Chitosan-coated copper sulfide liposomes enhance chemo/immuno/chemodynamic therapy via enhanced ferroptosis-mediated...

Gliomas pose a considerable challenge to complete eradication through standard surgical resection because of their highly infiltrative growth. Currently, immunotherapy has achieved significant advances in the treatment of numerous cancers; however, gliomas do not respond effectively to immunotherapy because of their unique immunosuppressive tumor microenvironment. This study demonstrated a substantial enhancement in the efficacy of immunotherapy for glioma using liposomes (LCSG). The LCSG were characterized using various analytical and spectroscopic methods. Ferroptosis was examined by absorbance and fluorescence microscopy. The LCSG exhibited a size of approximately 200 nm, and the encapsulation efficiency and drug loading of chitosan were 58% and 8.3%, respectively. Following cellular endocytosis, glucose oxidase oxidizes glucose to generate gluconic acid, producing H₂O₂ as a byproduct and facilitating starvation therapy. These features may exacerbate the dysfunction of antioxidant systems and enhance Cu²⁺-mediated Fenton-like reactions, leading to lipid peroxidation and the onset of ferroptosis. Furthermore, the initiation of ferroptosis elicits immunogenic cell death and provokes the release of damage-associated molecular patterns, thereby facilitating cytotoxic T-cell infiltration (15.7%) and dendritic cell maturation (27.5%). In addition, all experiments confirmed that LCSG caused substantial glioma inhibition without any deleterious effects. Collectively, our findings indicate that manipulating the immunosuppressive tumor microenvironment via chemodynamic therapy may be a pivotal approach for enhancing glioma immunotherapy.