Cancer Biology & Therapy最新文献

Mesothelin (MSLN) is a glycosylphosphatidylinositol (GPI)-anchored membrane protein that promotes malignant behaviors including tumor cell proliferation, migration and immune evasion through activation of multiple signaling pathways, such as MAPK/ERK and PI3K/AKT. MSLN is widely overexpressed in malignant tumors but shows low expression levels in normal tissues. This differential expression pattern renders MSLN an important clinical therapeutic target. Currently, MSLN-based tumor-targeting approaches predominantly involve antibody-drug conjugates (ADC), cancer vaccines, oncolytic viruses and chimeric antigen receptor T-cell (CAR-T) therapies. These therapeutic modalities have demonstrated encouraging efficacy in preclinical studies and phase I/II clinical trials. However, challenges such as unclear molecular mechanisms of MSLN signaling pathways and extracellular domain shedding impose limitations on targeted therapeutic strategies. Therefore, this review comprehensively discusses the gene and protein structures of MSLN, its biological functions, and related targeted therapeutic strategies, providing new insights into MSLN-targeted cancer therapy.

Background: Triple-negative breast cancer (TNBC) is an aggressive subtype with a poor prognosis and limited treatment options. Tumor-associated macrophages (TAMs), the predominant and abundant immune cells in the tumor immune microenvironment (TIME), critically drive TNBC progression. Consequently, TAM reprogramming has emerged as a promising therapeutic approach. However, a major barrier remains the incomplete understanding of the molecular mechanisms governing TAM reprogramming.

Methods: The role of CD44v5 in TAM polarization was evaluated with a CD44v5 monoclonal antibody and CD44v5-knockdown cell lines. Subsequently, cell functional assays, including wound healing, invasion, and colony formation assays, were performed to assess changes in the MDA-MB-468 cell line. Cytokine secretion levels (IL-4 and IL-6) were measured by electrochemiluminescence immunoassay (ECLIA).

Results: We found that M2 macrophages and tumor-associated macrophages (TAMs) polarized through the IL4/IL4R signaling pathway and exerted similar protumorigenic functions, and that IL4 is the key protumorigenic factor secreted by M2 macrophages. Interestingly, CD44v5 blockade effectively inhibited M2 polarization and promoted the phenotypic shift to M1 macrophages, which was supported by increased CD86 expression and decreased IL-4 secretion. Furthermore, molecular docking analysis and colocalization microscopy confirmed that CD44v5 colocalized with IL-4Rα, preventing its internalization.

Conclusion: CD44v5 promotes M2 macrophage polarization by stabilizing and enhancing the IL-4Rα/STAT6/IL-4 signaling pathway, thereby facilitating the progression of triple-negative breast cancer. CD44v5 serves as an important therapeutic target for the reprogramming of both TAMs and M2 macrophages, thereby providing a novel strategy for the treatment of TNBC.

Background: Natural killer/T-cell lymphoma (NKTCL) presents highly aggressive clinical behaviour, and the outcomes for relapsed and refractory patients are still poor. Our previous study identified somatic mutations in GNAQ in 8.7% of cases through whole-exome sequencing, revealing the T96S mutation in the Gαq protein.

Materials: The proliferation, gemcitabine sensitivity and apoptosis of NKTCL cells were assessed by CCK-8 assays and flow cytometry. The downstream pathways of GNAQ were explored by mRNA sequencing, Western blotting and co‑immunoprecipitation. Additionally, we investigated the role of GNAQ in the activation of the RHOA pathway in NKTCL.

Results: We found that GNAQ significantly inhibited the aggressive function of NKTCL, whereas the T96S mutation abolished the ability of wild-type GNAQ to trigger cell apoptosis. Further investigation revealed that GNAQ modulated NKTCL cell functions through the activation of the RHOA pathway, which is regulated by the GNAQ-ARHGEF25 complex. Clinically, high expression of RHOA was associated with improved overall survival (HR = 0.317, 95% CI: 0.126-0.800, p = 0.015), whereas low expression of RHOA was correlated with poorer survival outcomes. The application of an RHOA pathway inhibitor or reactivation of the RHOA pathway significantly affected the biological functions of NKTCL cells both in vitro and in vivo.

Conclusion: In summary, RHOA is a critical downstream effector of GNAQ in NKTCL. GNAQ promotes RHOA activation through ARHGEF25, which in turn regulates cellular functions by modulating cell proliferation and apoptosis, thereby influencing the progression of NKTCL.

