Thioridazine, a phenothiazine drug, has a potential to induce tumor immunogenic cell death (ICD) and activate a tu-mor-specific immune response. In this study, we examined the ICD effect induced by Thioridazine and elucidated its underlying mechanisms using lung adenocarcinoma A549 and H1299 cells. Various concentrations of Thioridazine were employed to treat A549 and H1299 cells. The cell inhibition rate was determined using the methyl thiazol tetrazolium (MTT) assay, apoptosis rate was assessed by Flow Cytometry, extracellular ATP release was measured by using an ATP Assay Kit, and the presence of calre-ticulin (CRT) on the cell surface was evaluated via immunofluorescence. Furthermore, Western blot analysis was conducted to assess the expression levels of apoptosis-related proteins, including cleaved caspase 3, B-cell lymphoma-2 (Bcl-2), Bcl-2-asso-ciated X protein (Bax), and cytochrome C (Cyt C). Our findings revealed a significant, dose-dependent inhibition of A549 and H1299 cell proliferation and a marked increase in the apoptosis rate upon treatment with Thioridazine. Additionally, there was an elevation in extracellular ATP secretion and CRT expression on the cell surface, indicative of ICD occurrence. Consistently, the expression level of Bcl-2 decreased, while Bax, Cyt C, and cleaved caspase 3 were up-regulated that further indicate the in-duction apoptosis of tumor cell by Thiolidazine. Collectively, our results confirm that Thioridazine inhibits the proliferation of lung adenocarcinoma cells by inducing ICD through the mitochondrial stress signaling pathway.