A cGAS-STING pathway activating cobalt(III) cyclam prodrug for combined chemotherapy and immunotherapy of breast cancer

Abstract

Immunotherapy has had a tremendous impact on cancer treatments. Although frequently used inside the clinics, the application of immunomodulating compounds remains restricted due to the immunosuppressive tumor microenvironment. Among the promising methods, the activation of the stimulator of interferon genes (STING) pathway has emerged as a next-generation immunotherapeutic target. Despite promising preliminary results, the application of STING activating agents is strongly limited due to poor tumor selectivity and poor bioavailability. To overcome these limitations, herein, the first example of a cobalt(III) cyclam prodrug capable of inducing a chemotherapeutic effect and activating the STING pathway is reported. The cobalt(III) complex was found to be stable under physiological conditions, but released its axial ligands within the reducing cancerous microenvironment. While the reduced metal complex triggered a strong cytotoxic response by chemotherapy, the released organic ligands induced a strong immune response using the STING pathway, resulting in a multimodal treatment. To further enhance the pharmacological properties and provide tumor selectivity, the metal complex was encapsulated in polymeric nanoparticles. Upon injection into the blood stream, the nanoparticles accumulated in the triple-negative breast cancer tumor of the mouse model, activated the immune response inside the animal, and caused a nearly complete eradication of the tumor.