STING inhibitor C-178

A sequential scheme including PTT and 2’3′-cGAMP/CQ-LP reveals the antitumor immune function of PTT through the type I interferon pathway

Photothermal therapy (PTT) is really a promising antitumor treatment that’s simple to apply, non-invasive, and precisely controllable, and evokes strong antitumor immunity. We feel that the thorough elucidation of their underlying antitumor immune mechanisms would lead towards the rational style of combination treatments along with other antitumor strategies and therefore potentiate clinical use. Within this study, PTT using indocyanine eco-friendly (ICG) caused STING-dependent type I interferon (IFN) production in macrophages (RAW264.7 and bone marrow-derived macrophages (BMDMs)), as proven through a STING inhibitor (C178), and triggered STING-independent type I IFN generation in tumor cells (CT26 and 4T1), that was inhibited by DNase pretreatment. A singular liposome coloaded using the STING agonist 2’3′-cGAMP (cGAMP) and chloroquine (CQ) was built to attain synergistic effect with PTT, by which CQ elevated cGAMP entrapment efficiency and avoided STING degradation after IFN signaling activation. The consecutive combination treatment caused a substantial rise in tumor cell apoptosis, most likely because of interferon stimulating gene products 15 and 54 (ISG15 and ISG 54), and achieved a far more striking antitumor inhibition effect within the CT26 tumor model compared to 4T1 model, likely because of greater STAT1 expression and therefore more serious IFN signal transduction. Within the tumor microenvironment, the mixture STING inhibitor C-178 treatment elevated infiltrating CD8 T cells (4-fold) and M1-like TAMs (10-fold), and decreased M-MDSCs (over 2-fold) and M2-like TAMs (over 4-fold). Most importantly, in-depth search for the antitumor mechanism of PTT provides guidance for choosing sensitive tumor models and designing reasonable clinical schemes.