肝细胞癌（HCC）是最常见且具侵袭性的肝癌类型，占肝癌诊断和死亡人数的大部分。尽管肝细胞癌治疗方面近年来有所进展，但仍然是最致命的癌症之一。放射治疗（RT）是治疗无法手术切除或医学上无法手术切除的肝细胞癌的局部区域治疗方法之一。然而，放射抵抗性是一个重大挑战。研究表明，RT会诱导肿瘤细胞上调程序性死亡配体1（PD-L1）的表达，这可能会影响对PD-1基础免疫治疗的反应，从而提出了将PD-1/PD-L1抑制剂与放射治疗联合使用的理由。在这里，我们利用减毒沙门氏菌作为载体，探讨减毒沙门氏菌携带siRNA-PD-L1是否能够有效增强放射治疗对携带HCC的小鼠的抗肿瘤效果。我们的结果显示，siRNA-PD-L1和放射治疗的联合应用通过抑制放射治疗诱导的PD-L1表达具有协同的抗肿瘤效果。机制方面的研究发现，联合治疗能够显著抑制肿瘤细胞增殖，促进细胞凋亡，以及在肿瘤组织中刺激免疫细胞的浸润和激活。此外，联合治疗还增加了脾脏中CD4+ T细胞、CD8+ T细胞和NK细胞的比例。本研究提出了一种新的肝细胞癌治疗策略，特别适用于放射治疗抵抗性的患者。© 2023. 细胞死亡与分化学会（ADMC）。

Hepatocellular carcinoma (HCC), the most prevalent type of aggressive liver cancer, accounts for the majority of liver cancer diagnoses and fatalities. Despite recent advancements in HCC treatment, it remains one of the deadliest cancers. Radiation therapy (RT) is among the locoregional therapy modalities employed to treat unresectable or medically inoperable HCC. However, radioresistance poses a significant challenge. It has been demonstrated that RT induced the upregulation of programmed death ligand 1 (PD-L1) on tumor cells, which may affect response to PD-1-based immunotherapy, providing a rationale for combining PD-1/PD-L1 inhibitors with radiation. Here, we utilized attenuated Salmonella as a carrier to explore whether attenuated Salmonella carrying siRNA-PD-L1 could effectively enhance the antitumor effect of radiotherapy on HCC-bearing mice. Our results showed that a combination of siRNA-PD-L1 and radiotherapy had a synergistic antitumor effect by inhibiting the expression of PD-L1 induced by radiation therapy. Mechanistic insights indicated that the combination treatment significantly suppressed tumor cell proliferation, promoted cell apoptosis, and stimulated immune cell infiltration and activation in tumor tissues. Additionally, the combination treatment increased the ratios of CD4+ T, CD8+ T, and NK cells from the spleen in tumor-bearing mice. This study presents a novel therapeutic strategy for HCC treatment, especially for patients with RT resistance.© 2023. Cell Death Differentiation Association (ADMC).