Lactylation, a recently identified post-translational modification, has reshaped our understanding of lactate from a metabolic byproduct to a central regulator of tumor biology. Accumulating evidence reveals that lactate-driven lactylation orchestrates metabolic reprogramming, epigenetic remodeling, immune evasion, metastasis, and therapeutic resistance, thereby fueling malignant progression. Beyond histones, diverse non-histone substrates further expand its regulatory network across cancer signaling pathways. We highlight the crosstalk between lactylation and other modifications, its role in tumor heterogeneity, and the therapeutic opportunities arising from targeting this pathway. These insights establish lactylation as both a hallmark and a potential vulnerability of cancer, opening new avenues for precision oncology.

Background: Clear cell renal cell carcinoma (ccRCC), the most common kidney cancer subtype, is marked by lipid metabolism reprogramming and therapy resistance. Ferroptosis-an iron-dependent, lipid peroxidation-driven cell death-has gained attention as a therapeutic strategy. This study investigates the role of ACSL1, a key lipid metabolism enzyme, in ccRCC.

Methods: Using TCGA/GEO datasets, qPCR, immunohistochemistry, and immunofluorescence, ACSL1 expression and clinical significance were analyzed. Functional assays with ACSL1-overexpressing ccRCC cells and a xenograft mouse model evaluated its impact on tumor behavior. Transcriptomics and lipidomics, alongside ROS, ferroptosis, and p53 inhibitors, were applied to uncover mechanisms.

Results: ACSL1 is markedly downregulated in ccRCC and predicts poor prognosis. Overexpression suppressed proliferation and migration, induced cell death, and slowed tumor growth. Mechanistically, ACSL1 elevated ROS, activated p53, downregulated SLC7A11/GPX4, and triggered ferroptosis. Blocking ROS or p53 reversed these effects, confirming a ROS-p53-SLC7A11/GPX4 feedback loop.

Conclusion: ACSL1 functions as a tumor suppressor in ccRCC by inducing ferroptosis via the ROS-p53-SLC7A11/GPX4 axis. It holds promise as a prognostic biomarker and therapeutic target in ccRCC.

Background: Double-hit lymphoma (DHL) exhibits aggressive behavior due to dysregulated proliferation and resistance to apoptosis. Current therapies, including R-CHOP, show limited efficacy, necessitating novel strategies. 9-ING-41, a novel ATP-competitive small-molecule inhibitor that targets glycogen synthase kinase-3β (GSK-3β), has emerged as a promising therapeutic agent because of its ability to disrupt oncogenic signaling pathways associated with tumor progression and treatment resistance. However, the antitumor effects of 9-ING-41 in DHL remain unclear.

Materials and methods: DHL cell lines (Karpas-422 and SuDHL2) were treated with venetoclax and 9-ING-41, either alone or in combination. Cell viability in cytotoxicity assays was assessed using the CCK-8 assay, while apoptosis and cell cycle changes were analyzed via flow cytometry. Western blotting was employed to evaluate alterations in the levels of GSK-3β and WNT/β-catenin pathway proteins following treatment.

Results: In preclinical studies utilizing DHL cell models, the single agent 9-ING-41 demonstrated robust biological activity through inducing significant G1/S phase cell cycle arrest and triggering apoptosis. When coadministered with venetoclax, a clinically approved BCL-2 inhibitor, the combination exhibited marked synergistic cytotoxicity in DHL cells, achieving superior inhibitory effects compared to either agent alone. The combined treatment enhanced cell cycle arrest, significantly reducing the number of S-phase cells and reinforcing G0/G1 arrest. Further mechanistic studies revealed that the combination modulated key proteins in the GSK-3 pathway and downstream WNT/β-catenin pathway, revealing a potential synergistic mechanism.

Conclusion: The demonstrated single-agent efficacy and combination synergy with venetoclax support the potential of 9-ING-41 as a novel therapeutic strategy for DHL. These findings provide a proof-of-concept that may serve as a basis for future preclinical investigations in DHL.

Non-small-cell lung cancer (NSCLC) is the leading cause of cancer-related mortality worldwide. Although radiotherapy (RT) is used to treat over half of NSCLC patients, about 30% have inherent or acquired radioresistance leading to treatment failure. There's a clinically unmet need to investigate mechanisms of radioresistance that can be targeted in combination with RT. Among these, HMGB1 has been shown to play a key role in tumor progression. Our research investigates TLR4, a receptor for HMGB1, highly expressed in NSCLC tissues, as a mediator of radioresistance.

Methods: The TLR4 inhibitor, TAK242, was tested in NSCLC cell lines (murine: LLCI, KLN205; human: H1975, SW900). Cells were irradiated at 2 and 10 Gy. In vivo, KLN205 cells were implanted in DBA/2 mice and tumors were irradiated at 10Gy. Gene and protein expression of TLR4 and MyD88 were assessed in vitro and in vivo. HMGB1 secretion was quantified after RT. Clonogenic assays were performed to evaluate the effect of TAK242 on radiosensitivity in vitro. The combination of TAK242 and RT was investigated in vivo in mice bearing KLN205 tumors.

