Improved Immune Response for Colorectal Cancer Therapy Triggered by Multifunctional Nanocomposites with Self-Amplifying Antitumor Ferroptosis

Ferroptosis, as a type of regulated cell death, can trigger the release of damage-associated molecular patterns from cancer cells and lead to the enhancement of immune recognition. Fenton reaction-mediated chemodynamic therapy could initiate ferroptosis by generating lipid peroxides, but its efficiency would be greatly restricted by the insufficient H₂O₂ and antioxidant system within the tumor. Herein, this work reports the successful preparation of H₂O₂ self-supplied and glutathione (GSH)-depletion therapeutic nanocomposites (Cu₂O@Au) through in situ growth of Au nanoparticles on the surface of cuprous oxide (Cu₂O) nanospheres. Upon delivery into cancer cells, the released Cu₂O could consume endogenous H₂S within colorectal cancer cells to form Cu₃₁S₁₆ nanoparticles, while the released Au NPs could catalyze glucose to generate H₂O₂ and gluconic acid. The self-supplying endogenous H₂O₂ and lower acidity could amplify the Cu ion-induced Fenton-like reaction. Meanwhile, the consumption of glucose would reduce GSH generation by disrupting the pentose phosphate pathway. Additionally, the Cu²⁺/Cu⁺ catalytic cycle promotes the depletion of GSH, leading to lipid peroxide accumulation and ferroptosis. It was found that the onset of ferroptosis triggered by Cu₂O@Au could initiate immunologic cell death, promote dendritic cell maturation and T-cell infiltration, and finally enhance the antitumor efficacy of the PD-L1 antibody. In summary, this collaborative action produces a remarkable antitumor effect, which provides a promising treatment strategy for colorectal cancer.