Supramolecular co-assembly of platycodin-d-loaded iron nanocomposite enhances hepatocellular carcinoma immunotherapy with synergistic ferroptosis-photo-chemotherapy.

Immune checkpoint blockades (ICBs) have potential application in cancer therapy. The lack of adaptive resistance and immunogenicity in cells substantially restricts their preclinical efficiency. Immunogenic cell death (ICD), a form of regulated cell death, plays a crucial role in activating the adaptive immune response. A co-assembled metal coordination nanocomposite (PIF NCs) that improves cancer immunotherapy by promoting ICD via ferroptosis-photochemotherapy induction is developed. The PIF NCs demonstrated exceptional stability and biocompatibility and exhibited effective photodynamic therapy and photothermal therapy effects. PIF NCs disrupt the redox equilibrium and trigger ferroptosis by depleting glutathione (GSH), downregulating glutathione peroxidase 4 (GPX4) and solute carrier family 7 member 11 (SLC7A11), and increasing the production of lipid peroxides (LPO). PIF NCs initiate the ICD cascade, thereby augmenting tumor immunogenicity. In a Hep3B tumor model, combined treatment with PIF NCs and anti-PD-L1 exhibited substantial inhibitory efficacy and induced a prolonged immunological memory response. This synergistic treatment of multimodal therapy can potentially be used in the treatment of hepatocellular carcinoma.