Cancer Biol. Ther. [JOURNAL]
Sun
200 papers
Diagnostic and prognostic value of lncSPATA8-AS1 in prostate cancer and its regulatory effect on tumor progression.
Zhong J, Deng Y, Qin X … +1 more , Yang Q
Cancer Biol Ther · 2026 Dec · PMID 42187002 · Full text
BACKGROUND: Long noncoding RNAs (lncRNAs) have significant impacts on the occurrence and development of many cancers. However, their effects and mechanisms on prostate cancer (PCa) remain largely unknown. The study was t...
BACKGROUND: Long noncoding RNAs (lncRNAs) have significant impacts on the occurrence and development of many cancers. However, their effects and mechanisms on prostate cancer (PCa) remain largely unknown. The study was to explore the influence of lncSPATA8-AS1 on PCa and its molecular mechanism of action. METHODS: In the GSE179321 dataset, lncSPATA8-AS1, which was upregulated in PCa tumor tissues, was selected. The expression levels of lncSPATA8-AS1, miR-328-5p, and EPHB2 were detected using RT-qPCR. experiments were conducted to investigate the effects of lncSPATA8-AS1 on the malignant biological behaviors of PCa cells. Finally, the mechanism of lncSPATA8-AS1 was revealed through methods such as biotin-labeled RNA pull-down, luciferase assay, and rescue experiments. RESULTS: LncSPATA8-AS1 was upregulated in PCa tissues, serum, and cell lines. Clinically, lncSPATA8-AS1 could serve as a biomarker for the diagnosis and prognosis of PCa. Silencing lncSPATA8-AS1 can inhibit the cell viability of PCa tumor cells, suppress epithelial-mesenchymal transformation (EMT), cell migration, and invasion. Mechanistically, lncSPATA8-AS1 affects the expression of EPHB2 by interacting with miR-653-5p, thereby regulating the malignant biological behavior of PCa. CONCLUSION: The expression of lncSPATA8-AS1 is upregulated in the serum of PCa patients, and it has great potential as a biomarker for the diagnosis and prognosis of PCa. The lncSPATA8-AS1/miR-328-5p/EPHB2 axis drives the malignant biological behavior of prostate cancer.
Impact of leucine-rich diet on placenta's proteomic and metabolomic profiles of pregnant tumor-bearing rats.
Dos Santos IF, Salgado CM, Carregari VC … +4 more , Dos Santos RW, de Souza DM, Viana LR, Gomes-Marcondes MCC
Cancer Biol Ther · 2026 Dec · PMID 42135921 · Full text
BACKGROUND: Cancer during pregnancy is a fragile scenario where the maternal body undergoes significant molecular changes, including at proteomic and metabolomic levels, with damage to placenta and fetal development. Pro...
BACKGROUND: Cancer during pregnancy is a fragile scenario where the maternal body undergoes significant molecular changes, including at proteomic and metabolomic levels, with damage to placenta and fetal development. Proteomic and metabolomic interaction analyses can clarify the complex dynamics in cancer associated with pregnancy. Leucine is involved in protein synthesis and metabolic regulation and may attenuate tumor-induced damage. OBJECTIVE: We investigated placental proteomic and metabolomic profiles in the complex relationships among pregnancy, cancer, and leucine supplementation. MATERIALS: Exploratory, non-targeted proteomic (mass spectrometry) and metabolomic (NMR spectrometry) analyses were performed on the placenta tissue of four pregnant groups: control (PC), Walker-256 tumor-bearing (PW), leucine (PL), and tumor-bearing fed a leucine-rich diet (PWL). Statistical comparisons were performed on technical replicate data within each group. RESULTS: Tumor affected maternal weight, but leucine attenuated the decrease in placental weight and fetal resorption. Leucine supplementation restored the placental proteins involved in the nuclear structure, cytoskeleton, and immune response. Tumor evolution impaired pathways related to protein folding and chromosome localization, whereas leucine modulated interferon-gamma and hydrogen peroxide responses. PW placentas exhibited decreased adenosine, glucose, glutamate, and succinate, with enhanced lactate, creatine, and histamine levels, whereas leucine supplementation restored adenosine and pyridoxine and reduced lactate levels. The affected alanine/aspartate/glutamate and purine metabolism, beta-alanine metabolism, and the citrate cycle were minimized in leucine treatment (PWL), which mainly modulates purine and alanine/aspartate/glutamate pathways and pyruvate metabolism. CONCLUSION: A leucine-rich diet partially restored placental protein and metabolite levels, leading affected pathways to shift towards amino acid biosynthesis and pyruvate metabolism and minimizing effects on fetal development.
Prolonged intratumoral treatment with TLR7/8 agonist R848 regulates the tumor immune microenvironment resulting in enhanced antitumor activity.
