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.