratified analyses focused on BRAF p.V600E-positive gliomas and glioneuronal tumors. Among 413 BRAF-altered brain tumors, 344 were classified as gliomas and glioneuronal tumors after harmonization. Within this cohort, the major alteration contexts included BRAF p.V600E-positive tumors (n = 166), KIAA1549::BRAF fusion-positive tumors (n = 60), amplification-only tumors (n = 15), and tumors with other BRAF alterations (n = 109), with overlap in a subset. KIAA1549::BRAF fusion-positive tumors were mainly associated with low-grade glioma contexts, particularly pilocytic astrocytoma. Amplification-only tumors showed marked enrichment of MET alterations, all representing MET amplification, together with frequent EGFR and TP53 co-alterations, supporting a receptor tyrosine kinase-amplified, copy-number-rich context. Among 118 grade-evaluable BRAF p.V600E-positive gliomas and glioneuronal tumors, CDKN2A/B homozygous deletion and TP53/ATRX alterations were enriched in higher-grade groups, and high-grade tumors showed increased tumor mutational burden, although hypermutator phenotypes were rare. BRAF alteration classes define distinct clinicogenomic contexts in gliomas and glioneuronal tumors. These findings highlight both the opportunities and methodological challenges of nationwide real-world cancer genomic profiling datasets in central nervous system tumor research.</p>","PeriodicalId":48943,"journal":{"name":"Cancer Science","volume":" ","pages":""},"PeriodicalIF":4.3,"publicationDate":"2026-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149220983","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Evolution of CAR-T Therapy: Functional Engineering, Manufacturing Innovation, and Future In Vivo Strategies.","authors":"Yukimi Sakoda","doi":"10.1111/cas.70567","DOIUrl":"10.1111/cas.70567","url":null,"abstract":"<p><p>Chimeric antigen receptor (CAR)-T cell therapy has transformed the treatment of hematologic malignancies and established a new paradigm for engineered cellular immunotherapy. However, its broader clinical application remains constrained by complex autologous manufacturing, high cost, limited scalability, variable product quality, suboptimal efficacy in solid tumors, and treatment-related toxicities. To address these challenges, recent advances in CAR-T cell therapy can be viewed across four interconnected dimensions: functional engineering, manufacturing innovation, alternative cell sources, and in vivo CAR programming. Functional engineering includes cytokine-armored, checkpoint-resistant, multi-targeting, and modular or switchable CAR platforms designed to enhance efficacy, persistence, and safety. In parallel, manufacturing innovations such as shortened culture protocols, automated closed systems, and preservation of less differentiated T-cell states aim to improve product potency while reducing production time and complexity. Alternative cell sources, including allogeneic donor-derived and induced pluripotent stem cell (iPSC)-derived platforms, may further enable standardized, scalable, and potentially off-the-shelf therapies. Finally, in vivo CAR programming has emerged as a fourth dimension in which endogenous immune cells are directly engineered within patients using viral or non-viral gene delivery systems. This review summarizes these interconnected advances and discusses how they may collectively shape the next generation of CAR-based immune therapies.