Attenuated Salmonella Carrying IL-21 Expression Plasmid Enhances the Efficacy of Radiotherapy for Hepatocellular Carcinoma

Despite the increasing utilization of radiotherapy in the clinical management of hepatocellular carcinoma (HCC), therapeutic efficacy is frequently compromised by radioresistance, which leads to local recurrence and metastasis. Improving the radiosensitivity of HCC cells has therefore become a key focus of current research. Interleukin-21 (IL-21) is a pleiotropic immune regulator known to induce the proliferation of tumor antigen-specific T cells, enhance NK cell cytotoxicity, and modulate the immune microenvironment. However, its role in the context of radiotherapy for HCC remains unclear. In this study, we investigated the anti-tumor effect of IL-21 combined with radiotherapy in HCC-bearing mouse models . We found that treatment with an attenuated Salmonella strain engineered to deliver an IL-21 expression plasmid, in combination with radiotherapy, effectively restored IL-21 levels within tumor tissues of HCC-bearing mice. This combination therapy significantly inhibited tumor growth, promoted tumor cell apoptosis, elevated the ratios of T lymphocytes and NK cells in the spleen, and enhanced lymphocyte infiltration and activation within the tumor microenvironment. Collectively, our findings demonstrate that attenuated Salmonella carrying an IL-21 expression plasmid effectively potentiates the anti-tumor efficacy of radiotherapy by enhancing systemic anti-tumor immune responses, providing a novel combinatorial strategy for improving radiotherapeutic outcomes in HCC patients.