Zhang Y, Sun X, Cheng S … +14 more , Qian S, Wan N, Xing F, Li H, Gu H, Wang Z, Dong M, Yang Z, Wu S, Zhang M, Han Z, Zhang X, Liu H, Chen Q
Cancer Biol Ther · 2026 Dec · PMID 42124329 · Full text
BACKGROUND: Toll-like receptor 7/8 agonists (TLR7/8a), such as resiquimod (R848), are highly potent in activating dendritic cells and thus hold promise for T cell-mediated tumor immunotherapies. However, the short half-l...
BACKGROUND: Toll-like receptor 7/8 agonists (TLR7/8a), such as resiquimod (R848), are highly potent in activating dendritic cells and thus hold promise for T cell-mediated tumor immunotherapies. However, the short half-life of these small molecules in the lesion and the associated systemic immunotoxicity post-leakage of the drug into the circulation make their clinical application challenging. MATERIALS: To overcome these shortcomings, we tested prolonged TLR7/8a therapy by intratumoral infusion of R848 for 25 h using a micropump to achieve durable therapeutic effects while minimizing the proinflammatory cytokine levels in the plasma post leakage of the drug into the circulation. RESULTS: The results showed that prolonged immunotherapy with R848 (as low as 1 μg) significantly suppressed tumor growth (inhibition rates up to 98%, < 0.01) in treated mice compared to control mice receiving regular intratumoral injection of R848. Higher levels of CD86or CD11c D.C.s, CD4/CD8/OX40 T cells, and cytokines (TNF-α/IFN-γ) were observed in the tumors and spleens of the mice in the treated group compared to the sham group ( < 0.05), indicating efficient activation of local and abscopal immunity by prolonged therapy with R848. Furthermore, the R848 functional concentration assay demonstrated that the micropump prolonged the treatment time of R848 drugs in tumors and reduced the requirement for higher doses, enhancing safety. CONCLUSION: Taken together, this study provides new insights into TLR7/8a immunotherapy for improved clinical performance, with potential benefits for patients with superficial tumors amenable to prolonged intratumoral infusion via micropump.
Centromere protein I promotes hepatocellular carcinoma progression by activating PI3K/AKT/mTOR-CDK2 cascade.
Liu D, Yang P, Wang J … +5 more , Li J, Wang X, Gu X, Liu C, Fang Y
Cancer Biol Ther · 2026 Dec · PMID 42124320 · Full text
BACKGROUND: Hepatocellular carcinoma (HCC) is characterized by high recurrence rates and limited targeted therapies. Centromere protein I (CENPI), a core kinetochore component linked to chromosomal instability, is dysreg...
BACKGROUND: Hepatocellular carcinoma (HCC) is characterized by high recurrence rates and limited targeted therapies. Centromere protein I (CENPI), a core kinetochore component linked to chromosomal instability, is dysregulated in multiple malignancies, yet its role and mechanism in HCC progression remain incompletely elucidated. METHODS: CENPI expression was quantified in paired human HCC tissues and orthotopic rat HCC models via immunohistochemistry (IHC) and western blot (WB). Gain- and loss-of-function assays were performed in HepG2 cells and validated in Hep3B cells to evaluate the effects of CENPI modulation on cell proliferation, migration, invasion, apoptosis, and cell cycle dynamics. Mechanistic analyses included pathway enrichment and WB, with validation via rapamycin in HepG2 cells and LY294002 in Hep3B cells. In vivo tumor growth and signaling alterations were assessed in orthotopic HCC models following CENPI silencing. RESULTS: CENPI was upregulated in HCC tissues and orthotopic tumors, correlating with poor survival. CENPI depletion suppressed proliferation, migration, invasion, and epithelial-mesenchymal transition (EMT), while enhancing apoptosis and inducing G1 arrest; overexpression was pro-oncogenic. Mechanistically, CENPI activated the PI3K/AKT/mTOR-CDK2 axis, upregulating CDK2, and modulating EMT markers. Rapamycin abrogated CENPI-induced oncogenic signaling in vitro, and CENPI silencing reduced in vivo tumor burden by 65% while suppressing the pathway and EMT. CONCLUSION: CENPI may function as an oncogenic regulator in HCC through activation of the PI3K/AKT/mTOR-CDK2 cascade, linking cell cycle progression to EMT-associated invasiveness. These findings provide a preclinical rationale for further evaluating CENPI and its related signaling axis as potential prognostic and therapeutic targets in broader HCC models and clinical cohorts.
Inhibition of STAT3-mediated glycolysis by bruceine D suppresses non-small-cell lung cancer progression and .
Zhu Y, Xu X, Hong X … +11 more , Zhang J, Zhou Y, Sun A, Ye Y, Xu Y, Xu H, Zhao H, Zhao C, Jin X, Yang L, Zheng J
Cancer Biol Ther · 2026 Dec · PMID 42100892 · Full text
BACKGROUND: Non-small-cell lung cancer (NSCLC) is one of the deadliest malignancies in the world. Signal transducer and activator of transcription 3 (STAT3) plays an important role in the progression of NSCLC. Bruceine D...