</p>","PeriodicalId":48943,"journal":{"name":"Cancer Science","volume":" ","pages":""},"PeriodicalIF":4.3,"publicationDate":"2026-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149220658","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"CDK4/6 Inhibitors and Curcumin Synergistically Suppress HER2- Breast Cancer via Lethal ROS and Inhibition of Metastasis.","authors":"Chenyu Wang, Yiqin Zou, Chunyu Chang, Siyue Liu, Xiankun Ke, Liang Hu, Di Wang, Yukang Lu, Shiwen Luo, Sijian Huang, Yilan Hu, Wenqi Yu, Aiping Deng, Ming Yue, Jue Jiang","doi":"10.1111/cas.70557","DOIUrl":"10.1111/cas.70557","url":null,"abstract":"<p><p>CDK4/6 inhibitors represent a key therapy for HR+/HER2- breast cancer, yet resistance and limited efficacy in triple-negative breast cancer (TNBC) remain significant challenges. Using a self-established drug combination prediction platform, we identified a strong synergy between the CDK4/6 inhibitor palbociclib and the natural compound curcumin across both HR+/HER2- and TNBC models, an effect that was also observed with ribociclib. Mechanistically, the combination led to a collapse of redox homeostasis. Despite upregulating transcriptional antioxidant responses, the treatment downregulated critical ROS-detoxifying enzymes (e.g., GPX4) and depleted glutathione. This imbalance induced lethal oxidative stress, lipid peroxidation, and extensive DNA damage. Furthermore, excessive ROS accumulation contributed to suppression of epithelial-mesenchymal transition (EMT) and reduced migratory and invasive phenotypes. The antioxidant N-acetylcysteine (NAC) attenuated both cytotoxicity and migration inhibition, supporting a central role for ROS in these effects. Together, these findings identify a redox-based mechanism underlying the combination and provide a rationale for further preclinical evaluation in HR+/HER2- breast cancer and TNBC.</p>","PeriodicalId":48943,"journal":{"name":"Cancer Science","volume":" ","pages":""},"PeriodicalIF":4.3,"publicationDate":"2026-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149220975","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Serotonergic and Cholinergic Signaling Pathways Drive Gastric Precancerous Lesions and Its Potential Mechanism.","authors":"Shengli Gao, Xufei Feng, Nana Zhang, Jia Su, Yuyan Wang, Linghan Kong, Jianing Zhou, Hui Dong, Feifei Guo","doi":"10.1111/cas.70563","DOIUrl":"10.1111/cas.70563","url":null,"abstract":"<p><p>Gastric cancer (GC) is a leading lethal malignancy globally. Gastric precancerous lesion (GPL) represents a critical step in GC, but its neural regulatory mechanisms remain largely unclear. We combined bioinformatics, patch-clamp recording, immunofluorescence, and chemogenetics to investigate serotonergic and cholinergic signaling in GPL. An N-methyl-N-nitrosourea (MNU) -induced mouse model was used for in vivo validation. High 5-HTR1D expression correlated with poor survival in gastric adenocarcinoma patients and was upregulated in AGS and MKN45 cells, as well as in gastric tissues of GPL mice. 5-HT evoked non-selective cation currents involving 5-HTR1D and TRPV4 in gastric epithelial and cancer cells, as supported by both pharmacological inhibition and siRNA-mediated TRPV4 knockdown. Blockade of 5-HTR1D or TRPV4 attenuated intestinal metaplasia and dysplasia, and this improvement was accompanied by reduced AKT/mTOR activation in GPL mice. Increased gastric M3R/5-HT co-localization was associated with elevated acetylcholine and overactivated cholinergic neurons in the dorsal motor nucleus of the vagus (DMV). Chemogenetic inhibition of DMV cholinergic neurons decreased ChAT and 5-HT levels and alleviated gastric pathology in GPL mice. These findings suggest that 5-HT/5-HTR1D signaling may promote TRPV4-involved cation currents, contributing to mucosal pathology and intestinal metaplasia in GPL model mice, whereas DMV cholinergic neurons projecting to the stomach may facilitate gastric 5-HT secretion and thereby potentially contribute to GPL progression. This work establishes a novel neuro-epithelial network linking vagal cholinergic output to serotonergic signaling that may be involved in GPL progression, providing potential targets for prevention and intervention.