Work

Vorinostat restores iNKT cell functionality in aggressive cholangiocarcinoma

Year: 2025

Type: article

Abstract: In this study, we explored the potential of histone deacetylase (HDAC) inhibitors, with a focus on Vorinostat, to restore the functionality of invariant natural killer T (iNKT) cells—a unique subset of T cells with potent anti-tumor activity that are often impaired within the tumor microenvironment. Using aggressive cholangiocarcinoma (CCA) cell lines lacking CD1d molecules, we observed a marked decline in iNKT cell reactivity within 48 h of exposure to CCA cells. Through a systematic approach that included the utilization of the L1000FWD search engine, Vorinostat emerged as a promising candidate for mitigating iNKT cell dysfunction. Vorinostat induced significant molecular alterations in iNKT-nonresponsive CCA cells, enhancing CD1d expression, the production of inflammatory cytokines and the activation of T cell receptor (TCR) signaling pathways. These changes effectively reactivated iNKT cells and restored their anti-tumor functionality. In the mouse xenograft model, combined treatment with Vorinostat significantly inhibited tumor growth. These findings suggest that Vorinostat may offer a novel therapeutic strategy for patients with cholangiocarcinoma who are resistant to conventional chemotherapy. • CD1d absence and cytokine impairment hinder iNKT activation in CCA. • Vorinostat restores iNKT function by reversing gene profiles and boosting CD1d expression. • Vorinostat enhances IL-2/STAT5, granzyme A, IFNG, and reduces inhibitory receptors on iNKT. • Combined iNKT and Vorinostat treatment significantly reduces CCA tumor growth in xenografts.

Source: Biomedicine & Pharmacotherapy

DOI: 10.1016/j.biopha.2025.117964