BACKGROUND: Non-small-cell lung cancer (NSCLC) is one of the deadliest malignancies in the world. Signal transducer and activator of transcription 3 (STAT3) plays an important role in the progression of NSCLC. Bruceine D is a bioactive quassinoid compound extracted from , a plant widely used in traditional Chinese medicine. METHODS: Tests of cell function were performed to observe the effects of bruceine D on human NSCLC cell lines (H460, PC-9, and SKMES-1). Levels of STAT3, phosphorylated STAT3, Survivin, and other apoptosis-related proteins were detected via Western blotting. The binding of bruceine D to STAT3 was examined using molecular dynamics simulations and surface plasmon resonance spectroscopy. The effect of bruceine D on STAT3 nuclear localization was examined by immunofluorescence. Furthermore, the glucose uptake, lactate production, and extracellular acidification rates of NSCLC cells were analyzed to confirm that bruceine D inhibited glycolysis in NSCLC. The efficacy of bruceine D was evaluated in a mouse xenotransplantation model. RESULTS: Bruceine D significantly reduced the viability of NSCLC cells, promoted apoptosis, and inhibited the growth of tumors in a mouse xenograft model. Bruceine D was found to bind directly to STAT3, inhibiting glycolysis in NSCLC cells. Western blotting results suggested that the antitumor effects of bruceine D might be mediated by the inhibition of the phosphorylation and nuclear translocation of STAT3. CONCLUSION: Bruceine D exerts a strong inhibitory effect on NSCLC and . Bruceine D has potential application prospects in the field of anti-NSCLC therapy.
MBD2 suppresses SFRP1 expression and promotes colorectal cancer development by blocking MED19 binding to its methylated promoter.
Huang X, Luo T, Ke L … +5 more , Guan S, Wu H, Li B, Liu Y, Qi J
Cancer Biol Ther · 2026 Dec · PMID 42084802 · Full text
BACKGROUND: The Wnt signaling pathway antagonist SFRP1 is frequently silenced by promoter DNA hypermethylation in colorectal cancer (CRC). MBD2, a DNA methylation reader, is known to contribute to SFRP1 epigenetic silenc...
BACKGROUND: The Wnt signaling pathway antagonist SFRP1 is frequently silenced by promoter DNA hypermethylation in colorectal cancer (CRC). MBD2, a DNA methylation reader, is known to contribute to SFRP1 epigenetic silencing. Previous work showed that MBD2 critically suppresses SFRP1 expression without altering promoter methylation, though the underlying mechanism remained unclear. Elucidating how DNA methylation silences tumor suppressor genes, such as , could reveal novel therapeutic targets with significant clinical potential. METHODS: MBD2 was inhibited in CRC models using either siRNA or a small molecule inhibitor (KCC07). The effects on SFRP1 and β-catenin expression, Wnt pathway activity, cell proliferation, and apoptosis were assessed. Tumor growth was also evaluated in vivo. Mechanistic studies investigated the role of MBD2 in mediating MED19 binding to the SFRP1 promoter and its impact on RNA polymerase II CTD-S7 phosphorylation. RESULTS: The IC50 of KCC07 was 23.25 μM in SW480 cells, 26.83 μM in HCT116 cells, and 39.66 μM in NCM460 cells. Inhibition of MBD2, either genetically or pharmacologically with KCC07, upregulated SFRP1 expression, downregulated β-catenin, and suppressed the Wnt pathway. KCC07 treatment also inhibited CRC cell proliferation, promoted apoptosis, and suppressed tumor growth in vivo. Mechanistically, MBD2 was found to silence SFRP1 by blocking MED19 binding to its promoter, which subsequently reduced RNA polymerase II CTD-S7 phosphorylation and impaired transcription. CONCLUSIONS: This study reveals a novel mechanism whereby DNA methylation suppresses gene expression via MBD2, independent of changes in methylation status, by disrupting MED19 binding and subsequent transcription. Targeting MBD2 represents a promising therapeutic strategy for colorectal cancer.
IGF2BP3 promotes gastric cancer progression by inhibiting ferroptosis through ETV4-mediated regulation of GCH1.
Li K, Wei H, Li F … +2 more , Zheng Y, Zhou Y
Cancer Biol Ther · 2026 Dec · PMID 42068022 · Full text
BACKGROUND: Ferroptosis can be inhibited by insulin-like growth factor 2 mRNA-binding protein 3 (IGF2BP3) in cancers. ETS variant transcription factor 4 (ETV4) is aberrantly expressed in various cancers. Elevated transcr...
