Attenuated Salmonella carrying IL-21 expression plasmid enhances the efficacy of radiotherapy for hepatocellular carcinoma.

Despite the increasing utilisation 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 tumour 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-tumour 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 tumour tissues of HCC-bearing mice. This combination therapy significantly inhibited tumour growth, promoted tumour cell apoptosis, elevated the ratios of T lymphocytes and NK cells in the spleen, and enhanced lymphocyte infiltration and activation within the tumour microenvironment. Collectively, our findings demonstrate that attenuated Salmonella carrying an IL-21 expression plasmid effectively potentiates the anti-tumour efficacy of radiotherapy by enhancing systemic anti-tumour immune responses, providing a novel combinatorial strategy for improving radiotherapeutic outcomes in HCC patients.