ORIGINAL RESEARCH article
Front. Immunol.
Sec. Cancer Immunity and Immunotherapy
Volume 16 - 2025 | doi: 10.3389/fimmu.2025.1604154
This article is part of the Research TopicTargeting tumor-initiating cells to enhance cancer immunotherapy in digestive system tumorsView all 6 articles
Integrative genomic and single-cell framework identifies druggable targets for colorectal cancer precision therapy
Provisionally accepted
- 1Shanghai Jiao Tong University, Shanghai, Shanghai Municipality, China
- 2Wenzhou Medical University, Wenzhou, Zhejiang Province, China
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Background: Colorectal cancer (CRC) remains a leading cause of cancer-related mortality worldwide. Despite therapeutic advances, there is a critical need to identify novel, effective, and safe drug targets to improve precision treatment strategies.Methods: We developed a multi-layered framework integrating Mendelian randomization (MR), colocalization analysis, genome-wide association study (GWAS) data, and expression quantitative trait loci (eQTLs) to prioritize causal and druggable genes in CRC. Single-cell and bulk RNA sequencing were used to characterize gene expression within the tumor microenvironment. Phenome-wide association studies (PheWAS) assessed off-target effects, and drug repurposing potential was evaluated using OpenTargets, DrugBank, and DGIdb. Validation of key targets was performed through RT-qPCR and immunohistochemistry (IHC) in CRC patient samples.Results: Out of 4,479 druggable genes, MR analysis identified 47 candidates significantly associated with CRC risk. Six genes (TFRC, TNFSF14, LAMC1, PLK1, TYMS, and TSSK6) demonstrated strong colocalization signals and were further validated across replication datasets and subtype-stratified analyses. PheWAS analysis revealed minimal off-target effects for these genes. Notably, several of these genes have already been targeted by existing or investigational drugs, suggesting potential for repurposing. These genes exhibited distinct expression patterns in tumor and stromal cell types and were differentially expressed in CRC versus normal tissues. Among them, TNFSF14, an immune modulator, is particularly involved in regulating T cell activation within the tumor microenvironment.Conclusion: This study identifies and validates six promising druggable targets for CRC, providing a strong foundation for future preclinical studies. These findings open avenues for advancing precision oncology and drug repurposing strategies in CRC treatment, contributing to the development of more effective and personalized therapeutic approaches.
Keywords: colorectal cancer, Genetics, Druggable targets, Single-cell transcriptomics, precision oncology
Received: 01 Apr 2025; Accepted: 28 Apr 2025.
Copyright: © 2025 Hong, Li, Xu, Shu, Chen, Mi, Geng 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:
Yanggang Hong, Shanghai Jiao Tong University, Shanghai, 200240, Shanghai Municipality, China
Haigang Geng, Shanghai Jiao Tong University, Shanghai, 200240, Shanghai Municipality, China
Qian Li, Shanghai Jiao Tong University, Shanghai, 200240, Shanghai Municipality, China
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