Cancer Biology & Therapy最新文献

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 in vitro 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 in vivo 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.

Background: 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.

Materials and methods: 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.

Results and conclusion: 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.

Background: Gliomas, including glioblastomas (GB) and high-grade astrocytomas (HGA), are the most common brain tumors in adults, with poor survival rates around 15 months. Hormonal factors, particularly progesterone receptor (PR) activation, promote tumor growth. Current treatment involves surgery, radiotherapy and chemotherapy (temozolomide), but survival rates remain low. Repurposing mifepristone (MF), a contraceptive drug, shows promise for GB treatment, warranting further study.

Methods: PR expression in U87, U251 and C6 cell lines were assessed using immunofluorescence and Western Blot. PR isoforms were quantified by densitometry. Progesterone (P4) and 5α-dihydroprogesterone (5α-DHP) synthesis were evaluated using LC/MS. MF's effect on cell viability was determined by IC₅₀ and IC₂₀ values. Its impact on non-tumoral cells and 3D glioma sphere formation was also analyzed. The effects of in situ administration of MF were assessed in vivo using a rat model with C6 glioma implants. Clinical outcomes were evaluated in GB patients receiving MF alongside standard treatment.

Results: PR was predominantly nuclear in all cell lines, with U87 showing the highest PR-B isoform levels. Only U251 synthesized 5α-DHP significantly. MF reduced viability in U251, U87 and C6 cells without affecting non-tumoral cells. Sphere formation efficiency decreased with MF treatment. In rats, MF reduced tumor volume dose-dependently. Clinically, MF improved patient survival from 165 to 588days and enhanced quality of life without severe adverse effects.

Conclusion: MF effectively reduces GB cell viability, sphere formation efficacy and tumor volume. These findings support further investigation of MF as a therapeutic strategy in GB treatment.

Précis (condensed abstract): Our research highlights the critical role PR in GB progression using in vitro and in vivo models. MF, a PR modulator, effectively reduced cell viability and sphere formation in cellular assays and significantly decreased tumor volume in an in vivo study. The pilot trial demonstrated the pharmacological safety of using MF as an adjuvant in GB treatment. Patients treated with MF showed a significant increase in survival, with an 80% survival rate at 1 year compared to 0% in those who were treated with the standard treatment.

Background: The potential of Lenvatinib to synergize with combined radiotherapy and immunotherapy in LUAD remains incompletely characterized.

Methods: We investigated Lenvatinib's effects on radiation-induced PD-L1 in LUAD cells and VEGFR2 in HUVECs via Western blot, VEGFA expression via RT-qPCR/ELISA, and angiogenesis via immunofluorescence. LUAD-HUVEC crosstalk was modeled in vitro. In C57BL/6 mice bearing LUAD tumors, we evaluated the efficacy of RT and anti-PD-L1 with or without Lenvatinib, monitoring tumor growth, survival, and profiling the tumor microenvironment by mIHC and flow cytometry.

Results: Lenvatinib suppressed radiation-induced PD-L1 and VEGFR2 expression, inhibited angiogenesis, and disrupted HUVEC-facilitated LUAD proliferation. The triple-combination (RT + anti-PD-L1 + Lenvatinib) significantly suppressed tumor progression (P < 0.05) and extended median survival (34 vs. 29.5 days, P < 0.05) versus dual therapy. It also enhanced intratumoral CD8⁺ T-cell infiltration and cytotoxicity, promoted M1-like macrophage polarization, and reduced regulatory T cell frequency and microvessel density.

Conclusions: Lenvatinib potentiates RT and anti-PD-L1 therapy in LUAD through dual immune-vascular modulation, supporting the clinical translation of this triple-combination strategy.

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. L3MBTL4 is a new member of this family, but its function remains to be clarified.

Methods: Lentiviral infection was used to re-express L3MBTL4. 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 L3MBTL4 was regulated by methylation of the promoter region. L3MBTL4 inhibited cell proliferation and colony formation, and induced G1/S arrest and apoptosis in ESCC cells. L3MBTL4 promoted ATM signaling and inhibited NHEJ signaling by interacting with KU70. Epigenetic silencing of L3MBTL4 sensitized ESCC cells to NU7441, a DNA-PKcs inhibitor, both in vitro and in vivo.

Conclusion: L3MBTL4 is a potential tumor suppressor and methylation of L3MBTL4 is a sensitive marker of DNA-PKcs inhibitors.

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 N-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 (n = 5 per group) bearing KYSE150 xenografts.

Results: CD276 and SLC1A5 upregulated in ESCC tissues (P < 0.05). CD276 overexpression enhanced ESCC cell proliferation and migration by 42.3% and 58.7%, respectively (P < 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%, P < 0.001) in NOD/SCID mice, without affecting mouse body weight (P > 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.

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.

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 in vitro functional assays and in vivo 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 in vitro and promoted tumor growth in vivo. 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.

Background: Current risk stratification for neuroblastoma (NB) relies on limited markers like MYCN amplification. Coilin, a key Cajal body component, regulates cellular processes. This study investigates whether coilin expression in bone marrow (BM) serves as a predictive biomarker for NB progression and elucidate its function in this disease.

Methods: The functions and molecular mechanisms of coilin were investigated by employing cell lines and animal models. Coilin mRNA levels in patient samples were measured by RT-PCR, and their relationships with clinicobiological characteristics and outcomes were analyzed.

Results: Cisplatin induced dramatic changes of coilin distribution and expression. Databases showed that high expression of coilin exerted predictive values for poor outcome in NB. Coilin promoted proliferation in vitro and in vivo. Knockdown of coilin expression inhibited cell migration and invasion, promoted apoptosis and increased the Cisplatin drug sensitivity. Moreover, coilin activates p53/p21 signaling pathway and was a direct target of MYCN. Analysis of BM samples demonstrated that high expression of coilin was obviously associated with adverse clinical biological features. Importantly, the levels of coilin at diagnosis were markedly higher than those at the time before maintenance treatment in the exact paired patients. Survival analysis presented that high coilin expression in BM is associated with poor prognosis.

Conclusions: A novel and accessible coilin-targeted liquid biopsy method was developed, capable of detecting minimal residual disease (MRD) in early-stage NB and predicting disease progression and recurrence. Coilin was transcriptionally regulated by MYCN, offering potential avenues for the development of novel drugs or intervention strategies.