Discovery of a photoactivatable dimerized STING agonist based on the benzo[]selenophene scaffold.

Stimulator of interferon genes (STING) agonism presents a powerful weapon for cancer immunotherapy. This study reports a novel dimerized STING agonist diBSP01, which exhibited promising STING binding and activation properties , based on the benzo[]selenophene scaffold. Meanwhile, shielding the pharmacophores of diBSP01 with photoremovable protecting groups (PPGs) resulted in the generation of the first photoactivatable STING agonist, caged-diBSP01, that exerted no biological potency in the absence of light stimulation while regaining its STING agonistic activity after 400 nm irradiation. Optically controlled anticancer activity was also proven with caged-diBSP01 in a zebrafish xenograft model. Our study provides insights into developing novel STING agonists for cancer treatment and a solution for precise STING activation to avoid the on-target systemic inflammatory response responsible for normal cell damage caused by systemic STING agonism.