Sodium butyrate enhances sorafenib-induced ferroptosis and immunogenic cell death by modulating IRF2-Oasl2-cGAS pathway in colorectal cancer.

While much attention has been focused on the direct cytotoxic effects of anticancer agents on tumor cells, emerging evidence suggests that the induction of immunogenic cell death (ICD) and the consequent remodeling of the tumor microenvironment may critically influence overall therapeutic efficacy. Sorafenib, a multitargeted tyrosine kinase inhibitor, can induce ferroptosis and thereby trigger ICD, offering the potential to overcome chemoresistance and coordinate systemic antitumor immunity. However, its therapeutic efficacy in colorectal cancer (CRC) remains limited, attributing to its low efficiency in inducing ICD. Herein, this study investigates combined sodium butyrate (NaB) and sorafenib in liposomal co-delivery system (LipNaB@Sor) at an optimal 1:1 M ratio in CRC. LipNaB@Sor synergistically amplifies sorafenib-induced ferroptosis and consequent ICD, concurrently activating antitumor immunity through dendritic cell maturation and cytotoxic CD8(+) T cell recruitment. Mechanistically, IRF2-mediated Oasl2 downregulation activates the cGAS-STING pathway, augmenting DNA damage signaling cascades. In vivo validation demonstrates significant tumor suppression and prolonged survival without observable toxicity, establishing LipNaB@Sor as a translatable strategy to overcome therapy resistance in immunologically unresponsive CRC.