Spatiotemporally-controlled supramolecular hybrid nanoassembly enabling ferroptosis-augmented photodynamic immunotherapy of cancer

Photodynamic therapy (PDT) not only directly eradicates tumor cells but also boosts immunogenicity, promoting antigen presentation and immune cell infiltration. However, the robust antioxidant defense mechanisms within tumor cells significantly weaken the efficacy of photodynamic immunotherapy. Herein, a supramolecular hybrid nanoassembly is constructed by exploring the synergistic effects of the photodynamic photosensitizer (pyropheophorbide a, PPa) and the ferroptosis inducer (erastin). The erastin-mediated inhibition of system Xc− significantly downregulates glutathione (GSH) expression, amplifying intracellular oxidative stress, leading to pronounced cell apoptosis, and promoting the release of damage-associated molecular patterns (DAMPs). Additionally, the precise cooperation of PPa and erastin enhances ferroptosis efficiency, exacerbating the accumulation of lipid peroxides (LPOs). Ultimately, LPOs serve as a “find me” signal, while DMAPs act as an “eat me” signal, collectively promoting dendritic cell maturation, enhancing infiltration of the cytotoxic T lymphocytes, and eliciting a robust immune response. This study opens new horizons for enhancing tumor immunotherapy through simultaneous ferroptosis-PDT.