Activation of STING sensitizes melanoma cells to radiation through ROS-induced NLRP3

Melanoma is an aggressive malignancy with one of the highest mortality rates among skin cancers. Radiotherapy is a common treatment modality, but radioresistance remains a significant challenge. The stimulator of interferon genes (STING) pathway has been implicated in antitumor immunity and cancer treatment, yet its role in melanoma radiosensitivity is poorly understood.

This study aimed to investigate the role of STING in enhancing the radiosensitivity of cutaneous melanoma cells and to explore the underlying mechanisms involving reactive oxygen species (ROS) and the NLRP3 inflammasome.

Using TCGA database analysis, we examined the correlation between cGAS-STING pathway expression and melanoma patient survival. In vitro experiments were conducted on A375 and B16F10 melanoma cell lines, where STING was overexpressed or activated using the STING agonist cGAMP. Cell viability, apoptosis, ROS levels, and NLRP3/ASC complex activity were assessed following radiation treatment. In vivo studies involved tumor-bearing mice treated with cGAMP and radiation to evaluate tumor growth and survival.

High expression of cGAS and STING was associated with improved survival in melanoma patients. STING overexpression or cGAMP treatment significantly reduced cell viability, increased ROS levels, and enhanced apoptosis in irradiated melanoma cells. Mechanistically, the activation of STING elevated NLRP3/ASC complex activity, and the NLRP3 inhibitor CY-09 reversed the radiosensitization effects. In vivo, cGAMP combined with radiation suppressed tumor growth and improved survival in melanoma-bearing mice.

STING enhances radiosensitivity of melanoma through ROS-NLRP3 axis, and combining STING agonists with radiotherapy may be a new strategy to overcome radioresistance.