Valence‐State Transitive Selenium Nano‐Reservoir for Immuno‐Activated Cancer Phototherapy

Abstract Tumor immunotherapy activated by external stimuli holds great promise but is hindered by limited natural killer (NK) cell activation and biocompatibility issues of therapeutic agents. Herein, a selenium‐rich bismuth‐based heterojunction (Bi ₂ O _3−x Se _x ‐Se‐PEG, BOSS) as a valence‐state transitive selenium nano‐reservoir for immuno‐activated cancer phototherapy is engineered. Synthesized via a topochemical‐like strategy with polyethylene glycol (PEG) modification, BOSS exhibits aqueous dispersibility and biocompatibility. Under 730 nm near‐infrared (NIR) light irradiation, BOSS efficiently converts light energy into heat and generates reactive oxygen species (ROS). More importantly, NIR light and tumor microenvironment (TME)‐overexpressed H ₂ O ₂ trigger the valence transition of selenium in BOSS from low‐valent (−2, 0) to high‐valent (+4), which downregulates HLA‐E expression on tumor cells, relieves NK cell inhibition and enhances their cytotoxicity. Concurrently, BOSS‐mediated glutathione depletion synergizes with ROS and heat to induce immunogenic cell death, releasing damage‐associated molecular patterns that promote dendritic cell (DC) maturation and activate thymus‐dependent lymphocyte (T cells), macrophages, and NK cells. In vitro and in vivo studies demonstrate that BOSS inhibits primary and distal tumor growth by activating systemic immune responses, while reducing toxic side effects associated with pre‐existing high‐valent selenium. This light‐controlled, valence‐variable nano‐system provides a versatile strategy for multi‐immune cell‐mediated tumor therapy.