BACKGROUND: Ferroptosis can be inhibited by insulin-like growth factor 2 mRNA-binding protein 3 (IGF2BP3) in cancers. ETS variant transcription factor 4 (ETV4) is aberrantly expressed in various cancers. Elevated transcription of guanosine triphosphate cyclohydrolase 1 (GCH1) contributes to tumor malignancy. This study investigated the involvement of IGF2BP3, ETV4, and GCH1 in ferroptosis in gastric cancer (GC). METHODS: GC cells and tissue samples were used to detect IGF2BP3, ETV4, and GCH1 expression. The relationships between IGF2BP3, ETV4, and GCH1 were assessed using RNA immunoprecipitation assay, chromatin immunoprecipitation assay, and dual-luciferase reporter assay. BALB/c nude mice were utilized to establish GC tumor xenografts. Cell cloning and Transwell were used to detect the proliferation, migration, and invasion of cells. RESULTS: IGF2BP3 and ETV4 were upregulated in GC. IGF2BP3 regulated ETV4 protein level by mediating its mRNA stability. Knockdown of ETV4 inhibited GC cell proliferation, migration, and invasion, and promoted their ferroptosis. ETV4 also promoted the transcription of GCH1 by directly binding to its promoter region. GCH1 overexpression diminished the facilitating effect of ETV4 knockdown on ferroptosis in GC. Overexpression of GCH1 also eliminated the promoting impact of IGF2BP3 knockdown on GC cell proliferation, migration, and invasion. Lastly, inhibition of GCH1 reversed the promoting effect of IGF2BP3 overexpression on GC tumor growth . CONCLUSIONS: IGF2BP3 promotes tumor growth and inhibits ferroptosis in GC by regulating ETV4, while ETV4 promotes GCH1 expression by direct interaction with its promoter. GCH1 overexpression counteracts the effects of ETV4 and IGF2BP3 on GC.
Parthenolide inhibits the progression of intrahepatic cholangiocarcinoma by promoting ferroptosis through inhibiting UBD.
Xie Y, Wang J, Zhou J … +4 more , Peng Y, Wang Y, Wang Y, Song Y
Cancer Biol Ther · 2026 Dec · PMID 42050803 · Full text
OBJECTIVE: This study aimed to investigate the antitumor activity and molecular mechanism of Parthenolide (Par) against intrahepatic cholangiocarcinoma (ICC), a highly malignant liver tumor with poor prognosis, to explor...
OBJECTIVE: This study aimed to investigate the antitumor activity and molecular mechanism of Parthenolide (Par) against intrahepatic cholangiocarcinoma (ICC), a highly malignant liver tumor with poor prognosis, to explore potential new treatment strategies. METHODS: Par was identified through screening an FDA compound library. assays were performed to assess its effects on ICC cell proliferation, colony formation, invasion, migration, cell cycle, and apoptosis. An nude mouse tumor model was used to evaluate tumor growth inhibition. Transcriptomic analysis, molecular docking, and cellular thermal shift assays were employed to identify key targets and pathways. Changes in ferroptosis-related markers, including iron ion levels, lipid peroxides, SOD activity, and GPX4 expression, were measured. Rescue experiments with the ferroptosis inhibitor ferrostatin-1 were conducted to validate the role of ferroptosis. RESULTS: Par significantly inhibited ICC cell proliferation, colony formation, invasion, and migration, induced G2/M phase arrest, and promoted apoptosis ; and suppressed tumor growth . Transcriptomic analysis showed upregulation of HMOX-1 and downregulation of Ubiquitin D (UBD) after Par treatment. Par was confirmed to bind to the UBD protein. Enrichment analysis indicated ferroptosis as a key pathway, with Par treatment leading to increased iron ions, lipid peroxide accumulation, reduced SOD activity, and downregulated GPX4. Ferrostatin-1 partially reversed Par-induced inhibitory effects. CONCLUSION: This study demonstrates for the first time that Par exerts anti-ICC effects related to inhibition of UBD, thereby activating the ferroptosis pathway. These findings provide a novel potential strategy and therapeutic target for ICC treatment.
UCHL5 suppresses thyroid carcinoma progression via ZRANB1 stabilization and ferroptosis regulation.
Xiao W, Ding Y, Wu X … +4 more , Que F, Wang B, Hong S, Zhang F
Cancer Biol Ther · 2026 Dec · PMID 42037453 · Full text
OBJECTIVE: This study investigated the role of UCHL5 in thyroid carcinoma (THCA) progression, focusing on its tumor-suppressive mechanisms and regulation of ferroptosis. METHODS: We performed multi-omics analysis of TCGA...
OBJECTIVE: This study investigated the role of UCHL5 in thyroid carcinoma (THCA) progression, focusing on its tumor-suppressive mechanisms and regulation of ferroptosis. METHODS: We performed multi-omics analysis of TCGA and GEO datasets and validated the findings using clinical samples. The CRISPR/Cas9-mediated knockout and stable overexpression in THCA cell lines were constructed, followed by comprehensive functional assays including co-immunoprecipitation (Co-IP), ubiquitination analysis, xenograft tumor models, and ferroptosis sensitivity tests using erastin/ferrostatin-1 with BODIPY C11 lipid ROS measurement. Weighted gene co-expression network analysis (WGCNA) was performed to identify hub genes and to analyze associated pathways. RESULTS: Clinical data revealed significant downregulation of UCHL5 in advanced thyroid cancers, particularly in lymph node metastases. UCHL5 knockout markedly accelerated cell proliferation and xenograft tumor growth, while its overexpression suppressed both. Mechanistically, we identified a direct interaction between UCHL5 and ZRANB1 through co-IP, with UCHL5 extending the protein half-life of ZRANB1 by over 2-fold. In ferroptosis regulation, erastin treatment (10 μM) revealed that UCHL5 overexpression enhanced sensitivity, while UCHL5 knockout conferred significant protection, accompanied by altered GSH levels, Fe²⁺ accumulation, and lipid ROS production. Western blot analysis revealed that UCHL5 upregulated ZRANB1 and downregulated SLC7A11/GPX4 expression. CONCLUSION: This study demonstrates that UCHL5 acts as a critical tumor suppressor in thyroid cancer by stabilizing ZRANB1 through deubiquitination and regulating ferroptosis via the SLC7A11-GPX4 axis.
