Ferroptosis-inducing inorganic arsenic(II) sulfide nanocrystals enhance immune activation

Arsenic(II) sulfide is a stable inorganic arsenic compound with a different valence from arsenic trioxide, and has been widely applied to treat various diseases with low toxic side effects for a long time. However, its low solubility and complicated formulations restrict its further applications in modern medical industry. Meanwhile, as the tumour with the highest incidence rate among women, the low recurrence risk of breast cancer has been confirmed to be closely related to the high infiltration of immune cells. Herein, we synthesized and filtered novel biocompatible PEGylated arsenic(II) sulfide nanocrystals AsS@PEG with a size of 93.14 ± 0.49 nm by the gel method, which displayed excellent anticancer and immune activation activity in breast cancer model. Proteomic analysis suggested that the AsS@PEG induce ferroptosis in cancer cells and further activate antitumour immune responses via B-cell lymphoma 9-like (BCL9L) protein inhibition. Furthermore, mechanism studies revealed notable glutathione peroxidase 4 (GPX4) downregulation in cancer cells, dendritic cells (DCs) maturation and subsequent effector CD8⁺ T-cells production induced by the AsS@PEG in the tumour microenvironment. This study highlights biocompatible arsenic(II) sulfide nanocrystals that induce ferroptotic cell death and activate antitumour immune responses, providing insights into the path towards the immunotherapy assisted chemotherapy for breast cancer.