Ferroptosis enhances the therapeutic potential of oncolytic adenoviruses KD01 against cancer.

Oncolytic virotherapy has emerged as a promising strategy for cancer treatment by selectively targeting and lysing tumor cells. However, its efficacy is often limited in certain tumor types due to multiple factors. This study explores the combination of oncolytic adenoviruses with Erastin, a potent ferroptosis inducer, to enhance antitumor efficacy in oncolytic virus-insensitive cancer cell lines. In vitro experiments demonstrated that Erastin significantly increased the cytotoxicity of oncolytic virotherapy, leading to greater inhibition of cell proliferation and elevated rates of cell death compared to monotherapies. The combination treatment further promoted ferroptosis, as evidenced by increased reactive oxygen species (ROS) levels, enhanced lipid peroxidation, and disrupted redox homeostasis. RNA sequencing identified the downregulation of Dickkopf-1 (DKK1) as a key mediator of the enhanced ferroptotic effect. Restoring the expression of DKK1 partially mitigated the cytotoxic effects of the combination therapy, highlighting its crucial role in mediating the enhanced ferroptosis-induced oncolytic virotherapy efficacy. In vivo studies further validated these findings, demonstrating that the combined treatment significantly reduced tumor growth without inducing notable toxicity. This novel therapeutic approach has great potential to enhance the efficacy of oncolytic virotherapy in cancers resistant to oncolytic viruses by inducing ferroptosis. Further investigation in clinically relevant models is warranted to fully elucidate the underlying mechanisms and to optimize this combination strategy for potential clinical applications.