Abstract

Transarterial chemoembolization (TACE) is a first-line clinical therapy on hepatocellular carcinoma (HCC). However, the presence of TACE resistance leads to less than satisfactory treatment outcomes and prognosis. By genomic analysis on the 147 HCC patients in the Gene Expression Omnibus (GEO) database, in the present work, the key role of glycolysis on hypoxia and immunosuppressive tumor microenvironment (TME) was well verified, contributing to the development of TACE resistance. Aiming to the issue, radiofrequency (RF)-responsive liposome hydrogels (3BP-TSLIP) was successfully prepared by thin-film hydration of temperature sensitive polymers (DSPE- p NIPAM), cationic lipid, the glycolytic inhibitor 3-bromopyruvate (3BP) and other phospholipids. 3BP-TSLIP showed temperature sensitive sol-gel phase transition at nearby body temperature, allowing to a sufficient embolization by intubating super-selectively into tumor-feeding arteries. By synergizing with RF irradiation, 3BP-TSLIP inhibited tumor glycolysis, reduced lactic acid (LA) efflux, and alleviated hypoxia. It was attributed to the protection of TSLIP to 3BP from hydrolysis and its unique RF-heating effect, facilitating to glycolysis suppression of 3BP by RF-thermo-sensitization. In the VX2 tumor-bearing rabbit model, 3BP-TSLIP showed favorable embolization to tumor-feeding arteries, and the enhanced antitumor efficacy by co-treating with RF irradiation. 3BP-TSLIP can serve as RF responsive embolic agent for opening a new avenue to overcome TACE resistance.