Open Access

ARTICLE

DNA Polymerase θ Drives Colorectal Cancer Progression through Wnt/β-Catenin Activation and Shows Potential Association with Immunosuppressive Microenvironment Remodeling

Li Li^1,#, Jianhua Wang^1,#, Feilong Zhou², Lingjun Geng^1,*, Kongwang Hu^1,*

1 Department of General Surgery, The Fifth Affiliated Hospital of Anhui Medical University, Fuyang, China
2 Department of General Surgery, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, China

* Corresponding Authors: Lingjun Geng. Email: ; Kongwang Hu. Email:
# These authors contributed equally to this work as the first author

(This article belongs to the Special Issue: Metabolic Heterogeneity in Cancer: Mechanisms, Biomarkers, and Therapeutic Implications)

Oncology Research 2026, 34(10), 20 https://doi.org/10.32604/or.2026.080204

Received 04 February 2026; Accepted 04 August 2026; Issue published 14 September 2026

Abstract

Background: Colorectal cancer (CRC) is a leading cause of cancer-related mortality worldwide, with limited treatment options for advanced-stage patients. DNA polymerase theta (POLQ) is overexpressed in various cancers, but its role and underlying mechanisms in CRC remain not fully elucidated. This study aimed to investigate the expression, prognostic value, biological functions, and molecular mechanisms of POLQ in CRC. Methods: POLQ expression was analyzed using public databases and 55 paired clinical samples. Lentivirus-mediated knockdown and overexpression were employed to assess CRC cell proliferation, migration, and invasion. Single-cell transcriptomics and CellChat analysis were used to explore the tumor microenvironment (TME). Western blotting, immunofluorescence, and dual-luciferase reporter assays were performed to verify the Wnt/β-catenin pathway and epithelial-mesenchymal transition (EMT). Results: POLQ was significantly overexpressed in CRC tissues and cell lines, and high POLQ expression was associated with neural invasion, vascular tumor thrombus, lymph node metastasis, advanced TNM stage, and poor prognosis. Single-cell analysis revealed that POLQ was specifically enriched in malignant epithelial cells, which acted as communication hubs with prominent Wnt signaling. Functional experiments demonstrated that POLQ activated the Wnt/β-catenin pathway, induced EMT, promoted β-catenin nuclear translocation and TCF/LEF transcriptional activity, and enhanced CRC cell proliferation, migration, and invasion. The Wnt inhibitor XAV939 reversed the POLQ overexpression-induced malignant phenotype, while the Wnt activator SKL2001 partially rescued the knockdown phenotype. Additionally, single-cell transcriptomics and CellChat analysis generated a computational prediction that POLQ-high cells may be involved in remodeling of the immunosuppressive microenvironment; however, this inference requires direct experimental validation through immune cell profiling in future studies. Conclusions: POLQ promotes CRC progression by activating the Wnt/β-catenin-EMT axis. Bioinformatic inference suggests a potential association with an immunosuppressive microenvironment, but this finding remains correlative and requires experimental confirmation. These findings suggest that POLQ is a potential prognostic biomarker and therapeutic target, though further validation in prospective, multicenter cohorts is warranted.

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