Advances in natural killer cell immunotherapy for hematologic malignancies.
Hu H, Xiong Y, Xia M … +1 more , Sheng L
Cancer Biol Ther · 2026 Dec · PMID 42033215 · Full text
Natural killer (NK) cells are a unique subset of cytotoxic lymphocytes within the innate immune system. They play a pivotal role in antiviral and antitumor immunity. NK cell-based adoptive immunotherapy has advanced rapi...
Natural killer (NK) cells are a unique subset of cytotoxic lymphocytes within the innate immune system. They play a pivotal role in antiviral and antitumor immunity. NK cell-based adoptive immunotherapy has advanced rapidly in recent years. Innovative approaches, such as autologous/haploidentical NK cell infusion, chimeric antigen receptor NK cells, and NK cell engagers, have emerged, demonstrating promising potential in the treatment of various diseases. Currently, enhancement strategies for NK cell therapy primarily focus on two key aspects: improving expansion efficiency and persistence, with a positive effect on the therapy's potency and cytotoxic efficacy. The present review systematically introduces the functional mechanisms of NK cells and their specialized functional subsets. This review discusses the progress and optimization methods of NK cell therapy and provides an outlook on future research directions.
Real-world efficacy of Bruton tyrosine kinase inhibitor based maintenance therapy in diffuse large B-cell lymphoma: a multicenter retrospective cohort study with external historical control.
Lyu LW, Yao N, Liu ZX … +6 more , Wang YY, Li J, Zhou HB, Li LH, Li ZL, Wang L
Cancer Biol Ther · 2026 Dec · PMID 42015349 · Full text
INTRODUCTION: The selection of an optimal maintenance agent in diffuse large B-cell lymphoma (DLBCL) continues to pose a significant clinical challenge. This study aims to evaluate the prognostic impact of maintenance th...
INTRODUCTION: The selection of an optimal maintenance agent in diffuse large B-cell lymphoma (DLBCL) continues to pose a significant clinical challenge. This study aims to evaluate the prognostic impact of maintenance therapy (MT) in DLBCL. METHODS: We conducted a retrospective analysis of data from DLBCL patients undergoing first-line MT at four hospitals in Beijing between January 2019 and August 2024. The REMoDL-B trial database was selected as the control group. RESULTS: The MT group comprised 106 cases and a median follow-up duration of 25.4 months. The rates of progression and death were 11.32% (12/106) and 1.89% (2/106), respectively. The 2-y progression-free survival (PFS) and overall survival (OS) rates were 90% and 98%, respectively. The MT group demonstrated significantly superior PFS and OS compared to the control group ( = 0.024, = 0.008). Furthermore, multivariate analysis indicated that MT ( = 0.021, OR = 0.037, 95% CI, 0.002-0.605) was an independent prognostic factor associated with improved PFS. For patients receiving Bruton tyrosine kinase inhibitors (BTKi), the 2-y PFS and OS rates were 87.6% and 97.2%, respectively, both significantly better than those of the control group ( = 0.048, = 0.024). Despite 43.6% of patients being at high risk for central nervous system (CNS), no CNS recurrences were observed. The PFS of the MCD subtype is better than that of the A53 subtype. CONCLUSIONS: While limited by the retrospective study, our analysis raises the hypothesis that MT may correlate with improved DLBCL outcomes. A similar trend suggesting potential benefit from BTKi maintenance was noted, meriting further investigation in controlled settings.
Molecular mechanisms and therapeutic strategies: DNA methylation in pancreatic cancer.
Liu J, Xie J, Ding Y
Cancer Biol Ther · 2026 Dec · PMID 41879036 · Full text
OBJECTIVE: This narrative review examines DNA methylation dysregulation in pancreatic cancer, focusing on its mechanistic roles in tumorigenesis and applications in biomarkers and therapies. METHODS: We analyzed experime...
