Cancer-associated fibroblasts regulating nanomedicine to overcome sorafenib resistance in hepatocellular carcinoma with portal vein tumor thrombus.

Portal vein tumor thrombus (PVTT) is a common and severe indicator in advanced hepatocellular carcinoma (HCC), characterized by a poor prognosis and limited response to existing therapies. Cancer-associated fibroblasts (CAFs) play an important role in promoting HCC metastasis and contribute to resistance against sorafenib (SOR) resistance, which is a standard treatment for advanced HCC. The data from single-cell RNA sequencing highlights the critical role of C-X-C motif chemokine ligand 12 (CXCL12) in the activation of CAFs. To address these challenges, we develop a PVTT-targeted nanocarrier designed to co-deliver small interfering RNA (siRNA) and a multikinase inhibitor, aiming to enhance therapeutic outcomes for PVTT. This novel lipid-coated polylactide-co-glycolide nanoparticle system effectively downregulate CXCL12 expression in CAFs, leading to their inactivation and subsequent reshaping of the tumor microenvironment. The resulting modulation of the tumor microenvironment significantly suppress tumor cell migration, invasion, and resistance to SOR, thereby demonstrating potent anti-tumor effects in orthotopic mouse models of PVTT. Furthermore, RNA sequencing reveals key regulatory pathways and genes associated with the inhibition of SOR resistance and PVTT formation mediated by these nanoparticles. These findings suggest that modulating the tumor microenvironment, combined with targeted anti-tumor therapies, offers a promising strategy for treating HCC patients with PVTT.