Multiomics Approach Distinguishes SPTBN4 as a Key Molecule in Diagnosis, Prognosis, and Immune Suppression of Testicular Seminomas

International Journal of Genomics, Год журнала: 2025, Номер 2025(1)

Опубликована: Янв. 1, 2025

Background: Testicular seminomas, a common germ cell tumor, poses clinical challenges due to its molecular heterogeneity and limited biomarkers for precise diagnosis prognosis. Leveraging multiomics approaches enables the comprehensive dissection of tumor complexity facilitates identification key molecules influencing disease progression therapeutic response. Methods: Single-cell RNA transcriptomic sequencing (scRNA-seq) was utilized explore cellular transcriptional testicular seminomas. High-dimensional weighted gene coexpression network analysis (hdWGCNA) identified modules linked progression. Public datasets were integrated expression survival analyses, drug sensitivity patterns assessed using GDSC database. Results: scRNA-seq revealed heterogeneous epithelial populations, with Epi1 cells exhibiting SLC5A5 SPTBN4 as risk factors advanced hdWGCNA nine modules, M6 module significantly enriched in cells, implicating pathways such negative regulation ERAD selective mRNA degradation. markedly upregulated seminoma compared nonseminomatous tumors normal tissues, high associated poorer outcomes immunosuppressive microenvironments. Immune pathway analyses highlighted reduced antigen presentation increased neutrophil extracellular trap (NET) formation SPTBN4-high group, suggesting diminished immunotherapeutic efficacy. Conversely, group exhibited multiple chemotherapeutic agents, including thapsigargin sorafenib, indicating potential predictive marker chemotherapy. Conclusion: In conclusion, this study identifies central biomarker encompassing diagnostic, prognostic, dimensions. The integration single-cell transcriptomics, hdWGCNA, underscores seminomas highlights translational guiding personalized treatment strategies. These findings provide foundation leveraging advance management other malignancies.

Язык: Английский

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Dynamics of tertiary lymphoid structures and immune cross talk in early versus advanced colorectal cancer: potential implications for immunotherapy

Cancer Immunology Immunotherapy, Год журнала: 2025, Номер 74(6)

Опубликована: Апрель 26, 2025

Abstract Background Irrespective of microsatellite status, immune checkpoint inhibitor therapy shows superior efficacy in early-stage colorectal cancer (CRC) compared to advanced cases. The distinctions the tumor microenvironment (TME) and tertiary lymphoid structure (TLS) between early- advanced-stage CRC may represent a critical factor, yet remain incompletely elucidated. Methods We comprehensively analyzed single-cell RNA sequencing data, bulk transcription data pathological tissue investigate dynamic changes TME. features TLS tumors their potential impact on immunotherapy were explored using three in-house cohorts. Results provided fine maps landscape early CRC. Significant functional differences identified CD4 + Tfh BGC cells revealed CXCL13 expression CD8 Tex cells, along with CD40–CD40L interactions could be key regulators functionality subsequently affect response immunotherapy. Conclusions Our research shed light multilayered dysfunction elucidates alterations during progression CRC, providing insights for studies exploration target

Язык: Английский

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Spatially segregated APOE⁺ macrophages restrict immunotherapy efficacy in clear cell renal cell carcinoma

Theranostics, Год журнала: 2025, Номер 15(11), С. 5312 - 5336

Опубликована: Апрель 13, 2025

Background: Immunotherapy has revolutionized cancer treatment and holds great potential for them, including metastatic clear cell renal carcinoma (ccRCC). However, immune resistance remains a major obstacle, limiting its efficacy durability. Understanding the mechanisms of tolerance in tumor microenvironment (TME) is pivotal overcoming these challenges enhancing therapeutic outcomes. Methods: Over 2000 samples, real-world cohort 230 advanced ccRCC patients treated with checkpoint blockade (ICB) were analyzed. Single-cell RNA sequencing data from 13 regions categorized into ICB-exposed, ICB-resistant, ICB-responsive groups. Multiple robust algorithms multiplex immunofluorescence used to explore TME composition macrophage heterogeneity. Spatial communication dynamics further investigated. In vitro experiments performed evaluate impact SPP1 on 786-O 769-P cells. Co-culture THP-1-derived macrophages, followed by Western blot, flow cytometry, functional assays, investigate SPP1-mediated polarization progression. Results: The results revealed an elevated presence Apolipoprotein E (APOE)+ macrophages ICB-resistant ccRCC. Notably, higher APOE+ proportion indicated shorter prognosis worse response ICB (P < 0.001). Elevated expression CCAAT Enhancer Binding Protein Delta (CEBPD) was markedly linked several immunosuppressive pathways, hindering T recruitment, promoting exhaustion, ultimately diminishing poorer efficacy. Meanwhile, upregulated Secreted Phosphoprotein 1 (SPP1) significantly enhances proliferation, clonal formation, migration Tumor-derived SPP1. Additionally, signaling malignant cells appeared recruit margins, promotes M2-like macrophages. vicinity tumor, shape releasing abundant TGF-β signals, anti-tumor effector activity tumors, contributing Conclusion: This study reveals critical role suppression therapy By exhaustion signaling, particularly via localized TGF-β, spatially segregated undermine Targeting especially conjunction ICB, presents promising strategy overcome enhance outcomes patients.

Язык: Английский

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Nervous system–gut microbiota–immune system axis: future directions for preventing tumor

Frontiers in Immunology, Год журнала: 2025, Номер 16

Опубликована: Май 1, 2025

Tumor is one of the leading causes death worldwide. The occurrence and development tumors are related to multiple systems factors such as immune system, gut microbiota, nervous system. system plays a critical role in tumor development. Studies have also found that microbiota can directly or indirectly affect tumorigenesis With increasing attention on microenvironment recent years, has emerged novel regulator Some therapies based been tested clinical trials. However, not only interact with cells but through microbiota. system-mediated regulate tumorigenesis, growth, invasion, metastasis Here, we mainly explore potential effects system-gut microbiota-immune axis involve regulating which prevent Meanwhile, direct regulation by development, reviewed.

Язык: Английский

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Tertiary lymphoid structures in gliomas: impact on tumour immunity and progression

Journal of Translational Medicine, Год журнала: 2025, Номер 23(1)

Опубликована: Май 9, 2025

Tertiary lymphoid structures (TLSs) are ectopic formations that develop in chronically inflamed tissues, including various solid tumours. In the context of gliomas, presence TLSs has recently attracted considerable attention because their potential implications tumour immunology and therapy. The immune microenvironment (TIME) plays a crucial role cancer progression, tumour-infiltrating cells (TILs) key players this environment. These cell aggregates, known as TLSs, display distinct characteristics across different However, central nervous system (CNS) tumours highly heterogeneous, environment within these is often more deficient than peripheral tissue This leads to differences formation function CNS variations particularly relevant glioma immunotherapy could have important for treatment strategies. review focuses on composition examines complexity glioblastoma (GBM) microenvironment, highlights unique GBM, providing new theoretical insights practical foundations targeting immunotherapy.

Язык: Английский

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