Cancer Biology & Therapy最新文献

{"title":"PI3Kγ inhibition drives M1 macrophage differentiation and synergizes with PD-L1 blockade to improve survival in poorly immunogenic head and neck squamous cell carcinoma.","authors":"Pete P Jordanides, Sushmitha Jagadeesha, Puja Upadhaya, Nathan M Ryan, Kelvin Anderson, Felipe F Lamenza, Suvekshya Shrestha, Arham Siddiqui, Anna R Bopp, Sherefuddin H Pracha, Peyton Roth, Reegan Kehres, Xiaokui Mo, Steve Oghumu","doi":"10.1080/15384047.2025.2600701","DOIUrl":"10.1080/15384047.2025.2600701","url":null,"abstract":"<p><strong>Background: </strong>Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer globally with high mortality rates, highlighting the urgent need for novel therapeutic strategies. We investigated the efficacy of combining phosphoinositide 3-kinase gamma (PI3Kγ) inhibition with programmed death-ligand 1 (PD-L1) blockade in a poorly immunogenic HNSCC model.</p><p><strong>Materials and methods: </strong>Mouse bone marrow-derived macrophages (BMDMs) were differentiated and polarized in the presence or absence of the PI3Kγ inhibitor IPI-549 or culture supernatants from MOC2 cells treated with or without IPI-549. MOC2 cells were orthotopically injected into C57BL/6 mice, and treated with anti-PD-L1, IPI-549, combined anti-PD-L1 and IPI-549 or vehicle control. Tumor burden, survival, and immunological responses were evaluated.</p><p><strong>Results and conclusion: </strong>Dual inhibition of PI3Kγ (using IPI-549) and PD-L1 demonstrated nearly significant reduction in primary tumor burden and significantly increased survival compared to single or control treatments. PI3Kγ inhibition promoted macrophage differentiation toward an antitumoral M1 phenotype. In the bone marrow, dual therapy significantly increased MHC-II expression across various myeloid cell subsets and effectively normalized myelopoiesis. Notably, combination therapy increased CD8+ T-cell infiltration into tumors while decreasing T-cell exhaustion marker (LAG-3, CTLA-4, and TIM-3) and protumoral cytokine (IL-4). Combined PI3Kγ and PD-L1 inhibition offers a promising strategy for treating poorly immunogenic HNSCC by simultaneously targeting multiple immunosuppressive mechanisms. These findings provide a strong rationale for combining PI3Kγ and PD-L1 inhibitors as a therapeutic strategy for poorly immunogenic HNSCC, potentially improving clinical outcomes for patients.</p>","PeriodicalId":9536,"journal":{"name":"Cancer Biology & Therapy","volume":"27 1","pages":"2600701"},"PeriodicalIF":4.6,"publicationDate":"2026-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12758254/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145809559","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Methodological insights regarding the prognostic value of lncRNA PGM5P4-AS1 in breast cancer.","authors":"Rashad Ismayilov, Arzu Oguz","doi":"10.1080/15384047.2026.2614802","DOIUrl":"10.1080/15384047.2026.2614802","url":null,"abstract":"","PeriodicalId":9536,"journal":{"name":"Cancer Biology & Therapy","volume":"27 1","pages":"2614802"},"PeriodicalIF":4.6,"publicationDate":"2026-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12802980/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145958895","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"<i>NSUN2</i> mediates <i>SALL2</i> m5C methylation to inhibit ferroptosis and promote breast cancer progression.","authors":"Jiawei Li, Min Li, Jianran Guo, Dongbao Li, Yumin Yao, Wei Zhang, Chuanyou Cui, Bo Fu","doi":"10.1080/15384047.2026.2695501","DOIUrl":"10.1080/15384047.2026.2695501","url":null,"abstract":"<p><strong>Background: </strong>Due to the heterogeneity of breast cancer (BRCA) and the limited therapeutic efficacy in specific molecular subtypes, identifying new and effective therapeutic targets remains an urgent clinical need. The transcription factor <i>SALL2</i> has been shown to play distinct roles in tumorigenesis and progression, but its specific role in BRCA remains unclear. Therefore, this study investigates the effects of <i>SALL2</i> on BRCA progression.