Mammalian apurinic/apyrimidinic endonuclease 1 (APE1, APEX1) is a multifunctional enzyme that maintains cell homeostasis. It is involved in the base excision repair (BER) pathway and plays a key role in radiation-induced DNA damage response. Nevertheless, 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 the para-carcinoma tissues and it promoted the proliferation and invasion of the 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 detected by RNA-seq and co-Immunoprecipitation. Taken together, APE1 protects LUAD cells against radiation-induced damage and induces radio-resistance by targeting the STING pathway. could induce pyroptosis and negatively regulate by interaction with AIM2 and DDX41. APE1 inhibitors should be considered for enhancing the radiosensitivity of LUAD cells and improving patient prognosis and therapeutic outcomes. Thus, APE1 may play a role in affecting tumor immune microenvironment and tumor immunotherapy.