Multifunctional Tumor-Targeting Carbon Dots for Tumor Microenvironment Activated Ferroptosis and Immunotherapy in Cancer Treatment.

ABSTRACT

As an emerging cancer treatment strategy, ferroptosis is distinguished by the perturbation of lipid metabolism equilibrium and the accumulation of lipid peroxidation. However, the efficacy is consistently hindered by excessive GSH in the tumor microenvironment (TME). Here, this work designed and prepared multifunctional tumor-targeting carbon dots (FG-CDs@Cu) for ferroptosis and immunotherapy. Cu2+ in FG-CDs@Cu rapidly depletes high concentrations of GSH and inhibits glutathione peroxidase 4 (GPX4) expression in an acidic TME. Meanwhile, the generated Cu+ produced reactive oxygen species (ROS) through Fenton-like reaction. Due to the high efficiency of ROS production and GSH depletion, ferroptosis mediated by oxidative stress is significantly enhanced by FG-CDs@Cu in vivo, which can induce immunogenic cell death and promote CD8+ T cell infiltration. Meanwhile, the generated O2 effectively improves the hypoxic environment of the cells and leads to the reduction of hypoxia factor-1α (HIF-1α) expression, which activates the transformation of tumor-promoting M2-type tumor-associated macrophages (TAMs) to tumor-inhibiting M1-type TAMs, further enhancing the immune response and ferroptosis. The in vivo tests suggested that FG-CDs@Cu could efficiently suppress tumor growth in the mouse model and did not cause obvious toxicity. The combination with antiprogrammed death-ligand 1 (αPD-L1) synergy immune therapy could effectively restrain the growth of distal tumors, suggesting the significant potential of FG-CDs@Cu in augmenting ferroptosis and immunotherapy for efficacious cancer treatment.