</p><p><strong>Methods: </strong><i>SALL2</i> expression in the TCGA and clinical BRCA tissue samples was analyzed. Cell and animal models were established to validate the effects of <i>SALL2</i> on BRCA cell proliferation, migration, and tumorigenicity. Molecular experiments were performed to investigate the association between NSUN2 and SALL2 in BRCA and cellular ferroptosis regulation by SALL2.</p><p><strong>Results: </strong><i>SALL2</i> is significantly overexpressed in BRCA tissues and cell lines, knocking down <i>SALL2</i> reduces BRCA cell growth, migration, and tumorigenesis <i>in vitro</i> and <i>in vivo</i> models. The m5C methyltransferase NSUN2, together with the reader protein YBX1, modifies <i>SALL2</i> mRNA with m5C, which stabilizes the transcript. <i>SALL2</i> then acts as a transcriptional repressor by binding directly to the promoter region of <i>ACSL4</i> and inhibiting its transcriptional activity. Suppression of <i>SALL2</i> activates ferroptotic cell death by lowering the antioxidant defences of GPX4/SLC7A11 and increasing the expression of <i>ACSL4</i> and <i>COX2</i>. Ferroptosis inhibitors can reverse the growth-inhibiting effects caused by <i>SALL2</i> depletion.</p><p><strong>Conclusion: </strong>In BRCA, <i>SALL2</i> is precisely regulated by m5C RNA methylation modification, further promoting cancer progression by inhibiting cell ferroptosis, suggesting its potential as a prognostic biomarker and a target for therapy.</p>","PeriodicalId":9536,"journal":{"name":"Cancer Biology & Therapy","volume":"27 1","pages":"2695501"},"PeriodicalIF":5.7,"publicationDate":"2026-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13327353/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148350917","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"ENPP3 drives ccRCC progression by cGAMP hydrolysis and STING-IFN suppression.","authors":"Jiaxing Ma, Yayun Wu, Guangzheng Lin, Xin Sun, Hao Geng, Tao Zhang, Dexin Yu","doi":"10.1080/15384047.2026.2632995","DOIUrl":"10.1080/15384047.2026.2632995","url":null,"abstract":"<p><strong>Objective: </strong>Clear-cell renal cell carcinoma (ccRCC) is an immune-desert tumor. This study investigates the role of ectonucleotide pyrophosphatase/phosphodiesterase 3 (ENPP3) as a potential therapeutic target and immune-checkpoint enzyme in ccRCC.</p><p><strong>Methods: </strong>ENPP3 expression and its link to hypoxia and prognosis were analyzed in ccRCC. Functional roles were tested using gain/loss-of-function studies <i>in vitro</i> and in xenograft models, followed by therapeutic anti-ENPP3 antibody administration, alone or with anti-PD-L1. Mechanisms were explored via promoter analysis, cGAMP measurement, flow cytometry, cytokine profiling, and <i>in vivo</i> neutralization with STING- or interferon-α/β receptor-1 (IFNAR1) blocking antibodies.</p><p><strong>Results: </strong>ENPP3 is hypoxia-inducible via HIF-1α, upregulated in ccRCC, and predicts poor prognosis. ENPP3 overexpression accelerated tumor growth, while its knockdown or antibody blockade inhibited progression and synergized with anti-PD-L1. Mechanistically, ENPP3 hydrolyzes extracellular cGAMP. Its depletion elevated extracellular cGAMP, expanded anti-tumor immune cells (M1 macrophages, cDC1s, and cytotoxic T cells), reduced Tregs, and induced a STING- and IFNAR1-dependent type I interferon signature in macrophages. The anti-tumor efficacy of ENPP3 blockade was abrogated by IFNAR1 inhibition.</p><p><strong>Conclusion: </strong>ENPP3 is a hypoxia-driven, cGAMP-targeting innate immune checkpoint in ccRCC. Its inhibition reactivates STING-dependent anti-tumor immunity, providing a strong preclinical rationale for targeting ENPP3 therapeutically.