Haining Zhen

Liver metastasis (LM) poses a formidable barrier to effective immunotherapy, largely due to its uniquely immunosuppressive microenvironment and resistance to immune checkpoint blockade (ICB).Among emerging mechanisms, WNT11, a non-canonical WNT ligand, has been identified as a preclinical modulator of immune evasion in LM. Acting through a calcium-dependent CAMKII signaling pathway axis, WNT11 suppresses CD8 ⁺ T-cell recruitment via downregulation of chemokines such as CXCL10 and CCL4 and promotes M2-like macrophage polarization through IL17D induction. This dual mechanism contributes to the formation of an immune-excluded, tolerogenic niche that undermines the efficacy of anti-PD-1 therapies. Targeting the WNT11/CAMKII axis restores immune infiltration and sensitizes LM to ICB in preclinical models, highlighting a promising therapeutic strategy. Although no direct WNT11-targeted therapies are currently available, multiple pharmacological strategies targeting its proximal and downstream effectors—such as FZD/ROR, CAMKII, PKC/JNK/NFAT, and associated crosstalk pathways like TGF-β, IDO1, and myeloid axes—are under active exploration. Additionally, circulating WNT11 levels may also serve as a predictive biomarker for patient stratification and treatment monitoring. Despite challenges related to pathway complexity and tumor heterogeneity, this mini review synthesizes recent advances in understanding the WNT11-driven tumor-immune axis and proposes a translational roadmap for combination strategies to overcome ICB resistance in liver metastasis.

Glioma is an aggressive brain tumor characterized by its high invasiveness, which complicates prognosis and contributes to patient resistance against various treatment options. The HOMER family, consisting of HOMER1, HOMER2, and HOMER3, has been implicated in various cancers, yet their specific roles in glioma remain inadequately understood. This study conducted a comprehensive pan-cancer analysis to evaluate the expression profiles of HOMER family members across different tumor types, utilizing data from public databases such as TCGA and GTEx. Our findings indicate significant dysregulation of HOMER1, HOMER2, and HOMER3 in multiple cancers, with HOMER3 emerging as a potential prognostic biomarker, particularly for lower-grade glioma. Elevated expression levels of HOMER3 were associated with shorter overall survival and disease-specific survival in LGG patients, supported by Cox regression analysis that confirmed HOMER3 as an independent prognostic factor. Furthermore, HOMER3 expression correlated positively with advanced clinical stages and key tumor markers. To elucidate the mechanisms behind HOMER3 dysregulation, we identified ELK4 as a transcription factor that binds to the HOMER3 promoter, promoting its expression in glioma cells. Functional assays demonstrated that silencing HOMER3 significantly reduced glioma cell proliferation and metastatic potential in vitro and in vivo, highlighting its oncogenic role. Additionally, HOMER3 was found to influence the Wnt/β-catenin/EMT signaling pathway, with knockdown resulting in altered expression of critical EMT markers. Collectively, our results indicated that HOMER3 plays a crucial role in glioma progression and metastasis, underscoring its potential as a therapeutic target and prognostic biomarker in glioma management.

Mitochondrial dysfunction has emerged as a critical factor in the progression and prognosis of low-grade glioma (LGG). In this study, we explored the role of mitochondrial-related genes through consensus clustering analysis using multi-omics data from the TCGA, CGGA, and other independent datasets. Patients were categorized into three clusters (Cluster A, B, and C), with Cluster B consistently associated with poorer prognosis. Mutation landscape analysis revealed distinct genetic alterations and copy number variations among clusters, particularly in Cluster B, which exhibited unique genetic signatures. Immune infiltration analysis showed that Cluster B had higher expression levels of immune checkpoint genes, stronger immune evasion activity, and greater immune cell infiltration, suggesting an immunosuppressive tumor microenvironment. Furthermore, we identified mitochondrial-related prognostic markers and developed a MITscore based on gene expression patterns, which stratified patients into high- and low-risk groups. High MITscore groups displayed stronger stemness characteristics, poorer survival outcomes, and differential responses to chemotherapy and immunotherapy. Cross-validation with drug sensitivity and immunotherapy cohorts indicated that high MITscore patients were more sensitive to certain chemotherapeutic agents and responded better to immunotherapy. Finally, using the SRGA method, we identified novel biomarkers (KDR, LRRK2, SQSTM1) closely associated with mitochondrial function, which may serve as potential targets for therapeutic intervention. These findings highlight the critical role of mitochondrial dysfunction in LGG prognosis, tumor microenvironment regulation, and treatment response, providing new avenues for precision oncology.