OBJECTIVE: This narrative review examines DNA methylation dysregulation in pancreatic cancer, focusing on its mechanistic roles in tumorigenesis and applications in biomarkers and therapies. METHODS: We analyzed experimental and clinical studies on aberrant DNA methylation patterns, emphasizing their links to invasion, metastasis, therapy resistance, and immune modulation. RESULTS: Pancreatic cancer exhibits recurrent tumor suppressor gene hypermethylation and locus-specific hypomethylation, driving progression and resistance. Methylation-based biomarkers (tissue/cfDNA) show promise for early detection and prognostication, though evidence remains largely retrospective or preclinical. DISCUSSION: DNA methyltransferase inhibitors, alone or combined with immunotherapy/targeted agents, demonstrate preclinical and early clinical efficacy. Key challenges include mechanistic gaps, tumor heterogeneity, and assay standardization. CONCLUSION: DNA methylation is a actionable regulatory layer in pancreatic cancer, but further mechanistic and clinical validation is needed for translational impact.
Epigenetic silencing sensitizes esophageal cancer to DNA-PKcs inhibitor.
Li Y, Gao A, Yao Y … +4 more , Zhang M, Jin L, Tao Q, Guo M
Cancer Biol Ther · 2026 Dec · PMID 41876459 · Full text
BACKGROUND: Esophageal squamous cell carcinoma (ESCC) remains a deadly disease, with no effective therapeutics available for advanced stages. The application of the "synthetic lethality" principle to cancers with abnorma...
BACKGROUND: Esophageal squamous cell carcinoma (ESCC) remains a deadly disease, with no effective therapeutics available for advanced stages. The application of the "synthetic lethality" principle to cancers with abnormal epigenetic changes provides more opportunities for developing novel therapeutic strategies. It is necessary to identify more molecules that are involved in the DNA damage repair response or cell fate determination to reach this end. Malignant brain tumor (MBT) domain proteins are important for development and cell fate. is a new member of this family, but its function remains to be clarified. METHODS: Lentiviral infection was used to re-express . Immunoprecipitation, immunofluorescence, comet, homologous recombination (HR), and non-homologous end joining (NHEJ) reporter assays were performed to explore the mechanism involved. RESULTS: The expression of was regulated by methylation of the promoter region. inhibited cell proliferation and colony formation, and induced G1/S arrest and apoptosis in ESCC cells. promoted ATM signaling and inhibited NHEJ signaling by interacting with KU70. Epigenetic silencing of sensitized ESCC cells to NU7441, a DNA-PKcs inhibitor, both and CONCLUSION: is a potential tumor suppressor and methylation of is a sensitive marker of DNA-PKcs inhibitors.
The MYBL2-GTSE1 axis promotes laryngeal squamous cell carcinoma progression by regulating PI3K/AKT-dependent glycolytic reprogramming.
Liang Y, Wang C, Ren T … +4 more , Zhang B, Liu Y, Fu R, Feng J
Cancer Biol Ther · 2026 Dec · PMID 41866755 · Full text
BACKGROUND: Laryngeal squamous cell carcinoma (LSCC) is a common head and neck malignancy with poor prognosis. The role of MYBL2, an oncogenic transcription factor, in the glycolytic reprogramming of LSCC remains unclear...
BACKGROUND: Laryngeal squamous cell carcinoma (LSCC) is a common head and neck malignancy with poor prognosis. The role of MYBL2, an oncogenic transcription factor, in the glycolytic reprogramming of LSCC remains unclear. METHODS: We integrated RNA-sequencing with public databases (TCGA, GEO) and tissue microarrays to assess MYBL2 expression and its clinical significance. Transcriptional regulation was verified by ChIP-qPCR and luciferase reporter assays. Signaling pathways and metabolic profiles were examined using Western blotting and Seahorse analysis (ECAR/OCR). Biological functions were evaluated by functional assays and xenograft models in female BALB/c nude mice. RESULTS: MYBL2 was significantly overexpressed in LSCC tissues and correlated with poor prognosis. Mechanistically, MYBL2 directly activates GTSE1 transcription. This regulation stimulates PI3K/AKT signaling to upregulate key glycolytic proteins (PKM2, HK2, GLUT1, LDHA), thereby driving metabolic reprogramming characterized by elevated glycolysis (ECAR) and suppressed mitochondrial respiration (OCR). Functionally, MYBL2 overexpression enhanced the proliferation, migration, and invasion of LSCC cells and promoted tumor growth . Importantly, these oncogenic effects were effectively reversed by GTSE1 knockdown or PI3K inhibition with LY294002, validating the pathway's functional significance. CONCLUSION: The MYBL2-GTSE1 axis promotes LSCC progression through PI3K/AKT-mediated metabolic reprogramming, representing a promising therapeutic target.
Deguelin inhibits perineural invasion in esophageal squamous cell carcinoma via targeting BDNF/TrkB axis.
Wei Q, Bai L, Yan L … +5 more , Wang Z, Jin R, Li B, Cao W, Mo S
Cancer Biol Ther · 2026 Dec · PMID 41851958 · Full text
BACKGROUND: Perineural invasion (PNI) represents a uniquely distinctive pathway for tumor metastasis, but its underlying molecular mechanisms and therapy remain unclear. METHODS: Bioinformatics analysis and transcriptomi...
