Exosomes are carriers of intercellular information and regulate the tumor microenvironment. They play an important role in drug resistance by transporting RNA molecules and proteins. However, their effects on sorafenib resistance in hepatocellular carcinoma (HCC) are not completely understood. Exosomes were isolated from two invasive hepatoma cell lines (MHCC-97 L and MHCC-97H), and their roles in regulating sorafenib resistance in liver cancer cells as well as the underlying molecular mechanisms were determined. The exosomes were analyzed by TEM (transmission electron microscopy), DLS (dynamic light scattering) and Western blotting. Cell viability, cell death and the effects of exosomes on the HGF/c-Met/Akt signaling pathway in cancer cells were analyzed by MTT assays, FACS analysis and Western blotting, respectively. Moreover, the effects of exosomes on sorafenib resistance in vivo were investigated using a subcutaneous transplantation tumor model in athymic nude mice. Exosomes derived from HCC cells were of the expected size and expressed the exosomal markers CD9 and CD63. They induced sorafenib resistance in vitro by activating the HGF/c-Met/Akt signaling pathway and inhibiting sorafenib-induced apoptosis. They also induced sorafenib resistance in vivo by inhibiting sorafenib-induced apoptosis. Moreover, exosomes derived from highly invasive tumor cells had greater efficacy than that of exosomes derived from less invasive cells. These data reveal the important role of HCC cell-derived exosomes in the drug resistance of liver cancer cells and demonstrate the intrinsic interaction between exosomes and their targeted tumor cells. This study suggests a new strategy for improving the effectiveness of sorafenib in treating HCC.

Purpose: The prognosis of hepatocellular carcinoma (HCC) with extrahepatic metastases (EM) is poor. The efficacy and safety of transcatheter arterial chemoembolization combined with lenvatinib plus anti-programmed cell death 1 inhibitors (triple therapy) for HCC with EM remains unclear. In this study, we aimed to determine the efficacy and safety of triple therapy in HCC patients with EM. Patients and Methods: This study retrospectively reviewed HCC patients with EM who received triple therapy and analyzed their survival rate using the Kaplan–Meier method. Univariate prognostic analysis of each data point was performed using the Log rank test, and multivariate prognostic analysis was performed using the Cox proportional risk regression model. Results: Among 60 HCC patients with EM who underwent triple therapy, the most common sites of metastasis were as follows (in descending order): the lungs (n=27), lymph nodes (n=22), and bones (n=10). After triple therapy, the median progression-free survival and median overall survival were 6 and 18.63 months, respectively. The 6-month, 1-year, and 2-year cumulative survival rates were 87.7%, 68.6%, and 26.8%, respectively. In the multivariate analysis, neutrophil-to-lymphocyte ratio (NLR) ≥ 4 and alpha-fetoprotein (AFP) level ≥ 400 ng/mL were independently associated with overall survival. Conclusion: Our findings revealed that triple therapy is an effective, well-tolerated regimen for HCC patients with EM. AFP level and NLR are prognostic risk factors for triple therapy in this patient population.

Background: Triple therapy of transcatheter arterial chemoembolization (TACE) combined with lenvatinib and anti-PD-1 antibodies has demonstrated excellent efficacy in unresectable hepatocellular carcinoma (uHCC). However, tumor drug resistance is still a major problem and the rate of complete response in uHCC following triple therapy is relatively low. This study aimed to investigate the efficacy and safety of sequential radiotherapy after triple therapy in patients with uHCC to improve tumor response rate. Methods: This retrospective study included 29 patients with uHCC who received sequential radiotherapy after achieving partial response (PR) or stable disease (SD) in tumor response per the modified Response Evaluation Criteria in Solid Tumors (mRECIST) after triple therapy. The overall survival (OS), progression-free survival (PFS), and objective response rate (ORR) were analyzed to evaluate the efficacy of this regimen. Treatment-related adverse events were assessed to determine the safety profile. Results: Among the 29 patients, the median OS had not yet reached, and the median PFS was 19.43 months. The 24-month OS and PFS rates were 72.8% and 46.5%, respectively. The lesions of 6 patients initially with tumor response of PR achieved complete response, and the lesions fo 12 patients with SD achieved PR after sequential radiotherapy. All adverse events were manageable, and no treatment-related death occurred. Conclusion: Sequential radiotherapy after triple therapy enhanced tumor response and survival benefits for uHCC patients, with manageable adverse effects.

Hepatocellular carcinoma (HCC) is a heterogeneous, lethal cancer with a poor prognosis. Transarterial chemoembolization (TACE) combined with lenvatinib and