Abstract
The combination of ferroptosis inducers and immune checkpoint blockade can enhance antitumor effects. However, the efficacy in tumors with low immunogenicity requires further investigation. In this work, a water-in-oil Pickering emulsion gel is developed to deliver (1S, 3R)-RSL-3 (RSL-3), a ferroptosis inducer dissolved in iodized oil, and programmed death-1 (PD-1) antibody, the most commonly used immune checkpoint inhibitor dissolved in water, with optimal characteristics (RSL-3 + PD-1@gel). Tumor lipase degrades the continuous oil phase, which results in the slow release of RSL-3 and PD-1 antibody and a notable antitumor effect against low-immunogenic hepatocellular carcinoma and pancreatic cancer. Intriguingly, the RSL-3 + PD-1@gel induces ferroptosis of tumor cells, resulting in antitumor immune response via accumulation of helper T lymphocyte cells and cytotoxic T cells. Additionally, the single-cell sequence profiling analysis during tumor treatment reveals the induction of ferroptosis in tumor cells together with strong antitumor immune response in ascites.