</p>","PeriodicalId":9536,"journal":{"name":"Cancer Biology & Therapy","volume":"27 1","pages":"2632995"},"PeriodicalIF":5.7,"publicationDate":"2026-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12928646/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146225679","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Bis-(di-4-phenyl-benzylaminethiocarbonyl)disulfide sensitizes ABCC2/ALDH3A1 overexpressing NSCLC cells to cisplatin.","authors":"Jolanta Kryczka, Jakub Mateusz Kryczka, Łukasz Janczewski, Sho Shimida, Andrzej Frączyk, Beata Kolesińska, Joanna Boncela, Ewa Brzeziańska-Lasota","doi":"10.1080/15384047.2026.2683169","DOIUrl":"10.1080/15384047.2026.2683169","url":null,"abstract":"<p><strong>Background: </strong>Lung cancer presents complex etiopathology involving a mix of genetic predispositions and environmental factors. The best treatment modality is surgical resection. However, it becomes ineffective in the advanced metastatic stage. Thus, cisplatin-based chemotherapy, though restricted by an intrinsic and/or acquired chemo-resistant phenotype, remains the first-line therapy for advanced non-small-cell cancer (NSCLC).</p><p><strong>Methods: </strong>Various tools were used to verify the mRNA expression and protein levels of ABC and ALDH proteins in patient-derived non-small-cell lung cancer (NSCLC) samples (GSE102287, GSE43580) and cell lines A549 and NCI-H158 (including their respective cisplatin-resistant variants) to verify the cisplatin-sensitizing abilities of newly synthesized bis-(di-4-phenyl-benzylaminethiocarbonyl)disulfide-non-toxic ALDH and ABCC2 inhibitors.</p><p><strong>Results: </strong>We identified significant molecular differences in the expression levels of ABCC1, ABCC5, ABCC3, ALDH7A1, and ALDH3A1. Additionally, a fairly significant patient subgroup (Z-score > 1.5), characterized by ABCC2 and ALDH3A1 overexpression, was identified. Importantly, <i>in vitro,</i> ABCC2 and ALDH3A1 accompany the acquisition of cisplatin resistance in A549 cells. Bis-(di-4-phenyl-benzylaminethiocarbonyl)disulfide reverses cisplatin resistance in a cisplatin-resistant variant of A549 cells (via ALDH and ABCC2 inhibition) but not in NCI-H158 cells.</p><p><strong>Conclusions: </strong>Molecular categorization of NSCLC cancer is essential for predicting therapy outcomes, enabling the use of bis-(di-4-phenyl-benzylaminethiocarbonyl)disulfide as a cisplatin therapy enhancer for NSCLC patients' subpopulation with significant ABCC2 and ALDH3A1 overexpression.</p>","PeriodicalId":9536,"journal":{"name":"Cancer Biology & Therapy","volume":"27 1","pages":"2683169"},"PeriodicalIF":5.7,"publicationDate":"2026-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13387110/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148520059","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"ADAR1-circRAB5A-BIP axis governs radiotherapy resistance in colorectal cancer through coordinating protective autophagy and apoptosis.","authors":"Wangsheng Chen, Xu Zhang, Zhengfei Zhao, Wang Xin, Jianxin Li, Xiangming Che","doi":"10.1080/15384047.2026.2677975","DOIUrl":"10.1080/15384047.2026.2677975","url":null,"abstract":"<p><strong>Background: </strong>Colorectal cancer (CRC) ranks among the most prevalent malignancies globally, and radiotherapy remains a critical treatment modality. However, its efficacy is frequently compromised by acquired radioresistance. The endoplasmic reticulum chaperone protein BIP plays a pivotal role in regulating radioresistance by coordinating the balance between protective autophagy and apoptosis, though the regulatory roles of circular RNAs (circRNAs) in this process remain poorly understood.</p><p><strong>Materials: </strong>Differentially expressed circRAB5A (hsa-circ-0123297) was identified from the GSE186940 dataset. Its expression was validated in radioresistant CRC clinical samples and cell lines. Mechanistic investigations involved ADAR1 binding assays, circRAB5A gain/loss-of-function studies, autophagy-apoptosis profiling, ubiquitination analysis, TRIM21-mediated degradation assays, and <i>in vivo</i> xenograft models.