Elevated TARDBP expression correlates with an unfavorable prognosis, immune evasion, and poor immune efficacy in hepatocellular carcinoma

Background: Transactivation response element DNA-binding protein (TARDBP), encoding TDP-43, contributes to multiple oncogenic processes, yet its prognostic and immunological significance in hepatocellular carcinoma (HCC) remains unclear. This study aimed to comprehensively characterize TARDBP expression, its clinical correlations, and its role in the tumor immune microenvironment (TIME).

Methods: TARDBP expression was analyzed using The Cancer Genome Atlas (TCGA) data and validated by quantitative real-time polymerase chain reaction (qRT-PCR) and immunohistochemistry (IHC) in clinical specimens. Functional enrichment analyses were performed to identify associated signaling pathways. Correlations with immune modulators, tumor mutational burden (TMB), microsatellite instability (MSI), immunophenoscores, and drug sensitivity were systematically evaluated. Single-cell RNA sequencing was employed to map TARDBP expression across distinct cell subsets. Multiplex immunofluorescence was utilized to investigate the spatial relationship between TARDBP and immune cell infiltration.

Results: TARDBP was significantly upregulated in HCC tissues and correlated with advanced tumor stage and poor prognosis. Single-cell analysis revealed that TARDBP expression was minimal in immune cells but highly enriched in invasive and proliferative tumor phenotypes. Experimentally, TARDBP knockdown attenuated oxaliplatin-induced nuclear factor-κB (NF-κB) activation and reduced programmed cell death ligand 1 (PD-L1) levels, suggesting a tumor-intrinsic mechanism of immune evasion. Clinically, elevated TARDBP expression correlated with lower immunophenoscores, higher TMB, poor overall survival, and reduced response to immune checkpoint blockade.

Conclusions: High TARDBP expression in HCC confers a poor prognosis and is associated with an immunosuppressive microenvironment characterized by impaired immune cell infiltration. These findings suggest that TARDBP serves as a viable prognostic biomarker and a potential therapeutic target for enhancing immunotherapy efficacy in HCC.