BACKGROUND: Perineural invasion (PNI) represents a uniquely distinctive pathway for tumor metastasis, but its underlying molecular mechanisms and therapy remain unclear. METHODS: Bioinformatics analysis and transcriptomic sequencing were first employed to investigate the involvement of the BDNF/TrkB axis in the ESCC PNI, which was validated with ESCC cells co-cultured with a dorsal root ganglia system (ESCC/DRG model), a mouse PNI model, and ESCC tissues, mainly using microscopic imaging, IVIS Spectrum imaging, Western blot (WB), and immunohistochemistry (IHC). Additionally, transcriptomic sequencing and WB were conducted to analyze the downstream molecular mechanisms of the BDNF/TrkB axis. Similar experiments were applied to investigate the role of Deguelin in ESCC PNI. Deguelin's interaction with BDNF was assessed using computational docking, pull-down assays, cellular thermal shift assays, surface plasmon resonance (SPR) and WB. Its inhibitory effects on the ESCC PNI were further evaluated through rescue experiments, where BDNF overexpression was used to counteract Deguelin's activity. RESULTS: The BDNF/TrkB axis is closely associated with the PNI in ESCC. This pathway plays a pivotal role in driving PNI progression via Akt signaling. Deguelin was identified as an effective inhibitor of PNI in ESCC. Mechanistically, BDNF was revealed to be a key binding target of Deguelin, which disrupts PNI development by modulating the BDNF/TrkB/Akt axis. Notably, overexpression of BDNF can counteract Deguelin's inhibitory effects on ESCC growth and PNI progression. CONCLUSION: The BDNF/TrkB axis promotes the progression of ESCC PNI, and Deguelin inhibits ESCC PNI by targeting this axis, enhancing the understanding of PNI's molecular mechanisms and offering new therapeutic options.
The role of copper and cuproptosis in digestive system cancers: novel therapeutic strategies and mechanistic insights.
Xu G, Yao N, Cheng R … +4 more , Yang L, Han F, Qu J, Li W
Cancer Biol Ther · 2026 Dec · PMID 41837409 · Full text
Recent research has highlighted the critical role of copper metabolism and a novel form of copper-dependent cell death, termed cuproptosis, in the progression and treatment of these cancers. Copper, an essential trace el...
Recent research has highlighted the critical role of copper metabolism and a novel form of copper-dependent cell death, termed cuproptosis, in the progression and treatment of these cancers. Copper, an essential trace element, plays a crucial role in various cellular processes, including mitochondrial function, antioxidant defense, and angiogenesis. However, the dysregulation of copper homeostasis in cancer cells can exacerbate genomic instability, promote angiogenesis, and reshape the immune microenvironment, thereby driving tumor progression. This review systematically explores the mechanisms of copper homeostasis and cuproptosis in digestive system cancers. We also explore innovative strategies for overcoming drug resistance and reshaping immune responses through copper chelators, copper ionophores, and nanomedicines that induce cuproptosis. By integrating basic research with clinical evidence, this review aims to provide a scientific perspective on understanding the biological significance of cuproptosis and developing new anticancer strategies, while also stimulating in-depth thinking on the intersection of metabolic intervention and cell death.
Research progress on the compositional characteristics of the tumor immune microenvironment and immunopredictive models in esophageal squamous cell carcinoma.
Wang G, Li Z, Tan S … +4 more , Ma J, Yin Z, Du J, Fan L
Cancer Biol Ther · 2026 Dec · PMID 41814475 · Full text
Esophageal cancer is one of the most prevalent malignant tumors of the digestive tract, with esophageal squamous cell carcinoma (ESCC) as its main histological type. In recent years, immunotherapeutic regimens centered o...
Esophageal cancer is one of the most prevalent malignant tumors of the digestive tract, with esophageal squamous cell carcinoma (ESCC) as its main histological type. In recent years, immunotherapeutic regimens centered on immune checkpoint inhibitors (ICIs) have achieved remarkable efficacy in patients with advanced ESCC. However, due to the heterogeneity of the tumor immune microenvironment (TIME), the degree of clinical benefit varies among patients. This heterogeneity not only affects the biological behavior of tumors but also determines the efficacy and prognosis of immunotherapy. Therefore, exploring the interactions between tumor cells and diverse immunological components inside the TIME in ESCC, as well as how to use ICIs to reshape the TIME, may bring new therapeutic opportunities for ESCC patients. This review looks at the important aspects of TIME and immunological prediction models and explores potential therapeutic strategies targeting both, providing a theoretical basis for improving immunotherapy outcomes in ESCC.
ENPP3 drives ccRCC progression by cGAMP hydrolysis and STING-IFN suppression.
Ma J, Wu Y, Lin G … +4 more , Sun X, Geng H, Zhang T, Yu D
Cancer Biol Ther · 2026 Dec · PMID 41715305 · Full text
OBJECTIVE: 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-ch...
OBJECTIVE: 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. METHODS: ENPP3 expression and its link to hypoxia and prognosis were analyzed in ccRCC. Functional roles were tested using gain/loss-of-function studies 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 neutralization with STING- or interferon-α/β receptor-1 (IFNAR1) blocking antibodies. RESULTS: 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. CONCLUSION: 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.
