Simultaneous inhibition of heat shock proteins and autophagy enhances radiofrequency ablation of hepatocellular carcinoma†

Radiofrequency ablation (RFA) is a commonly used minimally invasive treatment for hepatocellular carcinoma (HCC). However, incomplete radiofrequency ablation (iRFA) promotes tumor progression and metastasis. There is an urgent need to develop innovative strategies to enhance the efficacy of iRFA. The upregulation of heat shock proteins (HSPs) and activation of protective autophagy in tumor cells upon exposure to sublethal heat enhance the thermotolerance, thereby promoting tumor cell survival. Here, 3-methyladenine (3-MA) and lonidamine (LND) co-encapsulated liposomes (Lip@LND/3-MA) are designed to enhance the efficacy of iRFA by simultaneous inhibition of glycolysis and autophagy. On one hand, LND inhibits hexokinase, a key enzyme in glycolysis, and thus reduces ATP production and consequently suppresses the expression of HSPs. On the other hand, 3-MA, as an autophagy inhibitor, can inhibit protective autophagy after iRFA. Lip@LND/3-MA is confirmed to suppress the expression of HSPs and reduce the autophagy level during RFA. Therefore, the thermotolerance of tumor cells is significantly weakened, leading to remarkably enhanced therapeutic efficacy of iRFA. It is believed that simultaneous inhibition of HSPs and autophagy is a promising therapeutic strategy in clinical practice of RFA.