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 HO and antioxidant system within the tumor. Herein, this work reports the successful preparation of HO self-supplied and glutathione (GSH)-depletion therapeutic nanocomposites (CuO@Au) through in situ growth of Au nanoparticles on the surface of cuprous oxide (CuO) nanospheres. Upon delivery into cancer cells, the released CuO could consume endogenous HS within colorectal cancer cells to form CuS nanoparticles, while the released Au NPs could catalyze glucose to generate HO and gluconic acid. The self-supplying endogenous HO 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 Cu/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 CuO@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.