Size-tunable Nanoregulator-Based Radiofrequency Ablation Suppresses MDSCs And Their Compensatory Immune Evasion in Hepatocellular Carcinoma.

Radiofrequency ablation (RFA) is a widely used therapy for hepatocellular carcinoma (HCC). However, in cases of insufficient RFA (iRFA), non-lethal temperatures in the transition zone increased the risk of postoperative relapse. The pathological analysis of HCC tissues showed that iRFA-induced upregulation of myeloid-derived suppressor cells (MDSCs) in residual tumors is critical for postoperative recurrence. Furthermore, this study demonstrated, for the first time, that combining MDSCs suppression strategy during iRFA can unexpectedly lead to a compensatory increase in PD-L1 expression on the residual MDSCs, attributing to relapse due to immune evasion. To address this issue, a novel size-tunable hybrid nano-micro-liposome was designed to co-deliver MDSCs inhibitor (IPI549) and αPD-L1 antibody (LPIP) for multi-pathway activation of immune responses. The LPIP was triggered to release immune-regulators by the mild heat in the transition zone of iRFA, selectively inhibiting MDSCs and blocking the compensatory upregulation of PD-L1 on surviving MDSCs. The combined strategy of LPIP+iRFA effectively ablated the primary tumor by activating immune responses in the transition zone while suppressing the compensatory immune evasion of surviving MDSCs. This approach avoided the relapse of the residual tumor in a post-iRFA incomplete-ablation model and appears to be a promising strategy in RFA for eradication of HCC. This article is protected by copyright. All rights reserved.