Prognostic Significance of DNA Polymerase Theta and Its Association with Immune Infiltration in Hepatocellular Carcinoma

Background Hepatocellular carcinoma (HCC) is a common malignancy with a poor prognosis. DNA polymerase theta (POLQ) plays multiple roles in HCC, primarily in DNA damage repair, tumor progression, and resistance to chemoradiotherapy. However, the upstream and downstream signaling pathways regulated by POLQ, along with its association with immune cell infiltration, remain unclear. Methods We conducted comprehensive bioinformatics analyses to evaluate POLQ expression in HCC versus normal tissues using data from TCGA and Genotype-Tissue Expression databases. Functional enrichment analyses, including Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), gene set enrichment analysis (GSEA), and single-sample GSEA (ssGSEA), explored POLQ’s biological functions and immune-related pathways. Its prognostic significance was assessed via Kaplan–Meier (KM) survival analysis and univariate and multivariate Cox regression models. Immunohistochemistry (IHC) validated POLQ protein expression in HCC and adjacent normal tissues. Results POLQ expression was significantly upregulated in HCC tissues compared to normal controls. GO, KEGG, and GSEA analyses revealed POLQ's involvement in key processes such as nuclear division, antigen binding, immunoglobulin receptor binding, and cell cycle regulation. ssGSEA showed positive correlations between POLQ expression and infiltration of T helper (Th)2 and Th cells, but negative associations with activated Th17, dendritic, cytotoxic, and CD8 + T cells. KM curve analyses indicated that high POLQ expression predicted shorter overall survival, disease-specific survival, and progression-free interval in patients with HCC. Univariate and multivariate Cox regression confirmed POLQ as an independent prognostic risk factor. IHC results showed significantly higher POLQ protein levels in HCC tissues than in adjacent normal liver tissue. Conclusions These findings demonstrate that POLQ modulates immune infiltration in HCC and may serve as a novel prognostic biomarker.