</p>","PeriodicalId":48943,"journal":{"name":"Cancer Science","volume":" ","pages":""},"PeriodicalIF":4.3,"publicationDate":"2026-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13675666/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149208050","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":"Real-World Germline Variant Landscape and Clinical Management in Korean Patients Tested for Suspected Hereditary Cancer.","authors":"Min-Chae Kang, Ha-Eun Lee, Sang-Yoon Park, Seeyoun Lee, So-Youn Jung, Myong Cheol Lim, Han-Sung Kang, Chang Ahn Seol, Jun-Ha Jang, Sang Myung Woo, Jae Young Joung, Wonyoung Choi, Sung Chan Park, Sun-Young Kong","doi":"10.1111/cas.70562","DOIUrl":"10.1111/cas.70562","url":null,"abstract":"<p><p>Germline pathogenic/likely pathogenic (P/LP) variants inform cancer treatment and prevention, yet real-world detection patterns and downstream clinical management remain poorly characterized in East Asian hereditary cancer cohorts. This retrospective cohort study included 5829 patients with cancer who underwent germline testing at the National Cancer Center, Republic of Korea, between April 2006 and April 2023 using BRCA1/2-only testing or multigene panel testing. We examined P/LP variant prevalence, detection patterns under the revised national reimbursement criteria, gene group-stratified post-test clinical management, and variant reclassification outcomes. Among 5829 patients (96.6% female; median age, 51 years), 987 (16.9%) carried P/LP variants. Detection rates differed across reimbursement criteria, with the highest rates in patients with ovarian cancer (24.2%) and those meeting multiple criteria (up to 39.3%). Among P/LP carriers, 773 (78.3%) received at least one post-test clinical action; however, action rates differed substantially across gene groups, ranging from 84.3% among BRCA1/2 carriers to 46.0% among mismatch repair gene carriers. Of 1384 initial variants of uncertain significance, 25 (1.8%) were reclassified as P/LP, identifying 46 additional carriers. Overall variant frequencies were strongly shaped by the breast and ovarian cancer-predominant cohort composition, whereas documented post-test clinical actions varied across gene groups. Variant reclassification identified additional P/LP carriers, supporting the need for structured recontact and follow-up pathways.</p>","PeriodicalId":48943,"journal":{"name":"Cancer Science","volume":" ","pages":""},"PeriodicalIF":4.3,"publicationDate":"2026-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13675117/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149208003","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":"Distinct Clinical Features of Multiple Myeloma With t(11;14): A Post Hoc Analysis of JSH-MM-15 Study.","authors":"Taku Tsukamoto, Yuji Shimura, Shinsuke Mizutani, Takahiro Fujino, Haruya Okamoto, Mitsuhiro Itagaki, Hiroshi Handa, Takayuki Shimizu, Morio Sawamura, Tadao Ishida, Satoru Kosugi, Shuichi Ota, Makoto Yoshimitsu, Yutaka Shimazu, Isamu Sugiura, Hirohiko Shibayama, Shin-Ichi Fuchida, Hiroyuki Takamatsu, Akiko M Saito, Hitoshi Kiyoi, Koichi Akashi, Itaru Matsumura, Akifumi Takaori-Kondo, Junya Kuroda, Shinsuke Iida","doi":"10.1111/cas.70564","DOIUrl":"10.1111/cas.70564","url":null,"abstract":"<p><p>t(11;14) (q13;q32) occurs in approximately 15%-25% of multiple myeloma (MM) cases and has traditionally been regarded as a standard cytogenetic risk factor. However, recent evidence suggests that MM with t(11;14) exhibits heterogeneous biological characteristics and clinical outcomes distinct from those associated with other cytogenetic risk categories. In a post hoc analysis of the prospective JSH-MM-15 study, we investigated the prognosis of newly diagnosed MM patients to identify prognostic features unique to t(11;14)-positive cases and to evaluate treatment factors influencing outcomes. Among 482 patients evaluated for t(11;14), 131 (27%) were positive. Overall survival (OS) in t(11;14)-positive patients was intermediate between standard- and high-risk groups, whereas progression-free survival (PFS) was comparable to that of high-risk cases. Deep response rates, including ≥ complete response (CR)/stringent CR and ≥ very good partial response, were lower in t(11;14)-positive MM than in other risk groups, and these responses were not associated with survival in t(11;14)-positive cases, in contrast to t(11;14)-negative MM. Compared with t(11;14)-negative MM, t(11;14)-positive patients more frequently expressed CD20 and less frequently expressed CD56 on myeloma cells. Exploratory analyses showed that, despite higher ≥ CR rates, OS was worse in patients with CD20-negative/CD56-negative tumors among t(11;14)-positive MM. Among CD20-positive patients, PI-containing regimens were associated with better OS, although no significant PFS benefit was observed. These findings support the biological and clinical heterogeneity of t(11;14)-positive MM and highlight the need for prospective validation of subgroup-specific treatment outcomes.