</p><p><strong>Results & conclusion: </strong>CircRAB5A was significantly downregulated in radioresistant CRC clinical samples and cell lines. This downregulation was driven by ADAR1, which suppressed circRAB5A biogenesis by binding to Alu Jo/Jr elements. Functional assays showed circRAB5A depletion conferred radioresistance in CRC cells by promoting protective autophagy and inhibiting apoptosis. Mechanistically, circRAB5A destabilized BIP by enhancing TRIM21-mediated ubiquitination. The circRAB5A/BIP axis further modulates the autophagy-apoptosis balance through the p-Akt/Beclin1 signaling pathway, thereby influencing radiosensitivity. <i>In vivo</i> xenograft experiments demonstrated that stable knockdown of circRAB5A attenuated the anti-tumor effects of radiation, whereas knockdown of BIP sensitized CRC cells to radiotherapy even at low doses. Collectively, the ADAR1/circRAB5A/BIP molecular circuitry governs CRC radioresistance by regulating the autophagy-apoptosis balance. Our findings highlight that low circRAB5A expression may serve as a potential biomarker for radioresistance, and that targeting this axis, particularly BIP, represents a promising strategy for overcoming radioresistance in CRC.</p>","PeriodicalId":9536,"journal":{"name":"Cancer Biology & Therapy","volume":"27 1","pages":"2677975"},"PeriodicalIF":5.7,"publicationDate":"2026-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13285610/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148293377","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"CD69 blockade restores the bone marrow niche and delays leukemogenesis in a mouse model of <i>Nras</i> ^G12D-driven chronic myelomonocytic leukemia.","authors":"Yuchen Li, Xu Jiang, Yinfeng Gu, Xianfeng Zha, Jie Wu, Xiuli Wu, Chunli Qi, Shaohua Chen, Yangqiu Li, Zhenyi Jin, Chengxiang Xia, Ling Xu","doi":"10.1080/15384047.2026.2692184","DOIUrl":"10.1080/15384047.2026.2692184","url":null,"abstract":"<p><strong>Background: </strong>A subset of patients with chronic myelomonocytic leukemia (CMML) carries <i>NRAS</i> mutations, which are associated with shorter overall survival and an increased risk of transformation to acute myeloid leukemia. However, the effects of <i>NRAS</i> mutations on the bone marrow microenvironment (BME) remain unclear.</p><p><strong>Methods: </strong>We used a CMML mouse model driven by a single <i>Nras</i> ^G12D allele mutation to investigate alterations in the BME and the potential role of CD69 in immune suppression. <i>Nras</i> ^G12D-mutated CMML mice were treated with an anti-CD69 monoclonal antibody. Flow cytometry, hematoxylin-eosin staining, and RNA sequencing were performed to evaluate treatment-related changes.</p><p><strong>Results: </strong><i>Nras</i> ^G12D-mutated CMML mice showed increased infiltration of regulatory T (Treg) cells and CD69⁺ T cells in the BME, whereas CD69 expression on peripheral blood T cells remained lower than that on bone marrow T cells. Anti-CD69 monoclonal antibody treatment was associated with reduced generation of granulocyte-macrophage progenitor cells, prolonged survival, and decreased Treg accumulation in the BME.</p><p><strong>Conclusion: </strong>Our findings suggest that CD69 may serve as a biomarker of BME immunological dysfunction in CMML.</p>","PeriodicalId":9536,"journal":{"name":"Cancer Biology & Therapy","volume":"27 1","pages":"2692184"},"PeriodicalIF":5.7,"publicationDate":"2026-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13290085/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148301028","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"DNA-PKcs and PARP1 at the interface between DNA damage responses and cGAS-STING signaling: context-dependent roles and therapeutic implications.","authors":"Tiantian Miao, Jiaqi Zhao, Jinghong Wu, Jiabao Hou, Teng Ma, Guirong Wang","doi":"10.1080/15384047.2026.2728335","DOIUrl":"10.1080/15384047.2026.2728335","url":null,"abstract":"<p><strong>Aims: </strong>To explore the roles of DNA-dependent protein kinase catalytic subunit (DNA-PKcs) and poly(ADP-ribose) polymerase 1 (PARP1) in both the DNA damage repair (DDR) pathway and the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway mediated immune response, and to analyze the therapeutic potential of their inhibitors.</p><p><strong>Methods: </strong>This is a review article synthesizing recent findings on the functions of DNA-PKcs and PARP1 in DDR, their context-dependent effects on the cGAS-STING pathway and the therapeutic mechanisms of their inhibitors.</p><p><strong>Results: </strong>DNA-PKcs and PARP1 are key components of two major DDR mechanisms. Beyond their canonical repair functions, both factors significantly regulate the cGAS-STING pathway, a central mediator linking cytoplasmic DNA and the type I interferon response.