The diagnosis and treatment of gliomas have traditionally been both a research hotspot and a challenge in clinical medicine. Intracranial multiple gliomas are rare, and their diagnosis and treatment are often more difficult than those of solitary gliomas. In this article, we report our experience with the diagnosis and treatment of a case of intracranial multiple glioblastomas that closely resembled metastatic tumors in terms of neuroimaging and anatomy. This case may provide a useful reference and insight into the clinical management of this type of disease.

Background Gliomas are highly aggressive and lack of efficient targeted therapy. YAP, as a Hippo pathway downstream effector, plays a key role in promoting tumor development through the interaction with transcription factor TEAD on the NH3-terminal proline-rich domain. Therefore, targeting TEAD-interacting domain of YAP may provide a novel approach for the treatment of gliomas. Materials and methods We generated a truncated YAP protein which includes the TEAD-binding domain (YAPBD), and supposed YAPBD can interact with endogenous TEAD but lost the function to activate YAP target gene expressions. The association of YAP expression with the malignant characters of glioma tissues were determined by immunohistochemistry. TEAD-binding capacity of YAPBD was determined by co-immunoprecipitation. The cell proliferation and migration were determined by MTT assay, xenograft assay, wound healing assay and transwell assay, respectively. YAP target genes were detected by Western blot. Results YAP was highly expressed in glioma tissues and associated with tumor malignancy. YAPBD could block the TEAD–YAP complex formation by competing with YAP binding to TEAD. YAPBD could inhibit glioma cell growth both in vitro and in vivo, through the induction of cell cycle arrest and apoptosis. The cell cycle-related gene cyclin D1 and c-myc, and anti-apoptotic gene Bcl-2, Bcl-xL and survivin were inhibited after YAPBD overexpression. Furthermore, YAPBD also decreased cell migration and invasion, and repressed epithelial–mesenchymal transition. Conclusion YAPBD can block glioma cell survival and repress YAP-dependent gene expressions, indicating gene therapy which targets TEAD-YAP complex would be a potential and significant novel approach for human malignant gliomas.

Transcriptional coactivator with PDZ‐binding motif (TAZ), a Hippo pathway downstream effector, promotes tumor progression by serving as a transcriptional coactivator with TEAD. Here, we introduced a new construct which can express the TEAD‐binding domain of TAZ protein (TAZBD), and determined its antitumor effect in malignant glioma both in vitro and in vivo. We first observed that TAZ was upregulated in glioma tissues and related to malignant clinicopathologic characteristic, indicating the crucial role of TAZ during glioma progression. In U87 and U251 cells, TAZBD expression increased the proportion of apoptotic cells, and suppressed the colony formation and tumorigenicity. Further, TAZBD also decreased cell metastasis through the repression of epithelial‐mesenchymal transition. The mechanistic study showed that TAZBD suppression of glioma cells was predominantly through blocking the TAZ‐TEAD complex formation by competing with endogenous TAZ. Thus, the gene therapy of malignant glioma through blocking TAZ‐TEAD complex by TAZBD may provide a new way for the targeted therapy of glioma.

Background: LAT1/4F2hc heterodimeric complex is a major route for the transport of large neutral essential amino acids through the plasma membrane. Although it has been shown that LAT1/4F2hc is highly expressed in a variety of human tumors including gliomas, and LAT1 over-expression is associated with glioma grade and poor prognosis of glioma patients, the precise tissue location of LAT1/4F2hc in gliomas and the precise role of LAT1/4F2hc in glioma biological features remain unclear. Methods: In the current study, the expressions of LAT1, 4F2hc, CD34 and Ki-67 were investigated by immunohistochemistry in 62 cases of human brain glioma; LAT1/4F2hc expression level, Ki-67 labeling index (Ki-67 LI) and microvessel density (MVD) were measured semi-quantitatively; and the correlation of LAT1/4F2hc expression with histopathological features, Ki-67 LI and MVD in gliomas was further analyzed. Results: The results showed that both LAT1 and 4F2hc were expressed in all examined specimens. LAT1 but 4F2hc expression levels significantly correlated with the pathological grade and both expression levels significantly correlated with Ki-67 LI of gliomas. We also demonstrated that both LAT1 and 4F2hc immunoreactivity were observed in tumor cells as well as vascular endothelia; furthermore, the LAT1 expression level was markedly associated with glioma MVD as well. Conclusion: LAT1/4F2hc over-expression is closely correlates with the malignant phenotype and proliferation of gliomas, and LAT1 was associates with glioma angiogenesis. LAT1/4F2hc, especially LAT1, may become a novel potential molecular target for glioma biological therapy.