Glutamine transporter SLC1A5 inhibits autophagy-mediated CD276 degradation to promote esophageal cancer progression.
Wang C, Zhang H, Guan C … +3 more , Li Y, Yang S, Huang L
Cancer Biol Ther · 2026 Dec · PMID 41606955 · Full text
BACKGROUND: CD276/B7-H3 is an immune checkpoint molecule often overexpressed in cancers, representing a potential therapeutic target. The underlying mechanisms for CD276 upregulation remain unclear. This study investigat...
BACKGROUND: CD276/B7-H3 is an immune checkpoint molecule often overexpressed in cancers, representing a potential therapeutic target. The underlying mechanisms for CD276 upregulation remain unclear. This study investigates how glutamine metabolism affects CD276 protein stability and esophageal squamous cell carcinoma (ESCC) progression. METHODS: CD276 and SLC1A5 expression were analyzed in 90 ESCC clinical tissues and TCGA/GEO datasets. CCK-8, colony formation, wound healing and transwell assays were performed in KYSE150 and KYSE450 cells. Autophagy was quantified by immunofluorescence and western blot. Mitochondrial reactive oxygen species (ROS) levels measured by flow cytometry. Rescue experiments used -acetylcysteine (NAC) and chloroquine (CQ). Finally, antitumor effects of SLC1A5 inhibitor V9302 in the presence or absence of CD276 were evaluated in NOD/SCID mice ( = 5 per group) bearing KYSE150 xenografts. RESULTS: CD276 and SLC1A5 upregulated in ESCC tissues ( < 0.05). CD276 overexpression enhanced ESCC cell proliferation and migration by 42.3% and 58.7%, respectively ( < 0.01). CQ but not MG-132 increased CD276 expression in ESCC cells. SLC1A5 stabilized CD276 protein without altering CD276 mRNA levels, by suppressing ROS-dependent autophagic degradation. NAC reversed ROS-induced CD276 degradation, while CQ abrogated CD276 downregulation upon glutamine metabolism inhibition. Inhibiting glutamine metabolism could reverse ESCC cell proliferation induced by CD276 overexpression. Moreover, combination of V9302 and CD276 knockout significantly reduced KYSE150 cell-derived xenograft tumor volume by 65.2% (95% CI 58.3-72.1%, < 0.001) in NOD/SCID mice, without affecting mouse body weight ( > 0.05). CONCLUSION: SLC1A5 enhances CD276 stability by suppressing ROS-autophagy signaling, promoting ESCC progression. Targeting glutamine metabolism to enhance CD276 degradation might be a novel therapeutic strategy for ESCC.
Jujuboside A induces bladder cancer cell apoptosis by inhibiting ATP1A2-mediated mitochondrial energy metabolism regulation.
Zhu M, Liu Y, Jia Y … +3 more , Ren L, An S, Wang Y
Cancer Biol Ther · 2026 Dec · PMID 41533486 · Full text
BACKGROUND: Conventional treatments for bladder cancer exhibit various limitations. Therefore, natural products, such as jujuboside A (JuA), have been explored for their multi-target effects and low toxicity. However, th...
BACKGROUND: Conventional treatments for bladder cancer exhibit various limitations. Therefore, natural products, such as jujuboside A (JuA), have been explored for their multi-target effects and low toxicity. However, the specific effects of JuA in bladder cancer remain unclear. OBJECTIVE: To determine whether JuA affects mitochondrial energy metabolism and apoptosis in bladder cancer cells by regulating the ATPase Na+/K+ transporting subunit alpha 2 (ATP1A2) expression. METHODS: Differentially expressed genes (DEGs) in bladder cancer were analyzed using the GSE133624 dataset. ATP1A2 overexpression and knockdown bladder cancer cell models were constructed. Cell phenotypes and markers related to apoptosis and mitochondrial energy metabolism were assessed. Moreover, targeting effects of JuA were investigated. RESULTS: Interleukin (IL)-6, ATP1A2, and hydroxysteroid 11-beta dehydrogenase 1 were identified as potential JuA targets, with ATP1A2 being the main target. ATP1A2 overexpression enhanced the viability and inhibited the apoptosis of bladder cancer cells and promoted mitochondrial energy metabolism in vitro, whereas ATP1A2 knockdown had the opposite effects. JuA decreased cell viability, inhibited ATP1A2 expression, and disrupted mitochondrial energy metabolism. These anticancer effects of JuA were reversed by ATP1A2 overexpression. CONCLUSION: This study elucidated the molecular mechanism by which JuA regulates mitochondrial energy metabolism and induces apoptosis in bladder cancer cells through targeted inhibition of ATP1A2. These findings reveal the crucial role of ATP1A2 in the energy metabolism and survival of bladder cancer cells, providing a new molecular perspective for a deeper understanding of the pathological mechanisms of bladder cancer.
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