Abstract

Immunotherapy has shown limited efficacy in hepatocellular carcinoma (HCC) due to the immunosuppressive tumor microenvironment (TME). Previous studies show that asiatic acid (AA), a naturally occurring pentacyclic triterpenoid, exhibits potent inhibitory effects on tumor cell proliferation. In this study we investigated the effects of AA on the TME and immunotherapy in HCC. Both subcutaneous and orthotopic HCC models were established in male mice. The mice were treated with AA (50 mg·kg⁻¹·d⁻¹, i.g) for two weeks. At the experimental endpoint, mice were euthanized, and tumor-infiltrating immune cell populations were analyzed using flow cytometry. We showed that AA treatment effectively converted “cold tumors” into “hot tumors” by promoting CD8 + T cell infiltration and activation in HCC. We demonstrated that AA non-covalently bound and inhibited histone deacetylase 8 (HDAC8), increasing H3K27 acetylation at the CXCL10 promoter to enhance its expression. This epigenetic reprogramming elevated CXCL10 expression and drove robust CD8 + T cell recruitment. HDAC8 overexpression abolished these effects, confirming the target specificity. Importantly, we demonstrated that AA synergized with anti-PD-L1 therapy while maintaining a favorable safety profile. This study identifies AA as a novel HDAC8 inhibitor that remodels the TME, offering a promising strategy to overcome immunotherapy resistance in HCC.