Results: TAK242 significantly decreased NSCLC cell proliferation and migration. Radiation at 2 and 10 Gy increased TLR4 gene expression in vitro and in vivo in a dose-dependent manner. In vitro, TLR4 and HMGB1 protein expression was upregulated following radiation. TAK242 in combination with radiation enhanced radiosensitivity in vitro. TAK242 decreased the percentage of cells in the G1 phase, coupled with an increase in late S and G2/M, suggesting radiosensitization via cell cycle modulation. In vivo, the combination of RT and TAK242 significantly reduced growth of KLN205 tumors.

Conclusion: These findings show that TLR4 inhibition enhances RT sensitivity in NSCLC.

Background: Prostate cancer (PCa) is a major health concern, and current PSA screening is limited by low specificity and the risk of overdiagnosis. Extracellular vesicle (EV)-derived RNA biomarkers offer a promising non-invasive alternative for early detection.

Methods: We utilized a tethered cationic lipoplex nanoparticle (TCLN) biochip for amplification-free EV RNA detection at the single-vesicle level. Eight candidate RNAs (four miRNAs, three mRNAs, and one lncRNA) were profiled in serum and urine samples from PCa patients, benign prostatic hyperplasia (BPH) patients, and healthy controls (HC). Diagnostic and risk stratification performance was evaluated in discovery and validation cohorts, with qRT-PCR used for validation.

Results: TCLN reliably detected the candidate RNA biomarkers from PCa cell lines and clinical samples, with strong concordance to qRT-PCR. Serum EV RNAs (miR-141, miR-375, Let-7c) and urine EV RNAs (miR-141, miR-375, PCA3 lncRNA, T1-E2) effectively distinguished PCa patients from controls. Combined EV RNA biomarkers in serum and urine achieved diagnostic area-under-the-curve (AUCs) of 0.824 and 0.741, respectively, surpassing those of prostate-specific antigen (PSA) alone. Serum miR-141, miR-375, and urine miR-141, miR-375, and PCA3 lncRNA, also showed remarkable correlations with PCa Gleason score (GS), tumor stage, and metastatic status.

Conclusion: The TCLN biochip enables sensitive, amplification-free detection of EV RNA biomarkers from serum and urine. Key markers such as miR-141, miR-375, and PCA3 showed strong diagnostic and risk stratification value in PCa. This non-invasive approach holds promise for improving early detection and clinical risk assessment.

Background: Extracellular vesicle (EV) signaling is important in multiple malignancies, including pancreatic ductal adenocarcinoma (PDAC). In this coordinated cell‒cell signaling mechanism, genetically altered tumor cells signal to surrounding normal cells to promote tumor progression. Many efforts have been made to mechanistically interrogate this signaling axis by inhibiting EV secretion from cells. These techniques leverage our understanding of how EV biogenesis interferes with ceramide production or GTPase activity, which aids in membrane fusion with the plasma membrane.

Material and methods: Our group leveraged these methods in our orthotopic PDAC mouse model to investigate the importance of PDAC EV secretion. We interfered with the GTPases Rab27a and Rab35 and utilized an inhibitor of ceramide production (GW4869) to ablate EV secretion.

Results and conclusion: Overall, we found that these models did not perform as anticipated, and we could not consistently inhibit KPC cell EV secretion. These results emphasize the challenges of interfering with EV secretion, as several parallel pathways, such as direct membrane budding, can compensate. Further studies are needed to develop models for studying the role of EVs in vivo.

The cancer-immunity cycle is regulated by a series of stimulatory and inhibitory factors. The stimulator of interferon genes (STING) pathway, a key stimulator of type I interferon production, connects innate and adaptive immunity to promote antitumor responses. Using a syngeneic pancreatic tumor model, we characterized the single-cell landscape changes induced by STING stimulation. Our findings revealed that STING agonist treatment reprograms transcription across multiple cell lineages, enhances innate immune responses and activates lymphocytes, thereby promoting antitumor effects. Single-cell transcriptome sequencing identified significant increases in monocytes, neutrophils, macrophages, and CD8 T cells, indicating augmented tumor inflammation. Differential gene expression analysis highlighted upregulated genes related to immune cell effector mechanisms and antigen presentation. Functional assays confirmed the enhanced tumor killing effects induced by STING activation. These results underscore the potential of STING agonists in reprogramming the tumor microenvironment to potentiate antitumor immunity, although clinical translation remains challenging owing to pharmacokinetic limitations and potential systemic toxicity. Further research is needed to optimize STING agonist delivery and dosage for effective cancer immunotherapy.