</p>","PeriodicalId":48943,"journal":{"name":"Cancer Science","volume":" ","pages":""},"PeriodicalIF":4.3,"publicationDate":"2026-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13673057/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149197193","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 Novel Plasma Biomarker hsa_circ_0080018 Drives DLBCL Progression via M2 Polarization of Tumor-Associated Macrophages.","authors":"Yanfeng Liu, Yanan Gao, Chuanli Zhao","doi":"10.1111/cas.70554","DOIUrl":"https://doi.org/10.1111/cas.70554","url":null,"abstract":"<p><p>Noncoding RNAs, including circular RNAs (circRNAs), have been demonstrated to play vital roles in tumorigenesis. Uncovering the functions of circRNAs in tumorigenesis and their underlying regulatory mechanisms may suggest new approaches to the development of novel diagnostic and therapeutic strategies for human cancer. Here we report the important role of hsa_circ-0080018 in diffuse large B-cell lymphoma (DLBCL) progression and the potential impact of hsa_circ-0080018 in DLBCL tumorigenesis. Hsa_circ-0080018 was evidently upregulated in newly diagnosed DLBCL patient plasma, and as a reference to classify GCB and non-GCB subtypes. The high expression of hsa_circ-0080018 also appeared in plasma exosome and can transport to tumor microenvironment (TME). In addition, we found that at the molecular level hsa_circ-0080018 acted as a decoy for miR-625-5p and regulated tumor associated macrophage (TAM) polarization by suppressing miR-625-5p that led to IGF-1/IGF-1R pathway activation. The activated IGF-1/IGF-1R pressed macrophage polarizing to M2 and ultimately promoted tumor progression. Our results provided a new potential biomarker in DLBCL plasma that is correlated with cell of origin (COO). The mechanism of circ-0080018 in tumor progression was plasma generated circ-0080018 delivered to TME by exosome and pushed macrophage polarization. Our research may provide a new target for the DLBCL treatment and prognosis in future.</p>","PeriodicalId":48943,"journal":{"name":"Cancer Science","volume":" ","pages":""},"PeriodicalIF":4.3,"publicationDate":"2026-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13660449/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149185298","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":"Angiogenic and Stromal Remodeling Associated With Aggressive Fibrosarcomatous Dermatofibrosarcoma Protuberans.","authors":"Sakura Shiraishi, Takeshi Iwasaki, Ken Takigawa, Kengo Kawaguchi, Hiroki Sonoda, Kohta Miyawaki, Takumi Tomonaga, Taro Mori, Makoto Endo, Koji Kato, Yasuharu Nakashima, Yoshinao Oda","doi":"10.1111/cas.70558","DOIUrl":"10.1111/cas.70558","url":null,"abstract":"<p><p>Although collagen type 1 alpha 1 (COL1A1)-platelet-derived growth factor B-chain (PDGFB) gene fusion is a characteristic driver alteration in fibrosarcomatous dermatofibrosarcoma protuberans (FS-DFSP), an aggressive DFSP variant, the tumor microenvironment (TME) underlying the aggressive phenotype remains unclear. We investigated microenvironmental and molecular differences between pure-DFSP and FS-DFSP using integrated histopathologic and transcriptomic analyses of archival samples from 122 patients, including 39 with FS-DFSP. Histopathologic evaluation, immunohistochemistry, and transcriptomic analyses were performed to assess vascular features, cancer-associated fibroblasts (CAFs), macrophage infiltration, and