Sorafenib Induces Pyroptosis in Macrophages and Triggers Natural Killer Cell–Mediated Cytotoxicity Against Hepatocellular Carcinoma

<jats:p>Antiangiogenic and cytotoxic effects are considered the principal mechanisms of action of sorafenib, a multitarget kinase inhibitor approved for the treatment of hepatocellular carcinoma (HCC). We report that sorafenib also acts through direct immune modulation, indispensable for its antitumor activity. <jats:italic toggle="yes">In vivo</jats:italic> cell depletion experiments in two orthotopic HCC mouse models as well as <jats:italic toggle="yes">in vitro</jats:italic> analysis identified macrophages (MΦ) as the key mediators of the antitumoral effect and demonstrate a strong interdependency of MΦ and natural killer (NK) cells for efficient tumor cell killing. Caspase 1 analysis in sorafenib‐treated MΦ revealed an induction of pyroptosis. As a result, cytotoxic NK cells become activated when cocultured with sorafenib‐treated MΦ, leading to tumor cell death. In addition, sorafenib was found to down‐regulate major histocompatibility complex class I expression of tumor cells, which may reduce the tumor responsiveness to immune checkpoint therapies and favor NK‐cell response. <jats:italic toggle="yes">In vivo</jats:italic> cytokine blocking revealed that sorafenib efficacy is abrogated after inhibition of interleukins 1B and 18. <jats:italic toggle="yes">Conclusion</jats:italic>: We report an immunomodulatory mechanism of sorafenib involving MΦ pyroptosis and unleashing of an NK‐cell response that sets it apart from other spectrum kinase inhibitors as a promising immunotherapy combination partner for the treatment of HCC.</jats:p>