Antiangiogenic DPPA-nanoparticles combined with an immune checkpoint inhibitor for the treatment of unresectable hepatocellular carcinoma.

Hepatocellular carcinoma (HCC), the third leading cause of cancer-related deaths worldwide, is often diagnosed at an advanced, unresectable stage (uHCC), for which effective treatments remain limited. Current therapies, including tyrosine kinase inhibitors such as sorafenib and lenvatinib, modestly extend survival, and treatments that combine the use of antiangiogenic agents and immune checkpoint inhibitors (ICIs) have yet to prolong median overall survival beyond two years. Previously, we introduce lipid nanoparticles composed of dipalmitoyl phosphatidic acid (LNDPPA) as a novel therapeutic platform with inherent antiangiogenic and antitumor activities. Building on our prior work demonstrating LNDPPA's ability to encapsulate and deliver small molecules and small interfering RNA with high efficiency, we systematically evaluated its therapeutic potential-alone and in combination with an anti-PD-1 antibody-against HCC in this study. LNDPPA significantly inhibited tumor cell proliferation, migration, and invasion, as well as human umbilical vein endothelial cells proliferation, migration, invasion, and tube formation. In both subcutaneous and orthotopic allograft models, the combination of LNDPPA and an anti-PD-1 antibody enhanced CD8+ T cells recruitment and function and exhibited superior tumor growth inhibition compared to the conventional sorafenib plus an anti-PD-1 antibody. These findings suggest that LNDPPA, particularly in combination with an ICI, holds promise as a potent therapeutic strategy for uHCC, and also provide insight into the development of multi-targeted combination therapies for other tumor types.