Etomidate Improves Antitumor Immunity by Suppressing PD-L1 Expression in Hepatocellular Carcinoma Cells

Etomidate, a prevalent intravenous anesthetic agent, has been implicated in the attenuation of tumorigenesis. Our recent investigations elucidated its capacity to impede the malignant progression of hepatocellular carcinoma (HCC). This study aims to elucidate how etomidate modulates the immunosuppressive tumor microenvironment in HCC.

To investigate the multifaceted effects and underlying molecular mechanisms of etomidate, we employed an integrative approach encompassing in vitro and in vivo systems, including patient-derived HCC organoids, 3-dimensional co-culture platforms, patient-derived xenografts, and orthotopic HCC models. A suite of advanced methodologies such as single-cell cytometry by time-of-flight (CyTOF), multiplex immunohistochemistry, and flow cytometric analyses were applied.

Our data reveal that etomidate suppresses programmed death-ligand 1 (PD-L1) expression in HCC cells, thereby potentiating antitumor immunity. Mechanistically, etomidate inhibits the Janus kinase 2/signal transducer and activator of transcription 3 axis in tumor cells, leading to reduced PD-L1 transcription and increased infiltration and activation of cytotoxic CD8⁺ T lymphocytes.

These findings support the hypothesis that etomidate enhances antitumor immunity and boosts the therapeutic efficacy of immune checkpoint blockade, thereby laying a theoretical foundation for precision immunotherapy in HCC.