Radiotherapy (RT) has been reported to induce abscopal effect in advanced hepatocellular carcinoma (HCC), but such phenomenon was only observed in sporadic cases. Here, we demonstrated that subcutaneous administration of Toll-like receptor 3 (TLR3) agonist poly(I:C) could strengthen the abscopal effect during RT through activating tumor cell ferroptosis signals in bilateral HCC subcutaneous tumor mouse models, which could be significantly abolished by TLR3 knock-out or ferroptosis inhibitor ferrostatin-1. Moreover, poly(I:C) could promote the presentation of tumor neoantigens by dendritic cells to enhance the recruitment of activated CD8+ T cells into distant tumor tissues for inducing tumor cell ferroptosis during RT treatment. Finally, the safety and feasibility of combining poly(I:C) with RT for treating advanced HCC patients were further verified in a prospective clinical trial. Thus, enhancing TLR3 signaling activation during RT could provide a novel strategy for strengthening abscopal effect to improve the clinical benefits of advanced HCC patients.

中文翻译：

---

TLR3 激活通过促进肿瘤铁死亡来增强 HCC 放疗的远距效应。


据报道，放射治疗（RT）可在晚期肝细胞癌（HCC）中引起远隔效应，但这种现象仅在散发病例中观察到。在这里，我们证明，在双侧 HCC 皮下肿瘤小鼠模型中，皮下注射 Toll 样受体 3 (TLR3) 激动剂聚 (I:C) 可以通过激活肿瘤细胞铁死亡信号来增强放疗期间的远隔效应，而该信号可以通过以下方法显着消除： TLR3 敲除或铁死亡抑制剂 Ferrostatin-1。此外，Poly(I:C) 可以促进树突状细胞呈递肿瘤新抗原，从而增强活化的 CD8+ T 细胞向远处肿瘤组织的募集，从而在 RT 治疗期间诱导肿瘤细胞铁死亡。最后，Poly(I:C)联合RT治疗晚期HCC患者的安全性和可行性在前瞻性临床试验中得到进一步验证。因此，在放疗期间增强 TLR3 信号传导激活可以提供一种增强远隔效应的新策略，以改善晚期 HCC 患者的临床获益。