ORIGINAL RESEARCH article
Front. Immunol.
Sec. Cancer Immunity and Immunotherapy
Volume 16 - 2025 | doi: 10.3389/fimmu.2025.1619361
This article is part of the Research TopicMechanisms and Complexities Underlying the Cancer Cell Immune Evasion and its Therapeutic ImplicationsView all 4 articles
CRISPR/Cas9-based discovery of ccRCC therapeutic opportunities through molecular mechanism and immune microenvironment analysis
Provisionally accepted
Bo Han
Weiyang LiuWanhui WangZhuolun LiBosen You
Dongze LiuYunfeng NanTiankai DingZhou DaiYantong Zhang
Wei Zhang*Qing Liu*
Xuedong Li*- Department of Urology, The Second Affiliated Hospital of Harbin Medical University, harbin, China
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Renal cell carcinoma, particularly clear cell renal cell carcinoma, is a ubiquitous and invasive urological cancer characterized by rising incidence and unfavorable outcome due to frequent metastatic recurrence. To address the lack of reliable prognostic biomarkers, our study integrated pan-genomic CRISPR screening data from DepMap and transcriptomic profiles from TCGA to identify key genes associated with ccRCC pathogenesis. Differential expression analysis, validated by CRISPR-Cas9 technology and Chronos scores, identified 11 critical genes, with LASSO and multivariate Cox regression narrowing the selection to five core genes (GGT6, HAO2, SLPI, MELK, and EIF4A1) for constructing a prognostic model. The algorithm effectively categorized patients into high-risk and low-risk cohorts, showing significant survival disparities. High-risk scores correlated with elevated tumor mutational burden, immunosuppressive tumor microenvironment enriched with tumor associated immune cells ( regulatory T cells, M0 macrophages), and activation of cytokine-receptor pathways, while low-risk group exhibited metabolic pathway enrichment. Knockdown of MELK significantly suppressed ccRCC cell proliferation and migration. The drug sensitivity analysis revealed an increased response of high-risk patients to pazopanib, sunitinib, and temsirolimus. This multi-omics-driven model elucidates MELK-mediated mechanisms and TME interactions, and offer novel strategies for risk stratification and targeted therapy. Future studies will confirm these findings in independent cohorts and investigate the regulatory networks of MELK to identify potential therapeutic targets.
Keywords: CRISPR-Cas9 screening, ccRCC, Prognostic model, MELK, Immunotherapy
Received: 28 Apr 2025; Accepted: 23 Jun 2025.
Copyright: © 2025 Han, Liu, Wang, Li, You, Liu, Nan, Ding, Dai, Zhang, Zhang, Liu and Li. 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:
Wei Zhang, Department of Urology, The Second Affiliated Hospital of Harbin Medical University, harbin, China
Qing Liu, Department of Urology, The Second Affiliated Hospital of Harbin Medical University, harbin, China
Xuedong Li, Department of Urology, The Second Affiliated Hospital of Harbin Medical University, harbin, China
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