Mammalian apurinic/apyrimidinic endonuclease 1 (APE1, APEX1) is a multifunctional enzyme that maintains cellular homeostasis. It is involved in the base excision repair (BER) pathway and plays a key role in radiationinduced DNA damage response. However, the relationship between APE1-driven radiation resistance and pyroptosis in lung adenocarcinoma (LUAD) cells and the underlying molecular mechanisms remain unclear. We found that APE1 was significantly upregulated in LUAD tissues compared to para-carcinoma tissues and promoted the proliferation and invasion of LUAD cells in vitro and in vivo. Mechanistically, APE1 inhibited pyroptosis by inactivating the interferon gene stimulator (STING) pathway via direct interaction with AIM2 and DDX41, as detected by RNA-seq and co-immunoprecipitation. APE1 protects LUAD cells against radiationinduced damage and induces radio-resistance by targeting the STING pathway. It can induce pyroptosis and is negatively regulated by interactions with AIM2 and DDX41. Therefore, APE1 inhibitors should be considered to enhance the radiosensitivity of LUAD cells and improve patient prognosis and therapeutic outcomes. Thus, APE1 play a role in the tumor immune microenvironment and in tumor immunotherapy.