ORIGINAL RESEARCH article
Front. Oncol.
Sec. Cancer Molecular Targets and Therapeutics
Volume 15 - 2025 | doi: 10.3389/fonc.2025.1593011
This article is part of the Research TopicNovel Molecular Targets in Cancer TherapyView all 47 articles
NK Cell-Related Genes-Driven Novel Molecular Subtyping and Prognostic Signatures for Wilms Tumor: Uncovering the Therapeutic Potential of TGX-221 and Biomarker Role of HS2ST1
Provisionally accepted
- Chongqing Medical University, Chongqing, China
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Background: Wilms tumor (WT) lacks precise molecular subtyping tools, which limits the development of personalized therapies. To address this issue, we investigated whether NK cell-related genes (NKGs) could refine the molecular subtyping of WT, aiming to identify novel therapeutic strategies.Methods: Consensus clustering was employed for the molecular subtyping of WT. The immune microenvironment of different WT subtypes was assessed using immune profiling algorithms. Potential therapeutic compounds targeting the identified subtypes were screened using the CMap database, and their mechanisms of action were elucidated through molecular docking and molecular dynamics simulations.Transwell assays, were performed to assess the biological behavior of tumor cells. A prognostic signatures was constructed using machine learning algorithms, with its performance evaluated by ROC curves, calibration curves, and the concordance index.Additionally, cellular localization and expression of marker genes were investigated through single-cell analysis and validated using RT-qPCR.We developed novel molecular subtyping tools that classified WT into prognostically distinct subtypes: "immune-rich" and "immune-desert". Screening the CMap database identified the small-molecule drug TGX-221 as a candidate modulator.TGX-221 significantly inhibited the malignant progression of WT through a dualaction mechanism: blocking the key oncogenic Wnt/β-catenin signaling pathway and sensitizing tumor cells to NK cell-mediated cytotoxicity. Furthermore, a prognostic signatures based on HS2ST1, EPI3M, and PPP3CA effectively predicted patient outcomes. Notably, HS2ST1 emerged as a novel biomarker, potentially promoting cancer stem cell-like properties via heparan sulfate-mediated enhancement of Wnt/βcatenin signaling, highlighting its dual value as both a prognostic indicator and a therapeutic target.Molecular subtyping and prognostic signatures based on NKGs enable the precise identification of high-risk WT patients. Moreover, TGX-221 represents a promising novel therapeutic candidate, while HS2ST1 serves as a potential prognostic biomarker. These findings collectively provide tools for risk stratification and targeted therapy, advancing precision oncology for WT.
Keywords: Wilms Tumor, Natural Killer cells, Molecular subtyping, Prognostic signatures, TGX-221, Hs2st1
Received: 13 Mar 2025; Accepted: 14 Aug 2025.
Copyright: © 2025 Hong, Hu, Lin, Cui, Gao, Tian, Lin, Shi and Wei. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence:
Qinlin Shi, Chongqing Medical University, Chongqing, China
Hui Guang Wei, Chongqing Medical University, Chongqing, China
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