Synergistic ferroptosis-photo-chemo to disrupt redox homeostasis for augmenting cancer chemoimmunotherapy

Immune checkpoint blockade (ICB) holds broad application prospects in tumor treatment. However, the poor immunogenicity and the adaptive resistance cells severely limit the clinical efficacy. Immunogenic cell death (ICD) can sensitize the cells which were initially lower responsive to ICB. Based on this, we reported a metal coordination co-assembly nanocomposite (SIF NPs), which can enhance cancer immunotherapy by strengthening ICD induction through inducing ferroptosis-photo-chemo. The SIF NPs possess excellent biocompatibility and stability, and exhibit good PTT and PDT effects both in vitro and in vivo. The SIF NPs disrupt redox homeostasis and induce ferroptosis by consuming glutathione (GSH), downregulating the expression of solute carrier family 7 member 11 (SLC7A11) and glutathione peroxidase 4 (GPX4), and enhancing the generation of lipid hydroperoxides (LPO). Importantly, SIF NPs trigger an ICD cascade via inducing the cell death, thus enhancing the immunogenicity of tumors. In a tumor-bearing mice model, the synergistic‌ therapy of SIF NPs and anti-PD-L1 antibody demonstrated a powerful inhibition effectiveness on bilateral tumors and instigated a long-time immune memory effect. This study indicates that the combined treatment of ferroptosis-photo-chemo and immunotherapy possess promising application prospects.