Hyaluronidase optimizes TACE in hepatocellular carcinoma by remodeling tumor stroma and enhancing chemotherapy penetration.

Transarterial chemoembolization (TACE) remains the standard locoregional therapy for unresectable hepatocellular carcinoma (HCC). However, suboptimal intratumoral drug penetration due to elevated interstitial fluid pressure (IFP) limits its chemotherapeutic efficacy. This study investigated whether hyaluronidase (HYAL), a hyaluronan (HA)-degrading enzyme, could enhance drug delivery during TACE. Using HCC multicellular tumor spheroids (MCTS) and rabbit VX2 liver tumor models, we demonstrated that HYAL significantly degraded HA and increased doxorubicin penetration distance (34.1 vs. 10.5 μm, P < 0.001) in MCTS. In vivo, transarterial HYAL administration optimized HA degradation (with 2.4 % of the area showing strong HA-positive staining) and IFP reduction (a 47.2 % reduction). In addition, transarterial HYAL administration synergized with TACE, increasing intratumoral doxorubicin penetration (41.1 ± 9.8 vs. 29.1 ± 4.1 μm, P < 0.05), elevating intratumoral drug concentration (9326.4 vs. 3802.8 ng/g, P < 0.01) and improving tumor necrosis (90.6 % vs. 77.5 %, P < 0.001) and survival (60.5 vs. 42.5 days, P < 0.001) compared to TACE alone. Safety assessments revealed no increased risk of metastasis or hepatotoxicity. These findings position HYAL as a safe, stroma-targeting adjunct to TACE, with promising implications for improving HCC outcomes.