cGAS–STING Pathway Activation Enhances Antitumor Effect of Talaporfin Photodynamic Therapy Through ROS Production

Photodynamic therapy (PDT) is a noninvasive anticancer treatment that uses a photosensitizer and light irradiation. PDT generates reactive oxygen species (ROS), thereby inducing tumor cell death. Stimulation of the interferon gene (STING) activation is highlighted as an immunotherapeutic strategy for cancer treatment. However, the role of STING and ROS in cancer therapy remains unclear. We hypothesized that STING regulates ROS generation in PDT, and that STING loss alters ROS homeostasis and causes therapeutic resistance. We established STING knockout (KO) HCT116 cells and compared the therapeutic efficacy of talaporfin sodium (TS)-PDT in KO and parental cells. Cell death induction was analyzed by 3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide assay. ROS induction was analyzed using 2′,7′-dichlorofluorescin diacetate assay. STING-regulated gene activation was assessed by western blotting. Furthermore, the efficacy of STING agonist (2′-3′-cyclic GMP–AMP sodium and ADU-S100) and TS-PDT combination was assessed in a xenograft tumor model. STING KO suppressed cell death induced by TS-PDT (IC₅₀ 16.58 [±1.03] vs. 19.21 [±1.38] μmol/L). STING KO suppressed ROS generation of TS-PDT (mean fluorescence intensity, 4240 [±517.4] vs. 2234 [±551.9]). STING-dependent signaling was enhanced by TS-PDT, and these effects were eliminated by STING loss. The combination of STING agonist and TS-PDT exhibited significantly greater tumor growth inhibition than single therapy alone. STING is an important regulator of cellular ROS homeostasis and tumor cell susceptibility to ROS in PDT. Combining a STING agonist with PDT could enhance its therapeutic efficacy and may have potential for future clinical applications.