angiogenesis-related molecular alterations. FS-DFSP demonstrated increased CD31-positive vascular structures without a corresponding increase in αSMA-positive vascular structures, suggesting immature vascular features. CAF markers, including periostin and fibroblast activation protein, were significantly upregulated in intratumoral and invasive front regions of FS-DFSP. Gene expression analysis was performed separately for the fibrosarcomatous and DFSP components of the FS-DFSP cases and for the pure-DFSP cases. By targeted transcriptomic profiling, the DFSP and fibrosarcomatous components within the FS-DFSP cases shared molecular features, suggesting early tumor microenvironment-associated alterations that preceded overt fibrosarcomatous morphology. Integrated transcriptomic and protein analyses revealed upregulation of angiogenesis-related molecules, including vascular endothelial growth factor A (VEGFA), C-C motif chemokine ligand 2 (CCL2), and C-X-C motif chemokine receptor 4 (CXCR4) in FS-DFSP. Periostin-positive CAFs coexpressed VEGFA and CCL2, potentially contributing to angiogenic features within the tumor microenvironment. These findings reveal that FS-DFSP is characterized by coordinated angiogenic and stromal remodeling involving tumor cells and CAFs and suggest that the tumor microenvironment may represent a potential focus for future therapeutic investigation.</p>","PeriodicalId":48943,"journal":{"name":"Cancer Science","volume":" ","pages":""},"PeriodicalIF":4.3,"publicationDate":"2026-10-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13655322/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149168973","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":"Multi-Omics Integration Reveals Metabolic Reprogramming and EMT-Driven Metastasis in Triple-Negative Breast Cancer.","authors":"Yuheng Pang, Yuefeng Shang, Wenjing Wang, Tong Liu, Xiaolong Zou","doi":"10.1111/cas.70559","DOIUrl":"10.1111/cas.70559","url":null,"abstract":"<p><p>Triple-negative breast cancer (TNBC) is an aggressive subtype with high metastatic potential and poor prognosis, yet the molecular mechanisms driving metastasis remain incompletely understood. Here, we performed integrated transcriptomic, metabolomic, and imaging mass cytometry (IMC) analyses on tumor tissues from 52 TNBC patients stratified into NonMeta (long-term survival without metastasis, n = 39) and MetaPoor (metastasis-related death within 36 months after metastatic diagnosis, n = 13) groups. Transcriptomic analysis revealed significant enrichment of epithelial-mesenchymal transition (EMT), WNT signaling pathway, and angiogenesis pathways in MetaPoor tumors, with EMT identified as the top enriched hallmark by GSEA. Metabolomic profiling showed decreased branched-chain amino acids (BCAAs) and arginine derivatives, alongside elevated glycerophosphorylcholine (GPC), indicating enhanced metabolic demand and membrane remodeling. IMC-based spatial proteomics identified distinct tumor cell subpopulations, with MetaPoor tumors harboring higher proportions of stem-like and EMT-like cells characterized by upregulated HADHA (BCAA oxidation) and P38, and downregulated ATP5A (oxidative phosphorylation). Multi-omics integration revealed strong correlations between GPC and EMT markers, and between BCAA depletion and HADHA expression. Collectively, our multi-omics study demonstrates that metastatic TNBC is characterized by EMT activation, metabolic reprogramming toward altered BCAA metabolism and oxidative phosphorylation-related protein expression, and remodeling of the tumor immune microenvironment, suggesting candidate molecules that warrant independent validation and further mechanistic investigation.</p>","PeriodicalId":48943,"journal":{"name":"Cancer Science","volume":" ","pages":""},"PeriodicalIF":4.3,"publicationDate":"2026-10-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13655252/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149171465","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}