TLR3 activation enhances abscopal effect of radiotherapy in HCC by promoting tumor ferroptosis.

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. Synopsis: The abscopal effect, e.g., when local treatment affects both treated and untreated tumors, is rarely observed in HCC following radiotherapy. Subcutaneous administration of poly(I:C) during radiotherapy promoted the abscopal effects in irradiated HCC mice. Poly(I:C) enhanced radiotherapy efficacy in HCC by promoting tumor ferroptosis in both irradiated and non-irradiated tumors. Poly(I:C) improved tumor ferroptosis by promoting tumor antigen presentation by dendritic cells and activating TLR3 signaling in tissue-infiltrating CD8+ T cells. Poly(I:C) combined with radiotherapy was shown to be a safe and effective strategy for enhancing the abscopal effect in HCC patients. Administration of Toll-like receptor 3 (TLR3) agonist poly(I:C) strengthened the abscopal effect during radiotherapy (RT) through ferroptosis, and combination of poly(I:C) and RT improved the clinical benefits of advanced HCC patients. [ABSTRACT FROM AUTHOR]