</p><p><strong>Conclusion: </strong>DNA-PKcs and PARP1 connect genome maintenance with innate immune signaling through context-dependent mechanisms. Targeting these proteins represents a promising strategy for modulating cGAS-STING signaling and improving disease treatment.</p>","PeriodicalId":9536,"journal":{"name":"Cancer Biology & Therapy","volume":"27 1","pages":"2728335"},"PeriodicalIF":5.7,"publicationDate":"2026-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13568571/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148910990","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Synchronizing immunity and angiogenesis in lung adenocarcinoma: bridging biological synergy and clinical translation.","authors":"Pınar Peker","doi":"10.1080/15384047.2026.2728337","DOIUrl":"10.1080/15384047.2026.2728337","url":null,"abstract":"<p><p>The recent study by Liu et al. provided compelling preclinical evidence that lenvatinib enhances the efficacy of combined radiotherapy and PD-L1 blockade by modulating both angiogenesis and antitumor immunity in lung adenocarcinoma. In this correspondence, I discuss the translational implications of these findings and highlight several challenges that should be addressed before clinical implementation. These include the molecular heterogeneity of lung adenocarcinoma, interpatient variability in the temporal dynamics of vascular normalization and immune activation, and the limitations of relying solely on PD-L1 expression for patient selection. I further emphasize the need for biomarker-driven and adaptive clinical trial designs incorporating functional imaging, circulating biomarkers, and immune monitoring to optimize treatment timing and identify patients most likely to benefit from this therapeutic strategy. These considerations may facilitate the successful translation of promising preclinical observations into precision radioimmunotherapy for lung adenocarcinoma.</p>","PeriodicalId":9536,"journal":{"name":"Cancer Biology & Therapy","volume":"27 1","pages":"2728337"},"PeriodicalIF":5.7,"publicationDate":"2026-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13556970/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148905140","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"TFPI2 in tumor metastasis: a double-edged sword with clinical implications.","authors":"Zhanli Guo, Yuanke Luo, Jinyu Wen, Yifang Jiang, Qixuan Kuang, Qiong Ma, Chuan Zheng, Xueke Li, Fengming You, Xi Fu","doi":"10.1080/15384047.2026.2678642","DOIUrl":"10.1080/15384047.2026.2678642","url":null,"abstract":"<p><p>Tissue factor pathway inhibitor 2 (TFPI2), a serine protease inhibitor, plays a multifaceted role in tumor metastasis. Traditionally viewed as a metastasis suppressor, it inhibits extracellular matrix (ECM) remodeling, epithelial-mesenchymal transition, and angiogenesis. However, emerging evidence indicates that TFPI2 promotes tumor progression in glioblastoma, melanoma, and other cancers by fostering an immunosuppressive tumor microenvironment, mediating pathological ECM remodeling, and enhancing angiogenesis and hematogenous dissemination. Notably, even within the same metastatic cascade, TFPI2 exhibits divergent expression patterns and context-dependent opposing functions, acting either as a metastasis suppressor or promoter. This review summarizes its context-dependent regulatory mechanisms, investigates the underlying basis from structural duality, microenvironmental heterogeneity, and receptor differences, and evaluates its potential as a therapeutic target. Future research should elucidate spatiotemporal microenvironmental dynamics to support early screening and precise intervention.</p>","PeriodicalId":9536,"journal":{"name":"Cancer Biology & Therapy","volume":"27 1","pages":"2678642"},"PeriodicalIF":5.7,"publicationDate":"2026-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13224765/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148052827","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}