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 a promising antitumor treatment that is easy to implement, minimally invasive, and precisely controllable, and evokes strong antitumor immunity. We believe that a thorough elucidation of its underlying antitumor immune mechanisms would contribute to the rational design of combination treatments with other antitumor strategies and consequently potentiate clinical use. In this study, PTT using indocyanine green (ICG) induced STING-dependent type I interferon (IFN) production in macrophages (RAW264.7 and bone marrow-derived macrophages (BMDMs)), as proven by the use of a STING inhibitor (C178), and triggered STING-independent type I IFN generation in tumor cells (CT26 and 4T1), which was inhibited by DNase pretreatment. A novel liposome coloaded with the STING agonist 2′3′-cGAMP (cGAMP) and chloroquine (CQ) was constructed to achieve synergistic effect with PTT, in which CQ increased cGAMP entrapment efficiency and prevented STING degradation after IFN signaling activation. The sequential combination treatment caused a significant increase in tumor cell apoptosis, probably due to interferon stimulating gene products 15 and 54 (ISG15 and ISG 54), and achieved a more striking antitumor inhibition effect in the CT26 tumor model than the 4T1 model, likely due to higher STAT1 expression and consequently more intense IFN signal transduction. In the tumor microenvironment, the combination treatment increased 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). Above all, in-depth exploration of the antitumor mechanism of PTT provides guidance for selecting sensitive tumor models and designing reasonable clinical schemes.

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